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Errors in Diagnosing Types of Diabetes in Young Adult Patients – Constantly Valid Topic

DOI: 10.31038/EDMJ.2020421

Abstract

The correct differentiation of diabetes types is still a problem. This is especially true for groups of young adult patients between 20 and 55 years old. In this group of patients Type 2 diabetes is still routinely diagnosed, without a thorough analysis of the patient’s history, phenotype, as well as disregarding the need to perform all necessary laboratory tests. Such diagnostic irregularities lead to taking wrong therapeutic decisions. As far as the patient’s history is concerned, attention should be paid to the incidence or non-incidence of a positive history of diabetes in the patient’s family. In the autoimmune diabetes such incidence usually does not occur. In Type 2 diabetes it is usually high, whereas most often it occurs on the patient’s mother’s and well as father’s side. A feature that is usually very characteristic is high incidence on one side of the family, typical for monogenic diabetes. A very important indicator is the occurrence or non-occurrence of obesity. Clear obesity suggests the diagnosis of Type 2 diabetes, whereas in patients without obesity LADA or MODY diabetes needs to be taken into account. Conclusive in this respect are the results of tests checking the levels of C-peptide and the titre of autoantibodies, predominantly of a/GAD. When MODY diabetes is suspected, it is necessary to run genetic tests. It is extremely important to undertake efforts aiming at a correct diagnosis of the etiological cause of diabetes, i.e. determining whether we deal with the autoimmunization process, insulin resistance, or with a genetic defect, as it influences therapeutic decisions. In the presence of the autoimmunization process, it is recommended to provide the insulin therapy at an early stage. In patients with clearly marked insulin resistance an early onset of the insulin therapy should be avoided. The first choice drugs in this condition are metformin, incretin drugs, as well as drugs from the group of SGLT-2 inhibitors. In monogenic diabetes therapeutic decisions depend on the type of the genetic defect.

Keywords

diabetes, C peptide, anti-GAD antibodies, LADA diabetes, type 2 diabetes, MODY diabetes

Introduction

Differentiation of Types of diabetes has a long and still uncompleted history. After an era of regarding diabetes as a homogeneous disease, 1907 brought its differentiation into an acute and a chronic form. Over subsequent years criteria applied to the differentiation of diabetes were changing. The division in force at the moment dates back to 1999 and it differentiates four types of diabetes, that is Type 1 diabetes, Type 2 diabetes, other specific types of diabetes, and gestational diabetes mellitus.

The introduction of immunological and genetic tests broadened the possibilities of diagnosing mechanisms of glucose metabolism disorders. This is responsible for the fact that the breakdown of types of diabetes adopted so far has been becoming less and less legitimate. Still, it is a breakdown in force today [1]. Nevertheless, over subsequent years we should expect a revision of this classification [2- 5]. In the everyday practice, when the diagnosis of diabetes is based on the clinical picture and basic laboratory tests, the determination of the type of diabetes is often erroneous [6]. According to many authors, after some time in numerous cases it is necessary to verify the initially determined type of diabetes. It refers particularly to young adults. Correct diagnostics taking into account etiological indicators allows for a more precise determination of the type of diabetes, and consequently also the selection of the correct therapy [7]. Individual types of diabetes are triggered by different mechanisms leading to these disorders. The knowledge of these mechanisms leads to therapeutic decisions. Naturally, one should take into account that performing state-of-the-art diagnostics entails an increase of costs of the diagnostic process. There are, however, many elements which may be used in the initial diagnostics without any significant cost increase.

Medical History

This stage covers an assessment of the following elements:

− Dynamics of the development of symptoms of the disease,

− Occurrence or non-occurrence of obesity,

− The patient’s age,

− Positive history of diabetes in the patient’s family,

− Observation of insulin demand.

Rapid accumulation of clinical symptoms is suggestive of autoimmunological diabetes. This refers predominantly to adolescent patients with the ‘classical’ Type 1 diabetes. This process develops a bit more slowly in LADA diabetes, where the course of the process of autoimmune destruction of the β cells is fluctuate.

The occurrence or non-occurrence of obesity could be a certain indicator in the process of differentiating the types of diabetes. In Type 1 diabetes, LADA diabetes, and MODY diabetes, overweight is usually not present as of the moment of its diagnosis.

The occurrence of overweight, especially significant obesity, is characteristic for Type 2 diabetes. A diversified picture may refer to the group of secondary diabetes.

The age at which diabetes reveals itself may constitute a certain, although not final, indicator. Early manifestation of diabetes may refer to the ‘classical’ Type 1 diabetes, monogenic diabetes, as well as certain forms of secondary diabetes. In our latitude, rarely do we deal with Type 2 diabetes in young patients.

A positive family history of diabetes is very characteristic for monogenic diabetes, whereas in such cases it is principally on one side only. A positive family history on both sides is frequent in Type 2 diabetes. In autoimmune diabetes (Type 1 and LADA) such a family history is relatively rare.

The insulin demand can also constitute a certain indicator suggestive of the level of destruction of the β cells and insulin resistance.

Laboratory Diagnostics

In the laboratory tests, besides the routine monitoring of glycaemia, the content of sugar and acetone in urine and the level of glycated hemoglobin HbA1c, the possibility of determining the level of c-peptide is essential. The concentration of C-peptide in serum is used in the diagnostics of the efficiency of pancreatic islets in terms of insulin production [8-12]. Serum C-peptide concentration illustrates the function of β cells and is useful in differentiating types of diabetes [13, 14]. In the Type 1 diabetes, the concentration of C-peptide gets rapidly reduced and it is usually clearly lowered as of the clinical manifestation of diabetes. A different picture is presented by the level of C-peptide in the latent autoimmune diabetes of adults (LADA). Here the initial level of C-peptide as of the moment of the diagnosis is usually lowered, but it can be normal; the glucagon test, however, demonstrates the lack of the physiological increase of this level [15-17]. In Type 2 diabetes the level of C-peptide is usually elevated, especially in the early period. It is connected with the usually significant insulin resistance that accompanies this form of diabetes [18]. The level of C-peptide in this form of diabetes can get reduced in later stages of the disease, when the secondary insufficiency of the β cells occurs. In other forms of diabetes the level of C-peptide may be different. It depends on mechanisms that lead to the disease development. In monogenic diabetes the level of C-peptide is correct [19-21]. The determination of autoantibody titers is another very important indicator in the differentiation of diabetes types. Often precise differentiation of the form of diabetes requires immunological tests. At this stage these tests should be recognised as a routine in most cases [22- 25]. Antibodies against the antigens of pancreatic islets are connected with the development of autoimmune diabetes. This category covers the ‘classical’ Type 1 diabetes, but also the slowly developing latent autoimmune diabetes in adults (LADA) [26, 27]. The diagnostic sensitivity of GADA and IA-2 depends on the subjects’ age – at the same level of specificity. In patients aged below 40 the determination of the GADA antibodies is more useful, and in older patients – the determination of the IA-2 antibodies is more beneficial. Confirmation of a high titre of autoantibodies against the structures of pancreatic islets decides about diagnosing diabetes with autoimmune etiology (Type 1 diabetes, LADA). In Type 2 diabetes an elevated titre of antibodies is sometimes detected, as well; nevertheless, it is usually much lower than in diabetes with autoimmune aetiology and it usually soon disappears. Recently, many authors pay attention to the diverse picture of LADA diabetes. This applies to both the clinical picture and treatment options [28, 29]. One of the ideas is to link this diversity with the patient’s age at the time of LADA diabetes [30]. The assessment of the presence of autoantibodies is also useful in the differentiation of autoimmune diabetes and Type 2 diabetes in the elderly [31]. Studies in a group of 1,114 patients with LADA diabetes have shown that the type of autoantibodies is important. Presence of N-terminally truncated GAD65 autoantibodies is associated with the need for early implementation of insulin therapy [32]. In MODY diabetes the absence of the antibodies is recognised as a principle. It is established, however, that the presence of the antibodies in the group of monogenic diabetes may result from the presence of genetic defect of the β cell, as well [33]. Sometimes the final diagnosis requires that genetic tests are run. If the presence of the autoantibodies is not detected in young patients with mild course of diabetes, the suspicion of monogenic diabetes becomes very likely. Most frequently diagnostic errors concern young adult patients.

Case Studies

Several cases are presented to illustrate the diagnostic dilemmas.

1. A 25-year-old female patient, without obesity, with a negative family history of diabetes. In the patient history there was a persistent inflammation in the urethral fossa, vagina, and vulva, treated with no success. Due to deterioration of her health condition, increased thirst, and increased diuresis, the patient was admitted to hospital. At admission, the level of glucose in the blood serum was 425 mg/ dl (23.47 mmol/l), pH 7.4, creatinine 60 μmol/l. After administering insulin the level of glucose in blood was reduced to 225 mg/dl (12.74 mmol/l). The insulin treatment was ceased, metformin was started 3 x 500 mg. The level of C-peptide was determined to be 0.87 mg/l. The patient was discharged home on the fourth day of observation with a recommendation of a follow-up visit in the Primary Care Outpatient Clinic. The type of diabetes was not determined. Recommendations included a diet and metformin therapy. During the first days after the discharge, with a strict diet and the prescribed doses of metformin, the glucose levels in self-management oscillated within the range of 127- 192 mg/dl (7.05 – 10.7 mmol). The patient was referred to diabetes consultation. Due to the suspicion of the diagnosis of LADA diabetes, the autoantibodies tests was recommended, in which a very high titre of a/GAD was detected: 1080 IU/ml. This confirmed the diagnosis of LADA diabetes. Lantus insulin in 4 units was prescribed and selfcontrol was recommended.

2. A 36-year-old male patient, without obesity. At the age of 31 the patient was diagnosed with Type 2 diabetes, treated with insulin of short effect, and then with sulfonylurea derivatives. After 5 years after the diagnosis there was a deterioration of the general health condition, the patient was referred to diabetic consultation. Due to the suspicion of the diagnosis of LADA diabetes, intensive insulin therapy was administered. The level of C-peptide was 1.26 ng/ml; a/GAD > 2000 IU/ml, HbA1c 11.5%. Ophthalmological consultation revealed the occurrence of retinopathy. The suspicion of the diagnosis of LADA diabetes was confirmed.

3. A 28-year-old patient, with normal body weight. At the age of 25 he was diagnosed with Type 2 diabetes and a metformin preparation was prescribed. After 3 years, due to the deterioration of the general health condition, the patient was referred to diabetes consultation. During the consultation the level of HbA1c was 11.31%. On the basis of the clinical picture, LADA diabetes was diagnosed. Intensive insulin therapy was started. The results of the remaining tests confirmed the diagnosis: C-peptide 0.78 ng/ml; a/GAD 140 IU/ ml.

4. A 42-year-old male patient, without obesity. At the age of 39 he was diagnosed with Type 2 diabetes. Concentration of glucose in blood was 400 mg/dl; HbA1c 9.3%. Insulin therapy was started. After reaching improvement in the test results, the insulin therapy was stopped and metformin and a sulfonylurea derivative was prescribed. After a year pharmacotherapy was stopped. 3 years after the diagnosis, due to the deterioration of his general health condition the patient was referred to diabetes consultation. Due to the suspicion of LADA diabetes, insulin and diet therapy was started. The tests performed confirmed the diagnosis of LADA diabetes. Level of C-peptide 0.69 ng/ml; a/GAD >2000IU/ml.

5. A 37-year-old female patient with diabetes diagnosed as Type 2 diabetes, for three years treated with insulin mixtures. The patient chronically unbalanced HbA1c 84%. During the diabetes consultation a revision of the diagnosis was performed. The tests performed detected a low level of C-peptide 0.1 ng/ml; a high titre of the autoantibodies a/GAD 1251.94 IU/ML, which enabled to diagnose autoimmune LADA diabetes. A high titre of a/TPO 339.1 IU/ml and an elevated titre of parietal cell antibodies. Intense insulin therapy was prescribed, with the administration of analogue insulins.

Discussion

In research carried out over recent years it was demonstrated that 5-10% of diabetes diagnosed after the age of 35 as Type 2 diabetes is in fact LADA diabetes [2, 34, 35]. Analysis of cases qualified as LADA diabetes confirms the need to perform a thorough analysis of glucose homeostasis disorders in patients aged 25-55, especially in patients without obesity and without a positive family history of diabetes [36-38]. A factor that is decisive for the differentiation process is the assessment of the titre of antibodies. An early correct diagnosis of LADA diabetes and starting insulin therapy is extremely important due to the improvement of the metabolic control, as well as due to the fact that there is much evidence that apart from the substitution activity, insulin has also immunomodulating activity, influencing the inhibition of the process of destruction of pancreatic islets [39- 42]. The use of sulfonylurea derivatives in such patients is very disadvantageous, and it often results from a wrong diagnosis. In this age group it must be borne in mind that there can also occur monogenic forms of diabetes, predominantly MODY diabetes [43- 47]. Monogenic forms of diabetes are mainly associated with juvenile patients. Nevertheless, one needs to bear in mind that MODY diabetes can manifest itself in adults, in families where such a diagnosis has never been given before. Genetic tests are crucial in diagnosing MODY diabetes [48, 49]. However, it may also be useful to analyze other markers, including C-peptide levels, compared to clinical picture analysis [50, 51]. Type 2 diabetes is the form of diabetes that is still most often routinely diagnosed in adults, especially when the course of the disease is relatively mild [52]. The most common form is MODY2, which is a result of a mutation of the glucokinase gene, and MODY3 occurring due to a mutation in the HNF-1α gene, which is a transcription factor subjected to expression in pancreas, liver, and kidneys [53]. A rare form of diabetes is MODY5, related to a mutation in the HNF1B gene [54-56]. This issue has been discussed in earlier publications. They present cases where MODY diabetes was diagnosed [57, 58]. From amongst the four patients presented therein, in two patients the MODY3 type diabetes was diagnosed, MODY2 diabetes was diagnosed in one female patient, and in one male patient a rare form of MODY5 was detected. This publication also presents results of a discussion devoted to recommendations for genetic diagnostics in these syndromes.

Summary

To conclude, it should be once again emphasized how important the correctness of diagnosis of the diabetes pathogenesis is. This is decisive for the administered therapy. The most errors in the correct diagnosis pertain to the group of young adult patients. These errors result from the assessment of the patient’s history and phenotype that is not thorough enough. A serious source of mistakes is neglecting the test of the level of C-peptide, as well as of the titre of anti-pancreatic antibodies, predominantly GAD. It should be remembered that in this age group all types of diabetes can occur. A wrong diagnosis of Type 2 diabetes in cases of diabetes with the autoimmune etiology is particularly frequent. However, it should be also borne in mind that it is possible that monogenic diabetes will manifest itself, too. First secondary diabetes must be always ruled out.

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Global Approach to Neuroendocrine Tumors Neoplasms

DOI: 10.31038/MIP.2020122

Introduction

The incidence of neuroendocrine tumors (TNE) is about 2.5-5 new cases per 100,000 inhabitants annually. They can appear in any location and 15% are diagnosed in the small bowel. TNEs can be functional with diarrhea, hot flashes, weight loss … or not functionaries, that usually debut unspecifically with nausea, abdominal pain, anorexia intestinal obstruction and bleeding. This case reflects the evolution, monitoring and management of an intestinal TNE.

History

A 55-year-old male patient without medical illnesses to be highlighted consulted in June 2018 for 3-4 daily episodes of watery diarrhea, dizziness and loss of 5 kilos in the last two months.

Physical Examination

Constants: Blood pressure: 120/75 mmHg, 98% baseline saturation, afebrile.

Laterocervical, submandibular, supra or infraclavicular adenopathies are not palpated.

Pulmonary and cardiac auscultation was normal. The abdomen wasn`t pain and without megalias or masses.

Supplementary Tests

• Analytical with renal function, ions, liver profile and hemograme within normal.

• Basal chromogranin 159.5 ng / Ml (<84.7ng / ml), Urinary 5-hydroxyindoleacetic acid (5-HIAA): 21 μmol / d (0-14 μmol / d)

• Thoracoabdominopelvic CT scan showed a carcinoid tumor located in jejunal loops, liver metastases for all segments (the largest is 26 mm) and is located in the liver segment 4. (Figure 1)

• Somatostatin receptor imaging: Liver metastases and jejunal tumor is confirmed.

• Endoscopy: without injuries.

• Liver biopsy: metastasis of well-differentiated TNE GRADE 1 (WHO 2010). Ki-67 1-2%. The Cells are positive for neuroendocrine markers such as chromogranin, synaptophysin, CD56.

MIP-2-1-204-g001

Figure 1.Somatostatin receptor imaging: liver metastases

Diagnosis

Neuroendocrine tumor well-differentiated ileo-jejunal Grade 1 (Ki-67 1-2%) with metastatic involvement in all liver segments.

Treatment

The patient started treatment with lanreotide autogel 120 mg every 28 days in October 2018 with improvement of the carcinoid syndrome. The primary tumor is intervened in January 2019 (small bowel resection: p T3, N1, LV0, Pn1 R0.) No possibility of liver resection due to extensive tumor involvement without the possibility of leaving enough hepatic remnants.

Evolution

After surgery, the study with serum chromogranin A and 5-HIAA was normal.

The patient continued with somatostatin analogues since January 2019 being completely asymptomatic and with an excellent quality of life. The patient followed clinical controls and radiological images every 6 months.

In November 2019, he went again to the emergency room for asthenia and watery diarrhea (4-5 daily episodes) the week prior to the administration of the analog. Markers were not elevated.

A thoracoabdominopelvic scan showed hepatic tumor progression with growth of all hepatic metastases. No other visceral or adenopathic lesions.

The somatostatin analogue was taken biweekly, so the symptoms disappeared again.

A new somatostatin receptor imaging showed positivity for liver metastases. Chromogranin A markers and 5-HIAA did not rise at any time.

Once the case has been assessed in the TNE committee, it is agreed to start treatment with radionuclides (Lutetium-177) 200 mCi in December 2019 and maintenance of somatostatin analogues (monthly dosage) between Lutetium dose.

The patient to date has received three doses of 177-LUDOTETATE with excellent tolerance, asymptomatic and without any documented adverse effects. At the present time, there is no evidence of disease progression.

Discussion

This case reflects the evolution and management of a jejunal TNE with hepatic metastatic at baseline which was considered unresectable.

In all TNE, the possibility of primary surgery should always be assessed even if there is metastatic disease since up to 30% of these tumors have liver involvement at diagnosis and survival at 5 years after primary resection is greater than 95% [1].

After surgery, it was decided to continue treatment with analogue because it was a stage IV with liver metastases that could not be resected.

The treatment controlled the symptoms during 13 months, according to the CLARINET study [2].

After confirming the progression, systematic treatment with radionuclides (PRRT) is decided. The PRRT consists of the systemic administration of the Ytrio-90 or Lutetium-177 conjugated radionuclides with a somatostatin analogue, through the acid chelating agent 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA).

Radionuclide therapy has a phase III trial (NETTER-1) that compared treatment with 177Lu-DOTATATE every 4 weeks vs. LAR high dose octreotide, in patients with bowel TNE unresectable, with positive somatostatin receptors and with progression to analogs in the first line. Progression-free survival was 28.4 months versus 8 months in the control arm. (hazard ratio (HR) 0.21, 95% CI, 0.14-0.33, p <0.0001) [3].

In conclusion, PRRTs is indicated in patients with midgut TNEs well differentiated, metastatic, unresectable, in progression to somatostatin analogues and with positive somatostatin receptors.

References

  1. Chan DL, Moody L, Segelov E, Metz D, Strosberg J, Pavlakis N, et al. (2018) Follow-up for resected gastroenteropancreatic neuroendocrine tumours (GEP-NETs): a practice survey of the Commonwealth Neuroendocrine collaboration (CommNETs) and North American Neuroendocrine Tumor Society (NANETS). Neuroendocrinology107(1):32–41.
  2. Caplin MEPavel MĆwikła JBPhan ATRaderer M, et al. (2014)  Lanreotide in metastatic enteropancreatic neuroendocrine tumors.N Engl J Med371:224-33.
  3. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. (2017) Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med376:125–35

Exosome Extracellular Vesicles: A Vehicle for Simultaneous Immune and Genetic Therapy

DOI: 10.31038/MIP.2020121

Short Review

Exosomes are newly recognized universal minute nanosize particles made by all cells in all species that transfer genetic instructions between cells. They additionally can be made immune specific by antibody coating to achieve dual specific antigen targeting of particular acceptor cells, as well as being vehicles to deliver genetic information as RNAs to alter targeted cell function. Because of exceptional resistance properties, some therapeutic exosomes can be administered orally.

What are exosomes?

Exosomes are minute nano-sized lipid sacs called vesicles that are produced and then secreted by all cell types in all animal species. They are a sensational biologic discovery. As universal nano-particles of life, they are very small, but a big thing since they seem to be involved in nearly all biological and clinical processes. Importantly, these Nanovesicles may lead to new and highly advantageous therapies. Exosomes are the most common subset among a large very diverse group that exists outside of cells called extracellular vesicles. Exosomes are tiny spheres with an average diameter of 100 Nano meters, or about one hundredth the sizes of the producing cells (Figure 1). Production and release of extracellular vesicles, occurs in all animals, plants, fish, fungi and also in the basic single cell forms of life; such as bacteria and even most primitive archaea (Figure 2).

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Figure 1. Scanning electron microscopy of individual exosome that are spheres in their native state but here distorted in processing.

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Figure 2. Staphylococcus aureus outer membrane exosome-like vesicles pinched out from the surface of the bacteria.

The exosome nano world

Therefore, exosomes and other diverse extracellular vesicles from many cell types are present in all body fluids and can be described as a cloud of mixed nano particles between cells (Figure 4). In humans and mice, exosomes in the peripheral blood are about a billion per milliliter compared to white blood cells that are present at ten thousand per milliliter. Among the myriad of extracellular vesicle subsets, exosomes have been show to alter functions in targeted cells. The main and entirely new biologic function of exosomes is their ability to enter other acceptor cells, near or far via the blood stream, in order to transfer the genetic-acting molecules they carry [1-5].

In particular, they transfer micro RNAs (miRNAs) that are small ribonucleotide polymers of only about 22 base pairs (Figure 3). These exosomes carry and transfer extracellular miRNAs can produce modifications of the DNA in the nucleus of the acceptor cells to alter their genetic mediated production of proteins that in turn alters target cell function. In sum, exosomes are a completely unanticipated nano entity that can mediate entirely new biological processes, and alter molecular and metabolic pathways of acceptor cells. As such, they are likely involved in many diseases.

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Figure 3. Cross section of an individual idealized exosome showing surface signature of various adhesion molecules that can include antigen specific antibodies. These respectively can mediate semi-specific binding to comparable receptors on the surface of acceptor cells, or antigen specific targeting of acceptor cells. Inside the exosome are various RNAs, including miRNAs and proteins..

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Figure 4. Intercellular tissue cloud of various extracellular vesicles between the cells, of which some are secreted exosomes.

Clinical consequences

As the dominant mechanism for inter cellular transfer of genetic function, exosomes have great medical importance. They introduce many new possibilities; such as: better understanding of disease mechanisms, new ways for making diagnoses after isolation from blood and body fluids (so called liquid biopsies) and then analyzed molecularly, and as vehicles for new natural nano vesicle therapies. Appropois of this last point they have great advantages over the current numerous problems associated with designing artificial nano therapeutic particles that lack specificity, are unable to cross tissue barriers, and are rapidly eliminated by natural mechanisms that detect their artificiality.

Exosome therapies

Exosomes are a very promising therapy because of their very small size, their ability to cross natural tissue barriers such as those that protect the brain, and when administered into the circulation have prolonged life over days. This is because they are natural nanovesicles that are able to avoid host cells that remove the artificial particles. Compared to cells used for therapy, exosomes have unusual stability; resistance to noxious environments, and long storage ability of biologically active genetic contents. Exosome vesicles are a physiological natural system for delivering genetic and antiinflammatory molecules; thus constituting new treatment modalities for a variety of diseases.

Exosomes can be isolated from healthy individuals and easily enriched for delivery to individuals with a disease. Further, exosomes in some instances can be used across species, or even from plants can be used without concern for immunologic or genetic incompatibility, since the miRNAs are often universal across species. They usually contain no DNA and thus are without danger of transformation to cancers; compared to therapies with cells. New work in a variety of fields indicates that exosomes may be effective therapy for cancers, arthritis, stroke, spinal cord injury, myocardial infarction, lung fibrosis, and other diseases. Also, investigations have begun in autoimmune conditions, such as multiple sclerosis, and in degenerative conditions, such as Alzheimer’s or Parkinson’s diseases, and even in autism.

Exosomes have unusual durability, stability and ability to resist harsh conditions

Unlike cells, exosomes have special membranes composed of unusual proportions of lipid components, resulting in high surface viscosity and rigidity. This enables them to resist harsh conditions that cells cannot survive. These properties of resistance are postulated to be derived from their ancient origins near the beginning of biologic evolution. Some current exosomes are proposed as being related to the “pro cells” from that primordial era that existed before the development of bacteria.

Other unusual related properties of some current day exosomes, that are derived from activated immune cells, include the ability to bind antigen-specific antibody chains on their surface, and further accept added selected miRNAs. Together, these abilities can achieve unprecedented combined immune antigen-specific cell targeting via the surface antibodies binding the acceptor cells, as well as subsequent exosome delivery of particular gene-altering functional miRNAs.

Exosomes in milk survive harsh conditions of gastric digestion

Mothers breast milk is an outstanding example of the strong resistance of exosomes to harsh conditions. Milk is loaded with exosomes carrying diverse and unusual miRNAs, and have strong resistance to the noxious environment in the neonatal stomach. This consists of the combined actions of a variety of digestive enzymes in high acidity. Surviving this noxious gastric environment, the breast milk exosomes can be intestinally absorped by the neonate for subsequent transfer of their miRNAs to potentially regulate a variety of developing systems.

Successful therapy with exosomes; including dual immune and gene specific oral treatment

The unusual property of resistance to stomach degradation can allow oral administration of therapeutic exosomes to patients. These natural nano-vesicles can be constructed to be immune Ag-specific suppressive exosomes by surface sbinding of chosen antibody for specific acceptor cell targeting. Further, these exosomes can be constructed to carry chosen particular inhibitory miRNAs. After intestinal absorption, such exosomes can strongly suppress immune inflammatory antigen-specific T cell allergy responses in the skin of recipients for several days, as demonstrated in Figure 5.

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Figure 5.The figure shows experiments with milk protein (casein) allergy, expressed as swelling in the ear skin of mice following local injection. Systemic treatments with exosomes from suppressor T cells were begun at the 24 hour height of the positive ear swelling response (black line). These immune allergic tissue swelling responses and were strongly inhibited for the subsequent four days by administration of exosomes that were casein antigen-specific via surface antibody chains, and miRNA-150 transferring. They were adminisered by several routes, and were most strongly inhibitory when given orally (PO, red line), compared to the usually employed systemic routes of administration; such as intravenous (IV, orange line), or into the peritoneum (IP, purple line), or subcutaneous at a skin site distant from the ears (intradermal, ID, green line).

The oral route of administration has been superior (black line) compared to the usual intravenous, intraperitoneal and subcutaneous routes. This evidence suggests that oral treatment is a more physiological route of administration, compared to the usual injection routes. To our knowledge, such chosen dual antigen-specific and selected miRNA mediated gene expression altering exosome therapy has not been achieved previously. The prospect of efficacious oral administration would undoubtedly have greater patient acceptance and comfort, especially in children. For example, in treatment of cancers, exosome’s ability to target specific cells and regulate protein synthesis in combination with chemotherapy and radiotherapy, likely will allow their reduced dose which in turn lessens toxicity of these existing therapeutic approaches. (1114 words)

Acknowledgement

The author is grateful for grant support from the NIH, the hard laboratory work of Krzysztof Bryniarski and Katarzyna Nazimek who produced the quoted and presented data. I am particularly indebted to Dr. Irwin Braverman for his thorough review and recommendations.

References

  1. Krzysztof  Bryniarski, WlodzimierzPtak, Emilia  Sikora, KatarzynaNazimek, et al. (2018) Free extracellular  miRNA  functionally targets cells by transfecting exosomes  from  their  companion  cells, PLoS One 10:e0122991.
  2. Bryniarski K, Ptak W, Jayakumar A, Tuschl T, Hafner M, Püllmann K, et al. (2013) Antibody light chain coated antigen-specific exosomes deliver suppressor T cell-derived miRNA-150 to inhibit effector T cells. J Allergy ClinImmunol132:170-81.
  3. Krzysztof  Bryniarski, KatarzynaNazimek, WlodzimierzPtak, Tom Groot Kormelink, and Philip W Askenase (2020)Orally Administered T and B cell Antigen-Specific Suppressor Exosomes Deliver miRNA-150 to Inhibit DTH Via Their Surface Antibody Light Chains Binding Antigen Peptides in MHC on APC Targeted Cells.
  4. Magdalena Wąsik , KatarzynaNazimek , Bernadeta Nowak , Philip W Askenase , and Krzysztof Bryniarski (2019) Delayed-Type Hypersensitivity Underlying Casein Allergy Is Suppressed by Extracellular Vesicles Carrying miRNA-150.Nutrients11:9
  5. Carolina de la Torre Gomez , Renee V Goreham, Joan J Bech Serra, Thomas Nann and Martin Kussmann (2018)“Exosomics”—A Review of Biophysics, Biology and Biochemistry of Exosomes With a Focus on Human Breast Milk.Front Genet 27.
  6. Kamerkar S, LeBleu V, Sugimoto H. et al. (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546: 498–503.
  7. Jeppesen DK, FenixAM, Franklin JL, et al. (2019) Reassessment of Exosome Composition. Cell177:428–445.e18.
  8. Sukhvinder Gill, Ryan Catchpole and Patrick Forterre (2019) Extracellular membrane vesicles in the three domains of life and beyond.FEMS Microbiology Reviews43: 273–303
  9. Carmen Schwechheimer and Meta J Kuehn (2015) Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol13:605-19.
  10. Jack W Szostak (2016)On the origin of life. MEDICINA (Buenos Aires)76: 199-203
  11. Raposo G, Stoorvogel W (2019) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol200:373-383.
  12. ClotildeThéry (2011) Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep3:15.

Commercial fisheries in the Mediterranean, focusing on the environmental status and the corresponding management measures

DOI: 10.31038/AFS.2020214

Abstract

The Mediterranean Sea is the largest semi-enclosed European sea with an area of 2.5 million km² and bordered by 23 countries. The basin exhibits two openings, towards the Atlantic Ocean and towards the Indian Ocean through the Red Sea. It is known to be a sea rich in oxygen, oligotrophic and with higher salinity than other European marine waters. Its heterogeneity and isolation allowed the generation of a large number of habitats, leading to a high biodiversity and in turn, provision and sustenance of natural services and resources such as fisheries. Fisheries in the Mediterranean Sea are characterized by a fishing fleet of approximately 82000 vessels, of which small-scale accounts for 80 % of the total. The total catch from the Mediterranean marine fisheries rose from 420,000 tonnes in 1950 to approximately 1,000,000 tonnes in the 1980s, with a peak of 1,093,000 tonnes in 1995. Ever since, the level of catches has been slowly decreasing until today. The total landed value follows a similar pattern, with a clear peak in 1985 at US$ 3 billion followed by an almost-constant decrease trend, down to US$ 1.5 billion. Mediterranean fishery sector is very important from the social and economic view of supporting small rural fisheries-dependent communities, without at the same time, being an important part of the agriculture GDP of the bordering countries. Most of these fisheries are exploited at an unsustainable level, which directly threatens stocks with overexploitation, increasing economic costs and employment losses and creating negative rents. Within a period of 15 years (1991-2006) overexploitation of the Mediterranean fishery resources reached 60% with negative effects mainly on benthic-pelagic species and apex predators (tunas etc.). This is evident mainly for the north Mediterranean countries due to technological progress and high investment values.

Introduction

The Mediterranean Sea is the largest (2,969,000 km²) and deepest (average 1,460 m, maximum 5,267 m) semi-enclosed European sea, consisting of two major interacting sub-basins, the western and eastern Mediterranean, connected by the Straits of Sicily with depth ~ 350 m. The western basin is connected with the Atlantic Ocean through the Gibraltar Strait. The Ionian, Levantine, Adriatic and Aegean are located in the eastern basin, which communicates with the Black Sea through the Strait of Dardanelles and with the Red Sea through the Suez Canal. Several, smaller basins, are recognizable within the two main sections, which show remarkable differences in terms of general oceanographic conditions.

From the oceanographic point of view, which is a pressure to the fisheries state in the area, the Mediterranean Sea can be considered as comprising three main water masses.

a) the Atlantic Water, found in the surface layer, having a thickness of 150-200 m and characterized by a salinity of 36.2 ‰ near Gibraltar to 38.6 ‰in the Levantine basin;

b) the Levantine Intermediate Water (the main water body of the Mediterranean) formed in the Levantine Basin, from the overlying Levantine Surface Water (LSW) lying in depth between 200 and 500 m, and characterized by temperatures of 13-15.5 °C and salinity of 38.4-39.1 ‰;

c) the Mediterranean Deep Water formed in both the western and eastern basins; the Eastern Mediterranean Deep Water (EMDW) is characterized by a temperature of 13.6 °C and a salinity of 38.7 ‰.

It is known that the Mediterranean Sea is a sea rich in oxygen, poor in nutrients and saltier than other European seas. The Mediterranean Sea as a whole has been referred as an “evaporated basin” since surface evaporation, particularly in the Levantine region, accounts for this net inflow, and more than compensates for the inflow of lower salinity water from Black Sea, rivers and other freshwater inflows dominated by discharges, primarily of the rivers Po, Rhone, Nile and Ebro. The biological productivity of the Mediterranean is among the lowest in the world. Average primary production in the western basin corresponds to an assimilation of 50 gCm-2y-1 [1] while in the eastern basin the primary production amounts to about 26 Cm-2y-1 [2]. Primarily productivity can, however, be unusually high at mouths of the rivers and at urban centers.

Specificities of the Mediterranean Sea

The Mediterranean Sea has a very distinct geographical, climatic and biological nature that makes it very different from other sea basins. Its heterogeneity and isolation have generated a great number of habitats, which lead to a high biodiversity spot.

Biological Specificities

a) Biodiversity: in the Northern Hemisphere, marine biodiversity increases from the North Pole toward the equator. This is reflected in a greater number of commercial species in the Mediterranean Sea, with generally smaller individuals compared with the EU waters in the North Atlantic.

b) Increased complexity of the marine ecosystem: This is the direct result of a greater number of species, with greater potential interactions between them as well.

c) Presence of invasive species: while this can also be found in other closed or semi-closed seas such as the Baltic Sea, it is a very common phenomenon in the eastern Mediterranean, with a high number of invasive species coming from the Red Sea through the Suez Canal.

Governance Specificities

a) Shared stocks: Because of the distribution of territorial waters, most of the surface of the Mediterranean Sea is made up of international waters and most commercial fish stocks are shared with other coastal states, many of which are not part of the EU. This shared responsibility increases from west to east and not so much from north to south.

b) International management of fisheries: Fisheries on shared stocks are managed by two regional fisheries organizations:

• International Commission for the Conservation of Atlantic Tunas (ICCAT) for highly migratory species (these count for more than 10% of the value of the total catches in the Mediterranean)

• General Fisheries Council for the Mediterranean (GFCM) for other species.

The political context can also make disciplined management difficult in cases of political instability (wars, post-war situations, migratory movements, etc.).

Specificities in fleet composition and fleet activity

a) Daily activity of boats: the vast majority of Mediterranean fishing vessels come back to port every day, generally with catches mixing several species. As each species is usually below the 50 kg threshold set by the Control Regulation, the catches are not declared.

b) Fleet composition: most of the vessels composing the Mediterranean fleet are less than 10 m long and therefore not covered by the rules on registering catches. As a result, many catches are unrecorded. Small-scale operations involving small vessels with low daily catches represent 80 % of the Mediterranean fishing fleet, 60 % of jobs and 23 % of landings.

c) Economic performance: the 2015 Annual Economic Report noted a progressive deterioration in the economic performance of the small-scale coastal fleet. In sharp contrast to many EU fleets of other regions, which showed steady improvement, EU fleets in the Mediterranean region did not improve their economic performance significantly over the 2008-2013 period.

Effects of human activities on the marine ecosystem

Human socioeconomic activities along the Mediterranean coastline have been identified as pressures that lead to the degradation of the marine environment.

a) Pollution: Reduction of fish stocks due to localized pockets of pollution (in areas with strong human concentration and improper waste treatment).

b) Traffic: there is heavy maritime traffic (particularly south of Sicily and in the Alboran Sea).

c) Highly climate change: Mediterranean is a vulnerable region, with expected shifts on species’ distribution and fish population dynamics, and introduction of invasive species.

d) Biological blooms: there is a relatively high number of algal and jellyfish blooms, which may change the flux of energy of the food web (e.g. greater predation of fish food, eggs or larvae).

e) Top-predators: there is a decline in certain populations of toppredators, notably sharks, which otherwise help adjust the balance between fish populations.

Mediterranean biodiversity

Mediterranean Sea exhibits a high diversity of habitats, both pelagic and demersal. Most of these habitats (bathyal, mesopelagic or bathypelagic) are poorly known in relation to coastal and continental shelves ecosystems, which are more easily surveyed, while at the same time there is a relatively good knowledge of their commercial species stock status, by means of fisheries surveys and commercial captures. Some 12.000 marine species are counted in the Mediterranean Sea, while many of them are introduced. The number of introduced species (NIS) in the Mediterranean has increased spectacularly since the start of the last century. How many species are recent arrival? NIS enter the Mediterranean Sea mainly via the Suez Canal (actively or passively), but also via Gibraltar and Dardanelles through shipping (ballast water, fouling) and aquaculture (EEA 2006). Until the mid-20th century, the NIS introduction, establishment, and expansion rates were low. This number begins to increase at the last decade of the century, mainly because of the water temperature and salinity barriers between the Red Sea and the Mediterranean Sea [3-5]. Extrapolating from initial surveys of selected taxonomic phyla an overall estimate of about 1,000 invaders may not be unrealistic [6]. Following Zenetos [7] the number of reported alien species in the Mediterranean, reached 903 by April 2008 and 947 by October 2009 while the estimate of Galil [8] is of 573 species, 80 species introduced in the period 2000-2007. The lower level of biodiversity, at least as far as species diversity is concerned, in the eastern Mediterranean reflects a general trend of biodiversity reduction in the Mediterranean Sea from the West to the East, given that the conditions of the Levantine Basin are not conducive for the thriving of the Atlantic contingent, being so biased by a founder effect.

The Suez Canal, the Gibraltar Strait, and the Marmara Strait constitute a corridor going through different species from Red Sea, Atlantic Ocean and Black Sea respectively. A lot of marine species moving from Atlantic Ocean in the Mediterranean Sea through the Gibraltar Strait and established, mainly, in its western basin, where the faunistical and hydrological parameters are almost similar between the two areas, while a smaller number of species arrived the eastern basin. The Indo-Pacific and Erythrean origin marine species, which migrate to the Mediterranean through the Suez Canal, named Lessepsian immigrants. The main abiotic difference between the Red Sea and the Mediterranean is the temperature regime, which is stable in the tropical Red Sea, but appears wide fluctuations in the subtropical Mediterranean. Finally, some species migrate from Black Sea established mainly in the Aegean Sea, which act as a barrier for their ongoing distribution.

The fauna of the Mediterranean Sea is mainly temperate Atlantic origin with the Gibraltar Strait to be an important gate for the Atlantic originated fish species distribution in the Mediterranean Sea. On the other hand, tropical Indo-Pacific origin fishes from Red Sea entered in the eastern Mediterranean through the Suez Canal. This eastern region captures less than half of the known Mediterranean species diversity, with 43% of the total listed Mediterranean species. The ichthyofauna of the Eastern Mediterranean began to be actively studied only the last fifty years. Thus, it should be stressed that the inventory of the fishes in the area has been a matter of discussion only in the last four or five decades, in spite of the studies carried out during international scientific expeditions in the beginning of the twentieth century.

Several lists concerning the number of Mediterranean fish has been completed the last 50 years. Tortonese [9] registered 543 species in his list, including 579 species (501 Osteichthyes and 78 Chondrichthyes) in a later revision [10]. Quignard [11] lists a total of 562 species, while Whitehead et al. mention 589 species. Fredj and Maurin [12] list a total of 612 species (~ 30 uncertain). Quignard & Tomasini [13] increased the number at 664 species. According to the data available by Psomadakis et al. [14], the Mediterranean fish diversity can be summarized as follows: 602 (including subspecies) bony fish species (Osteichthyes), 79 cartilagineous fish species (Chodrichthyes) and 3 cyclostomes (Agnatha); making a total of 684 species, belonging to 173 families (147 Osteichthyes, 24 Chodrichthyes, 2 Agnatha).

Mediterranean living resources

Management of the fisheries resources

The Mediterranean Sea (GFCM – major fishing area 37) have sustained important fisheries activities since ancient times. Since the Mediterranean Sea is semi-enclosed sea, with an overall lack of exclusive economic zones (EEZs) and consequently with stocks that are often shared among fleets from different countries, the fishery sector has always played an important role in the region. Today, industrial, semi-industrial and small-scale fisheries coexist in the region, using a large variety of fishing gear. In contrast with other major fishing areas, Mediterranean Sea fisheries generally lack large mono-specific stocks, and instead exploit a variety of benthic and pelagic stocks of fish, as well as mollusks and crustaceans. In fact, despite its relatively low economic output compared to other economic activities in the region (e.g. tourism, oil and gas exploration), the annual production of roughly 1.12 million tonnes offers employment opportunities to several hundred thousand people, supplies seafood products for human consumption to local and regional markets, and creates many other indirect benefits, maintaining the social fabric of coastal communities. Fisheries are also an intrinsic part of the cultural landscape of Mediterranean Sea.

In the Mediterranean is essential the absence of the knowledge of the stock status as well as complete or independent information on fishery mortality, biomass estimation or other biological or management parameters. Lleonart [15] describing the fisheries assessment methodologies applied in the Mediterranean, concluded that the most fisheries research projects have a local contingency. The methods that have been using so far (technical measures, the recently established landing obligations, national management plans) are only good as ‘preventive’ measures. Even the ‘symptomatic treatments’ that occasionally administer (EU multiannual plans, GFCM management plans) take a long time to produce effects and anyway do not eradicate the ‘disease’. To treat the causes of this problem and reverse the steady decline of fish stocks, needs a proper cure. In this case the cure consists of immediate, exceptional measures at both EU and international level. Such measures need to be embraced by all Mediterranean countries in unison and need to take into account the economic risks as well as the environmental ones.

Knowledge of the status of the fish stocks is a prerequisite for the implementation of the management measures applied in the Mediterranean Sea. The first organize research effort named Mediterranean Trawl Survey (MEDITS) and organized and carried out by France, Greece, Italy and Spain at 1994 [16] funded from the EU. The MEDITS survey program at the beginning intended to produce basic information on benthic and demersal species in terms of population distribution as well as demographic structure on the continental shelves and along the upper slopes at a global scale in the Mediterranean. Nevertheless, the intention was to organize the protocols in such a way as to easily permit the enlargement of the program to other Mediterranean countries. One of the mail challenges of the project was the adoption of common standardized sampling protocols. The four first partners early in 1994 just before the first survey have adopted the basic protocols. These protocols included the design of the survey, the sampling gear, the information collected, and the management of the data as far as the production of the common standardized analyses of the data. The manual has been established from different experiences and particularly from that of the IBTS Group [17]. The protocols have been amended for the following surveys, and particularly in 1995 to take into account the experience gained during the first survey.

In 2002, the European countries bordering the Mediterranean made a commitment to curry out MEDITS surveys yearly according to Data Collection Framework (DCF). Permanent links were organized with the relevant EU bodies, such as the Regional Coordination Group of the Mediterranean and Black Sea and the Scientific and Economic Committee for Fisheries (STEFC). Thus, the program has been integrated as an indispensable obligation of all EU countries in all the community seas, in the context of the implementation of the Common Fisheries Policy (CFP). Links were also maintained with the General Fisheries Council for the Mediterranean (GFCM), the FAO regional fisheries management organization. The strength of the MEDITS surveys so far has been the agreement among the participants to share standardized methods as a Mediterranean level using the same gear, sampling scheme and protocols for collecting, checking and analyzing data. From 2008 the program was extended to include the small-scale fisheries and the small pelagic. At that time all the protocols changed in order to include all the new information with common methodologies e.g. small-scale fisheries with different fishing gear and small pelagic by acoustic methodologies. The program is commitment of all the Mediterranean countries, at the same time, similar programs are being implemented by all EU member states covering their surrounding seas. The program is constantly updated with new information aimed at a better management of fish stocks e.g. more target taxonomic categories and fish species, data collection on marine macro-litter, etc.

Recognizing the importance and peculiarities of fisheries in the Mediterranean, and the need for strong regional cooperation, the GFCM was established to promote the development, conservation, rational management and best utilization of living marine resources in the region. Among its various responsibilities, the GFCM since 1970, periodical updating of the research activities dealing with demersal and small pelagic Mediterranean living resources during working group occasions and technical consultation at a region level. The GFCM Data Collection Reference Framework (DCRF) is the first GFCM framework for the collection and submission of fisheriesrelated data in the GFCM area of application. FAO fisheries statistics data based has now uploaded until 1994. All this allows to draw a fairly complete panoramic synthesis of this situation. Time series of fisheries landings can provide important information for changes in a fishery, or changes to the underlying environment [18]. Often, as in the case of Mediterranean fisheries, this is essential in the absence of complete or independent information such as on the fishing intensity or fishing mortality affecting the stock. Mediterranean fisheries are now confronted with serious challenges originating from environmental impacts of coastal activities, climate change, over exploitation of fishery stocks and poor management of the shared resources [19].

It underpins the formulation of sound scientific advice by relevant GFCM subsidiary bodies (i.e. Scientific Advisory Committee on Fisheries), ultimately supporting the GFCM decision-making progress towards sustainable Mediterranean fisheries. Formalized in 2017, the DCRF covers in a standardized and optimized way catch (landing and catch per species), fishing fleet operating in the GFCM fisheries restricted areas, fishing effort (per fleet segment, fishing gear) socioeconomic data, and biological information such as stock assessment, length, size at first maturity, European eel abundance. The last years GFCM regularly reviews the state of fisheries, including the economic and social aspects of the fishing industry, as a basis for the formulation of scientific and management advice conducive to sustainable and responsible fisheries.

The scientific knowledge of large pelagic stocks and fisheries is annually updated for more than 40 years by International Commission for the Consultations of Atlantic Tunas (ICCAT). In general, EU catch limits or quotas are not applicable in the Mediterranean, with the exception of limits on Bluefin tuna that have been introduced in response to recommendations by the ICCAT for the protection of shared stocks.

In order to study, understand and implement the biodiversity and habitat productivity objectives in the Mediterranean, which are essential elements in ecosystem fisheries management of an extensive sea region, all states bordering the Mediterranean should organize and implement common management measures to control fishing. These measures should aim at protecting and conserving fishery resources, including legislation requiring the licensing of fishing vessels and regulating the characteristics and use of fishing gear. In addition, almost every Mediterranean country has designated marine or specially protected areas (although varying by type and objectives) and/or had adopted temporal closures to protect, in part, certain species during their reproductive period. Other management tools in use include total allowable catches (TAC) or quotas for large pelagics, minimal landing sizes, protected species and limits on the days at sea. Legislation regarding the treatment of by-catch is rare in the Mediterranean although this is to be expected given its mixed fisheries. Other than licensing, rights or incentive-adjusting measures are infrequently used.

Fisheries management is conducted by regional bodies based on data and scientific advice, and control measures to ensure that rules are applied fairly to and complied with by all fishermen. Intense international cooperation encourages all countries bordering the Mediterranean Sea to play by the same rules. However the European Commission believes an extra effort by all is now required. To avoid the collapse of fish stocks and its impact on the ecosystem, and to guarantee a future for the fisheries industry in the region, all Mediterranean countries need to act urgently and collectively.

CFP was first enforced in the 1970s and has been successively updated in 2002 and recently in 2014. The CFP keystone is the sustainable exploitation of marine resources both in environmental and socio-economic terms toward a dynamic fishing industry and ensuring a fair standard of living for fishing communities. The current CFP specifies that between 2015 and 2020 exploitation will be conducted according to MSY objectives based on the consensus that this strategy will maintain fish stocks in the long term. The impact of fishing on the marine environment is not fully comprehended and for this reason, CFP adopts a precautionary approach based on selective fisheries practices and a total ban of discards. Similarly, the Marine Strategy Framework Directive [20, 21] requires EU Member States to take measures to achieve Good Environmental Status (GES) of all European marine waters by 2020.

From the management perspective, Mediterranean countries limit their management plans mainly to control fishing effort and fishing capacity together with specific technical measures, such as gear regulation (mainly mesh size and net configuration, as for example for the purse seine), establishment of a minimum conservation reference size, and closures of areas and seasons for fishing to control which vessels have access to which waters and areas. Moreover, the Article 19 of Council Regulation 1967/2006 foreseen that management plans within their territorial waters are adopted for trawling and other fishing activities. In this context, it is important to notice that spatial and temporal closures apply mainly to trawls, which are prohibited within 3 nautical miles from the coast or within the 50 m isobath, where this is closer to the coast. Also, temporal closures regard bottom and mid-water trawl nets are mainly enforced for 30–45 days during summer (Demestre et al., 2008). A second set of management measures in the Mediterranean Sea incorporate the establishment of permanent marine protected areas. Apart from the general absence of catch limits, in all other respects the region is subject to the same type of EU management measures as the rest of the EU, including requirements relating to the EU vessel register, licensing, monitoring and control arrangements, and new data collection measures.

State of fish stocks

Based on different documents that have been submitted to the GFCM Technical Consultation, as well as on the 65-year-time series of landings in the Mediterranean some general observations can be reached for the West and the East Mediterranean (a) despite some significant differences, the overall pictures from the West to East Mediterranean are not strikingly different, (b) from the study of the trends, it is clear that a high proportion of species or species groups in both Mediterranean basins have shown increases in landings over the whole period; either of these increases were linear, or concave upwards or concave downwards, and (c) from the perspective of stock assessment, very few time series show stable yield levels, suggesting a considerable dynamism caused by environmental and/or trophic or fishery-related impacts in the fisheries of the sub-region.

According to the scientific advice, the large majority of fish stocks assessed are shrinking and some are on the verge of depletion. All in all, only 9 % of fish stocks assessed are fished at levels below MSY levels [20] (COM (2016) 396). Despite recent improvements, the number of stocks whose status is unknown remains still large. For fish stocks such as hake, red mullet, anglerfish and blue whiting, current fishing mortality rates have been more than six times higher than MSY. These species represent around 43 % in volume of the total reported trawl catches of the EU fishing fleet (source: STECF and GFCM reports). Fishermen themselves report that they catch fewer and fewer fish every year, with potentially serious repercussions on the industry’s performance and on the economy of coastal communities. There are several reasons for the poor state of fish stocks, with the most important the overfishing, while pollution and climate change certainly play a role, there can be no doubt that extensive overfishing is one of the key causes. The EU has been using a number of methods to counter overfishing: EU countries have been reducing their fleets and our legislation features national and international fisheries management plans, catch limitations and environmental requirements.

Fisheries provides around 314000 direct jobs (www.fao.org). Total landings in the Mediterranean Sea increased irregularly from about to 900000 tonnes in 1970 to almost 1750000 tonnes in 1982 (Figure 1). Total landings remained relatively stable during most of the ‘80s before declining abruptly at the end the decade largely due to the overfishing of pelagic fisheries. There is an increased in landings until 1994, reaching 1.087.000 tonnes, continuing with a limited increase to 1200000 tonnes in 2000. In the following years until 2005, the landings appear slightly up and down fluctuations since 2007 showing the maximum 1.300.000 tonnes until today. In the coming years, there is a continuous increase of 900000 tonnes in 2014. This production remains almost constant until 2018, with a modest increase of 930000 tonnes in 2016 (Figure 1).

AFS-2-1-204-g001

Figure 1. Annual fluctuation of fishing landings in the Mediterranean Sea since 2000 as a whole and by geographical areas.

In the GFCM Mediterranean area, the ranking of capture fisheries production in 2014-2016 dominated by Turkish production, followed by Italy, Algeria and Greece maintained almost the same percentage in landing contribution, while Tunisia and Croatia show an increase compared. Total annually landings for Spain slightly decreased between 2014 and 2016. Despite the long-term upwards trends, the short-term trends over the last 4 years (2014-2017) tell a different story. One tentative explanation is that multispecies landings may now be approaching a peak for the Mediterranean as a whole, with new increases (especially in South and East Mediterranean) being balanced by recent declines, especially in the West and North basins. (Table 1) (Figure1).

Table 1. Landings by major groups of species between 2014 and 2016 in GFCM and Black Sea.

Group of species

Landings (tones)

2014

2015

2016

contribution
average
values (%)

Herrings, sardines, anchovies

 518248

 693966

 576341

 48,7

Miscellaneous coastal fishes

 142160

 152776

 162137

 12,5

Miscellaneous pelagic fishes

 84482

 78503

 80487

 6,6

Squids, cuttlefishes, octopuses

 52602

 50132

 50525

 4,2

Clams, cockles, ark shells

 40963

 56808

 43413

 3,8

Shrimps, prawns

 39810

 44664

 44407

 3,5

Marine fishes not identified

 51875

 38537

 34273

 3,4

Cod, hakes, haddocks

 37625

 40031

 38219

 3,2

Shads

 13127

 21515

 23704

 1,6

Others

 136312

 137861

 183583

 12,5

Total

 1117204

 1314793

 1237089

Compared with the whole GFCM area including and the Black Sea, the main groups of species contributing to landing in the whole area are very similar. Nonetheless, the contribution of small pelagic species (e.g. sardines, anchovies, sprat, etc.) is slightly less important (48%) of the total landings, while the contribution of the other group species is slightly higher. In comparison with the average landings of the last three years in the Mediterranean and Black Sea (Table 1), the main groups of species contributing at least to 1% of the catches remain stable. According to GFCM [18] there groups of species, namely “herrings, sardines, anchovies” (596000 tonnes), “Miscellaneous coastal fisheries” (152400 tonnes) and “Miscellaneous pelagic fishes” (81000 tonnes), constitute around 69% of the total reported landings in the entire GFCM and Black Sea area. Six other groups of species contributing to more than 1% of the landings amount to 20% of the total landings, and the constitution of all remaining species amount to approximately 12% overall.

The Mediterranean Fishing Fleet

Fisheries in the Mediterranean Sea are characterized by a fishing fleet of approximately 75.000 vessels at 2017-2018 where small- scale accounts for 80 % of the total (though these numbers should be considered an underestimation). In the area, fish stocks are exploited by EU fishing vessels almost exclusively in the northwestern Mediterranean (e.g. the Balearic Islands, the Gulf of Lion, Corsica, Sardinia and the Ligurian and Tyrrhenian Seas) and in the north Adriatic Sea, while the central Mediterranean (e.g. the Strait of Sicily and the Ionian Sea) and the eastern Mediterranean (e.g. the Aegean Sea and the Levantine Sea) are jointly exploited with non-EU countries.

The Mediterranean fisheries according to EU regulations can be broken down into three main categories: (a) small-scale fisheries, (b) trawling and (c) seining fisheries. The term “small-scale fisheries” attempting to integrate aspects of the “coastal” and “artisanal” fisheries and to avoid the vagueness, inconsistencies and differences of the previous definition, is virtually absent from the official terminology of the most Mediterranean countries. This term was introduced at first at 1990 by the European Commission, when the commission presented a proposal (COM (90) 358 final of 7 September 1990) [18] to amend Regulation 4028/86 on measures to improve and structures in the fisheries and aquaculture sector.

GFCM proposed the following fleet segments for data reporting purpose; (a) Polyvalent (P), small-scale vessels without engine using passive gear, small-scale vessels with engine using passive gear and Polyvalent vessels; (b) Seiners (S), Purse seines and Tuna seiners; (c) Dredgers (D); (d) Trawlers (T), Beam trawlers, Pelagic trawlers and Trawlers; (e) Longines (L).

Official statistics from 2017-2018 for the total fisheries fleet suggest that in the GFCM Mediterranean countries appear 74.748 fishing units (Table 2), of which 74,8%, 8,3%, 4,6% and 4% are registered as Polyvalent, Trawlers, Purse Seiners and unallocated fishing vessels respectively [19]. A number of 62201 coastal vessels equipped with the above fishing gear, together with the dredgers and longliners operate in all the countries of the Mediterranean Sea. A number of 6183 trawlers operate in the Mediterranean and most of them could be considered as semi-industrial or industrial vessels, taking into account the international practice. The purse seines, one of the main fishing gear used in the area, amount 3423 vessels and are distinguished into two major types: purse -seines operating during the day and purse –seines operating during the night. There are no significant differences between the two types as far as equipment and their activity focus on different species. Concerning the total distribution of the Mediterranean fishing fleet, there and vessel construction are concerned. The difference is that they employ a different fishery methodology, are no significant differences between the Eastern (30,6%) and Central (30,5%) Mediterranean and less in the Western (20,0%) and Adriatic Sea (14,2%). The number of operating fishing vessels by a group of fleet segment in the different GFCM Mediterranean countries are presented in Figure 2.

Table 2. Fluctuation of Number of vessels and total tonnage between 1970 and 1995 (FAO-FIGIS).

1970

1975

1980

1985

1990

1995

Number of vessels

56.936

61.970

68,515

72,976

86.272

82.004

Total tonnage (GT)

1.538.195

1.860.553

2.084.836

2.101.905

2.613.136

1.832.318

AFS-2-1-204-g002

(*) The coastal category includes polyvalent, dredgers and longline vessels.

Figure 2. Number of operating fishing vessels grouped by fleet segment (2017-2018) in the different GFCM Mediterranean countries.

According to the most-up-to-date GFCM information, the capacity of the operating fishing vessels in the Mediterranean is about 769000 GT and 4720000 kilowatts (KW) unevenly distributed among the various countries, with four of them, Turkey (19,7%), Italy (16,2%), Egypt (13,7%) and Tunisia (11,3%) holding about 60% of the total fishing capacity. Other national fleet with substantial capacity (more than 50000 GT) are those of Greece, Algeria and Spain. (Figure 3).

AFS-2-1-204-g003

Figure 3. Number, capacity (GT) and kilowatts (KW) of operating fishing vessels by GFCM Mediterranean countries (2017-2018).

The evolution of the number and GT of the fishing fleet in Mediterranean Countries between 1970 and 1995 is summarized in Table 2 (source: FAO-FIGIS/Fisheries Global Information System). Of the data processed this way (Table 2), it can be concluded that until the beginning of the 1990s an expansion of the effort took place regarding vessels, and the capacity of Mediterranean fishing fleets of the countries analyzed. From the mid-1990s both dimensions started to decrease although, this reduction is especially important in fleets operating in other seas, such in the case of France, Spain and Morocco.

Employment

The human dimensions of Mediterranean fisheries are as complex and divers as the species and the ecosystems upon which they depend. For example the Mediterranean states’ economies range from lowincome food-deficit to highly developed, their coastlines from deserted to heavily urbanized, and their fisheries from unindustrialized and labor intensive to modern and capital intensive.

Although often overlooked in the statistics, these fisheries are important for the welfare of coastal inhabitants as well as job and income security. They also act synergistically with other activities (tourism, recreation etc.). According to GFCM and DCRF data collection program, total employment onboard fishing vessels for the Mediterranean account for 227250 jobs, an increase by 10% since 2016, while 900.000 others are employed in related services and industries. Four countries in the region represent 55% of all employment onboard fishing vessels: Tunisia, Turkey, Algeria and Italy (Figure 4).

AFS-2-1-204-g004

Figure 4.FAO [19] estimates that pre- and post-harvest labour, gleaning activity or other in-kind labour, such as support from family members may account for an additional 50% in employment figure (approximately additional 25000-26000 people) [22]. The central, eastern and western Mediterranean subregions jointly represent 85% of all employment onboard fishing vessels in the GFCM area of application.

Small-scale fisheries is a very important segment for the Mediterranean for job and income security of the fisheries dependent coastal communities. Even though, SSF accounts for 26% of total revenues of the region, they provide employment for the 59% of the total people working in the Mediterranean fisheries sector (approximately 135000 persons on board SSF vessels). SSF as a source of employment is more important for the Central Mediterranean region where it resents 75% of all on vessel employment. In the other Mediterranean regions (West, East Mediterranean and Adriatic Sea), 54% and 46% (on average) of the employment is offered by industrial fisheries and small-scale fisheries respectively (Figure 5).

AFS-2-1-204-g005

Figure 5.On-board fishing vessel employment (numbers and percent) per Mediterranean sub-region

Specific Case: The exploitation of tuna

The exploitation of tuna is one of the oldest and most complex fishing activities of the Mediterranean. It is practiced on a species of very high economic value whose main target is the Japanese markets, and this causes a strong fishing effort. Tuna is a trans-zonal species swimming in international and national waters of many countries and in large aggregates of individuals, which facilitates its location and capture on a large scale. It should be noted that tuna is characterized by complex breeding, low maturation and by being vulnerable to reductions in their feed (small pelagic) and very much affected by overfishing. Taking into consideration all these factors, it is easy to understand the critical situation of these resources. The ICCAT regulates the Bluefin tuna fishery, of which the EU and its Member States are members.

The source of information on production/capture data reported in Table 6 is FISHSTAT, and due to the characteristics of this fishery, the reliability and coverage of these data are limited. This circumstance also makes it difficult to determine these catches used for fattening. In accordance with available statistics, production of tunas, bonitos and billfishes in the Mediterranean Sea has been decreasing since the year 1995 (Table 6), after various decades of expansion. The expansion of production that took place between 1975 and 1985, when it more than doubled, has proved to be unsustainable. Amongst the species exploited, we could highlight the Atlantic Bonito, Atlantic Bluefin tuna and Swordfish. These three species account for 90% of the total capture of these large pelagic in the Mediterranean; some 130,000 t in 2005 (Table 3).

Table 3. Capture production (in tonnes) of tuna fishes in the Mediterranean and Black Sea by species (all countries included).

Species

 1975

 1985

 1995

 2000

 2005

Albacore

 500

 4,129

 1,587

 5,578

 3,657

Atlantic bluefin tuna

 11,266

 19,296

 37,560

 23,106

23,886

Atlantic bonito

 6,038

 18,487

 15,371

 18,760

77,460

Atlantic white marlin

 1

 1

Frigate and bullet tuna

 2,644

 5,240

 5,205

 2,763

 3,029

Little tunny (=Atlantic Black skipjack tuna)

 1,386

 2,040

 1,894

 3,298

 1,660

Marlins, sailfishes, etc.

 1

 1

 50

Plain bonito

 9

 115

 145

 5

Skipjack tuna

 6

 13

 43

 90

 29

Swordfish

 4,304

15,293

 12,432

 15,570

14,582

Tuna-like fishes nei

 780

 2,125

 1,264

 3,353

 4,739

TOTAL

 26,924

 66,632

 75,473

 72,665

129,097

Today the situation is changed and bluefin tuna is indeed a primary example of sustainable management, having gone from heavy over-exploitation to full recovery in the space of a few years thanks to a massive international effort led by the EU. The European Commission is pleased with the work and commitment of the Member states to ensure compliance with the rules in this fishery in the past few years, and is also appreciative of the significant role played by the European Fisheries Control Agency in ensuring the coordination of these controls. It will remain vigilant to ensure that all rules, and particularly the individual vessels’ quotas, are fully respected. Will be continued to monitor catches and analyze Vessel Monitoring System data (a satellite-based control system) on a constant basis and will continue to send out inspectors.

Following advice from ICCAT scientists in 2014, ICCAT has agreed to an increase of 60% of the Total Allowable Catch (TAC) over three years (2015, 2016 and 2017) [23-25]. In 2016, this brings the European TAC to 11203 tonnes. The quota is shared between the 8 EU countries actively involved in the bluefin tuna fishery (Spain, France, Italy, Croatia, Greece, Portugal, Malta, and Cyprus), with Spain and France having the largest shares.

To this date, it is the only stock in good state in the Mediterranean, while a great majority of stocks remains overfished. To ensure that no overfishing takes place and similarly to previous years, a strict control and inspection program are in place: it sets concrete control priorities and benchmarks and deploys a significant number of inspectors, patrol vessels and aircraft, all coordinated by the European Fisheries Control Agency and the Member States concerned. For the first time in 2016, ICCAT is also implementing the eBCD, a new state-of-the-art electronic tuna catch document system which greatly improves the traceability of all bluefin tuna products. The use of this program, combined with the rest of the measures of the recovery plan, makes this fishery one the most controlled in the world, and provides the best guarantees to consumers that the resource is being used sustainably.

References

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  2. Dugdale RC and Wilkerson FR (1988) Nutrient sources and primary production in the Eastern Mediterranean. OceanologicaActa9: 179-184
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  4. Galil BS (2007) Loss or gain? Invasive aliens and biodiversity in the Mediterranean Sea. Marine Pollution Bulletin55:314-322.
  5. Zenetos A, Meric E, Verlaque M, Galil P, Boudouresque CF, et al. (2008) Additions to the annotated list of marine alien biota in the Mediterranean with special emphasis on Foraminifera and Parasites. Mediterranean Marine Science9: 119-165.
  6. Galil BS,Froglia C, Noel P (2002) CIESM Atlas of Exotic Species in the Mediterranean. Crustaceans: decapods and stomatops2:192.
  7. Zenetos A (2010) Trend in aliens species in the Mediterranean. An answer to Galil (2009) Taking stock: inventory of alien species in the Mediterranean Sea». Biological Invasions12: 3379-3381.
  8. Galil BS (2009) Taking stock: inventory of alien species in the Mediterranean Sea. Biological Invasions11: 359-372.
  9. Tortonese E (1958b) Elenco dei Leptocardi, Ciclostomi, Pesci cartilaginei ed ossei del Mare Mediterraneo. Atti Società Italiana Di Scienze Naturale E Museo Civico Di Storia Naturale di Milano 97: 309-345.
  10. Tortonese E (1987) Pesci del Mediterraneo. Recenti studi intorno alla sistematica e distribuzione.Quaderni dell’ Istituto di Idriobiologia e Acquacoltura ‘G. Brunelli’, Numero Speciale: 111
  11. Quignard JP (1978) Introduction à l’ichtyologie méditerranéenne: aspect général edu peuplement. Bulletin de l’Office National des Pêches, Tunisie, 2 : 3-21.
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  15. Lleonart J (1997) Critical review of methodology, 40-51. In: Coordination of fisheries research in the Eastern Mediterranean, (G. Tserpes Ed.), IMBC & EE/DG XIV: 75
  16. Betrand JA, De Sola LG, Papaconstantinou C, Relini G and Souplet A (2002)The general specification of the MEDITS surveys. Scientia Marina(Suppl.2)9-17.
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  21. European Commission (2016) Consolidated treaties, charter of fundamental Rights. European Council 412.
  22. Sauzade D, Rousset (2013) Greening the Mediterranean fisheries: tentative assessment of theeconomic leeway. Plan  Bleu, Valbonne, France.
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Applying First-Order Perturbation Theory of Quantum Mechanics to Predict and Build a Postprandial Plasma Glucose Waveform (GH-Method: Math- Physical Medicine)

DOI: 10.31038/IMROJ.2020522

Introduction

In this paper, the author presents his techniques of applying firstorder perturbation theory of quantum mechanics to predict and build a Postprandial Plasma Glucose (PPG) waveform based on the “perturbation factor” of carbs/sugar intake amount. This is a part of his GH-Method: math-physical medicine research methodology.

Methods

Initially, he applied segmentation pattern analysis to analyze his 1,825 meals with 23,725 PPG Sensor data collected during a period of 5/5/2018- 12/13/2019. Initially, his two segments were based on both “first factor” of meal’s carbs/sugar intake amounts and “second factor” of post-meal walking steps. His low-carb meals occupy about 2/3 of the total meals (1,209 meals with 8.5 grams per meal) and high-carb meals occupy about 1/3 of the total meals (615 meals with 27.1 grams per meal). A standard waveform (curve) contains 13 data points for each PPG curve and one input data for each 15-minute time segment. His post- meal walking steps are comparable (4,238 vs. 4,282 steps). Therefore, he decided to focus on the first factor of carbs/sugar intake amount only.

Next, he applied the first-order perturbation theory of quantum mechanics to continue and extend his glucose prediction research work. The perturbation equation is expressed in the following:

A = ~ ( A0 + ε * A1 )

Where A0 would be the known solution to a simpler but solvable initial problem and A1 represents the first-order term which may be found interactively by some systematic procedure. For small ε (epsilon), this higher-order term in the series becomes successively smaller and derives to an approximate solution.

Since the second factor of post-meal walking steps are almost equal (4,238 vs. 4,282 steps) between the low-carb case and high-carb case, he will only focus on the first factor of carbs/sugar intake amount. The author conducted the two following perturbation analysis cases:

(1) Using a combination of weighted carbs/sugar amount, 14.6 grams, which is equal to (1/3 * high-carbs + 2/3 * low-carbs).

(2) Using an average carbs/sugar amount, 17.8 grams, which is equal to 1/2 * (high-carbs + low-carbs)

He will then be able to construct two new separate PPG waveforms (curves) between 0-minute throughout 180-minutes by applying the perturbation theory.

Finally, he used his collected data to calculate and construct a waveform with a gram of carb following very closely to the perturbed waveform with 17.8 grams of carb.

Results

Figures 1 and 2 display both the data table and waveforms chart of low-carb pattern vs. high-carb pattern. Although their opening glucoses at 0-minute (129mg/dL vs. 131mg/dL) and PPG curve shapes are quite similar (two “mountain” shapes with 58% correlation), their peak glucoses (140mg/dL vs. 156mg/dL) and closing glucoses at 180-minutes (127mg/dL vs. 140mg/dL) have different results. These differences have resulted from varying glucose decaying speeds after 60-minutes, which have deeper biomedical meanings, and are extremely critical to a patient’s risk probabilities of having diabetes complications. The significance of these differences from a segmentation analysis has already been discussed in his previous publications and presentations.

IMROJ-5-2-508-g001

Figure 1. Data table of low-carbs and high-carbs PPG values.

IMROJ-5-2-508-g002

Figure 2. Graphic chart of low-carbs and high-carbs waveforms.

Figures 3 and 4 illustrate both data table and two additional “perturbed waveforms” between low-carbs and high-carbs. It should be noted that the weighted combination PPG curve (14.6g) almost completely matches with the original PPG curve generated with real data. However, the average carb PPG curve (17.8g) is a newly generated waveform by using the perturbed factor, carbs amount, which is similar to those two original curves, low-carbs and high-carbs, but are not the same if you examine them closely. Through application of perturbation theory concept of quantum mechanics, the author could generate a predicted PPG waveform entirely based on the selected “perturbation factor” of 17.8 grams of carbs/sugar intake amount. Of course, this perturbed waveform is only an approximated curve based on the first perturbation factor, carbs/sugar intake amount.

IMROJ-5-2-508-g003

Figure 3. Data table of low-carbs, high-carbs, and two perturbed PPG values.

IMROJ-5-2-508-g004

Figure 4. Graphic chart of low-carbs, high-carbs, and two perturbed PPG waveforms.

For clarity of waveform comparison, Figure 5 further demonstrates these two newly generated perturbed waveforms by using two slightly different perturbed carb values.

IMROJ-5-2-508-g005

Figure 5. Waveforms comparison.

In Figures 6 and 7, the author selected 84 meals with an averaged carb amount of 18g and constructed a new waveform between 0-180 minutes. This measured PPG waveform with 18g and 138.21mg/dL is compared against the perturbed PPG waveform with 17.8g and 138.81mg/dL to achieve a combined (adjusted) prediction accuracy of 98.4%.

IMROJ-5-2-508-g006

Figure 6. Verification data comparison between measured PPG @ 18g and perturbed PPG @ 17.8g.

IMROJ-5-2-508-g007

Figure 7. Verification waveform comparison between measured PPG and perturbed PPG plus a 98.4% combined accuracy using perturbation prediction theory.

The deviation amount of PPG is 0.5% and the deviation amount of carbs gram is 1.1% (in an opposite direction). Therefore, the combined deviation is 1.6%, which yields an accuracy rate of 98.6%.

Conclusion

Glucose variance is an extremely complex biochemical and biophysical phenomenon. After a diabetes patient measures and establishes two separate initial waveforms with one low-carb meal and another high-carb meal separately, we can then collect the patient’s PPG data and draw two separate PPG waveforms accordingly. As a result, we can predict the glucose behavior by using the perturbation theory of quantum mechanics to obtain an approximated PPG waveform according to this selected carbs/sugar intake. Of course, the same method can also be applied using the second per nation factor, post-meal waking steps. In this way, a patient will have the ability to predict his/her own PPG behavior before consuming a meal or initiate post-meal exercise.

Applying the First-Order Interpolation Perturbation Method to Establish Predicted PPG Waveforms Based on Carbs/Sugar Intake Amounts (GH-Method: Math- Physical Medicine)

DOI: 10.31038/IMROJ.2020521

Introduction

In this paper, the author presents his numerical techniques of applying the first-order interpolation perturbation method to establish and predict a new Postprandial Plasma Glucose (PPG) waveform based on the “perturbation factor” of carbs/sugar intake amount. This is part of his GH-Method: math-physical medicine research methodology. He also uses two previously measured PPG datasets (waveforms) of high-protein breakfasts to validate this numerical methodology.

Methods

The exact solution of many nonlinear problems encountered in the biomedical field cannot be achieved analytically for most situations. Normally, a given complex function can get certain approximated solutions via a class of simpler operations. Most of the general complex problems can be expressed by the following polynomial function of nth degree:

IMROJ-5-2-507-e001

This nth degree polynomial function could be solved by approximating the values outside the available data table with the help of the calculating points that correspond to the approximate locations within the proximity of the available data table. This approach could be achieved via function approximation simplification and interpolation perturbation methods.

First, in many cases, this nth degree polynomial function could be further simplified via truncating off the higher order terms to achieve the following first-order polynomial function:

Y = f(X) = A0 + A1*X

Second, the above first-order polynomial function’s approximate solution could be obtained via a specific “interpolation or extrapolation” method.

Interpolation is implemented within the range covered by data of both the PPG due to high-carbs amount (“high glucose”) and PPG due to low-carbs amount (“low glucose”). The interpolation method replaces Y (glucose level) with an easily calculated function, usually a polynomial and a simple straight line. In short, the interpolation method, also known as the intermediate value, is a scientific term that could be defined as arriving at an unknown intermediate values (e.g. glucose level Ymg/dL) of a function by using known values (e.g., carbs amount X grams). For the complex problem of glucose variation study, this simplified equation can be expressed in the following format of Equation 1: New Glucose Ymg/dL at new X carbs gram

= function of carbs amount, i.e. f(X)

= Y1 + slope * (Y2 – Y1)

Where:

Slope = (new X – low carbs) / (high carbs – low carbs)

Y1 = low glucose

Y2 = high glucose

The above-described steps of the calculation (Equation 1) have utilized an applied mathematics methodology of “first-order interpolation perturbation method” which has been frequently used in quantum mechanics, fluid dynamics, and solid mechanics.

Results

The author has selected a period of 601 days (5/5/2018 – 12/26/2019) as the time window of his segmented PPG pattern analysis associated with two separate meal groups. The first one has 240 breakfasts with either an egg or McDonald’s breakfast, including egg, sausage, hash brown or muffin occasionally, and the other has 228 breakfasts at McDonald’s restaurant exclusively.

A summarized data table of breakfast PPG analysis is listed below with the format of (average carbs/sugar grams; average post-meal walking steps; average finger PPG; averaged sensor PPG):

The major difference between these two breakfast groups is the first perturbation factor of carbs/sugar intake amount, 7.5 grams for Egg vs. McDonald’s and 10.0 grams for McDonald’s

He was then able to construct two separated PPG waveforms (curves) between 0-minute and 180-minutes, for high-carbs input and low-carbs input. The data table and waveforms are shown in Figure 1.

IMROJ-5-2-507-g001

Figure 1. Low-carbs PPG and High-carb glucose.

Finally, he used these two breakfast cases (7.5g and 10g) as known values (X1, X2, Y1, Y2) to construct two new approximate waveforms associated 7.5g and 10g, respectively using interpolation perturbation methods (Equation 1).

Figures 2 depicts two data tables of these two-interpolation perturbation calculated results. Figure 3 shows the comparison between measured waveform versus perturbed waveform for 7.5g case and 10g case, respectively. Peaks are at 94% and 96% of measured PPG peaks, while the perturbed average PPG value is at 96% of measured average PPG value. Although these two perturbed breakfast PPG values are only approximated values, both of them still have ~ 95% degree of accuracy.

IMROJ-5-2-507-g002

Figure 2. Interpolation perturbation method to generate two datasets for both egg breakfast and McDonalds’ breakfast.

IMROJ-5-2-507-g003

Figure 3. Comparison between perturbed and measured PPG for both egg and McDonalds’ breakfasts.

Conclusion

Glucose variance is an extremely complex biochemical and biophysical phenomenon. In addition, glucose testing using finger piercing is both troublesome and painful. Most diabetes patients do not like to measure their glucose constantly.

The authors paper numbers 153-2019 and 154-2019 describe his application of perturbation theory to develop a 3-hour approximate PPG waveform based on one single input data, the carbs/sugar intake amount, with high accuracy.

Based on this technique and his developed artificial intelligence glucometer’s estimated carbs/sugar intake amount (via optical physics), a diabetes patient can predict and control his PPG in a much easier way.

After a diabetes patient measures and establishes two separate initial waveforms with low-carb meal and high-carb meal respectively, we can then apply this interpolated perturbation method to predict and plot out this patient’s 3-hour PPG waveform (curve) prior to eating. Even though these approximated PPG values sacrifice some degree of prediction accuracy, this prediction method is fast, easy, painless, and at no cost to diabetes patients to control their glucose levels.

Mondor’s disease of the breast concerning two cases collected in the Senology unit of the Gynecological and Obstetric Clinic of Aristide Le Dantec Hospital

DOI: 10.31038/IGOJ.2020312

Abstract

Mondor’s disease of the breast is a superficial thrombosis most often affecting the subcutaneous vessels of the anterior or lateral chest wall.

It is a rare pathology with less than 500 cases described in the literature.

The diagnosis is essentially based on physical examination. Ultrasound confirms diagnosis by visualizing the affected vein. Spontaneous evolution is always favorable.

Apart from the breast, other localizations are possible, particularly in the penis, abdomen and arm.

Through two cases supported in our structure, we present a review of the literature on clinical characteristics and on management.

Keywords

Mondor – Breast – Thrombosis

Introduction

Mondor’sDisease (MD) of the breast is characterized by superficial sclerosing thrombophlebitis of the subcutaneous veins of the anterior or lateral thoracic wall first described in 1939 by Henry Mondor. It generally involves one of this three veins: lateral thoracic, superior epigastric or thoracoepigastric (the most common) [1]. It has also been described in the arm, abdomen or penis [1, 2].

Its etiopathogenesis is not clearly defined. Referring to the few cases described in the literature, the development of this pathology would be reported after intense physical activity, pregnancy, trauma, surgical intervention (breast reconstruction, breast biopsy, oncological surgery, etc.) and various diseases (neoplasia , breast infection, inflammatory process) [1, 2, 3].

The diagnosis is essentially based on physical examination. We generally find a painful cord with the form of a groove, a straight gutter or, on the contrary, a linear relief. There is a particular “reticular” shape with the coexistence of two more or less parallel cords. The cord size is variable, from a few millimeters to several centimeters. It has a fibrous, indurated consistency and is located under the dermis [3, 4]. Breast ultrasound is the reference examination to confirm the diagnosis and finds the usual signs of venous thrombosis (non-compressibility of the vein under the probe and hypoechogenicendoluminal image) [4]. These symptoms persist for one to two weeks and disappear spontaneously or under symptomatic treatment.

Due to the rarity of this pathology in our countries, we report two cases collected from the Senology unit of the Gynecological and Obstetric Clinic of Aristide Le Dantec Hospital and a review of the literature to better understand this pathology.

Case report

Case 1: Mrs. S.B., 43 years old with no particular thrombotic history, had consulted for right mastodynia occurring intermittently following a fall from its height with reception on the right breast two years ago.

After her trauma, the patient would have noted recurrent pushes in the form of a very apparent and painful tubular formation in the breast which had motivated a consultation. The ultrasound found a superficial tubular formation with pseudo-cystic dilation above the nipple corresponding to a probable Mondor phlebitis. A breast MRI performed subsequently found a dilation of a supero-external superficial vein close to the nipple associated with a thickening of the skin suggesting Mondor’s disease. The spontaneous evolution was characterized by a progressive volume increase of the right breast passing from a cup B to a cup D.

The examination found a right breast increased in volume; the right supra-nipple superficial vein was very apparent, indurated and very sensitive. There was a sensitive homolateral axillary lymphadenopathy. Spontaneous evolution was favorable.

Case 2: Mrs. G.F., 34 years old has been followed in our service for 03 years for left breast cancer. The tumor was initially classified T2N1M1 (pulmonary).

Chemotherapy had been initiated with an anthracycline-based protocol and then she subsequently benefited from a conservative surgery such as tumorectomy with axillary dissection.Fifteen months after the intervention, there was a cancer progression which motivated the resumption of chemotherapy followed by a total mastectomy.

She presented, 15 days after the left mastectomy, a right mastodynia sitting at the external quadrant.

The physical examination found a painful cord measuring approximately 7 cm, located at the Supero-External Quadrant (SEQ) of the right breast (Figure 1) very suggestive of Mondor’s disease. Lymph nodes were free.

IGOJ-3-1-1-g001

Figure 1. Painful indurated cord of the SEQ of the right breast in favor of Mondor’s disease

The ultrasound performed found a dilated incompressible superficial breast vein without any endoluminal image (Figure 2). There was no associated breast mass identified by mammography.

IGOJ-3-1-1-g002

Figure 2. Ultrasound appearance in favor of a Mondor’s disease of the right breast with the presence of an incompressible superficial vein.

Treatment with non-steroidal anti-inflammatory (NSAIDs) drugs had been recommended with resolution of the pain and disappearance of the indurated cord after 10 days.

Discussion

Mondor’s disease, more commonly known as subacute subcutaneous trunculitis of the anterolateral chest wall, is a rare superficial thrombosis most often affecting the subcutaneous vessels of the anterior or lateral chest wall [1, 5].

The first reported case dates back to the end of the 19th century, but it was only in 1939 that Henry Mondor clearly reported a series of cases with a precise description of the physical symptomatology [6].

It is a rare affection with less than 500 cases described in the literature. The actual prevalence is unknown, only a few authors have reported an incidence of this affection which is between 0.5 and 0.8%. However, this affection is probably underestimated due to its mild nature with spontaneous resolution within a few days which means that patients do not always consult [6, 7].

The clinical form the most frequently found is chest wall and breast vessels damage as it was the case for our two patients.

Other localizations have been described like Mondor’s disease of the penis, the abdominal wall and the axillary space [1, 2, 8].

Despite the delay, since its first description, the etiopathogenesis of this affection stays unclear. Among the risk factors there are: intense physical activity, pregnancy, trauma, surgery (breast reconstruction, breast biopsy, oncology surgery, etc.), various diseases (neoplasia, breast infection, inflammatory process) and thrombophilia [5 , 6, 8, 9]. For the first patient, the likely aetiology was a direct trauma to the breast. Another likely risk factor is breast neoplasia, even if the cause and effect link has not yet been clearly etablished yet. One study found a rate of 12.7% of MD with no obvious cause occurring in the field of neoplasia. Another study by Hasegawa and Okita found a case of MD occurring on the left breast after a right breast neoplasia as it was the case for our second patient.

However, for this specific case, the aetiology found was a direct trauma resulting from the placement of an intravenous catheter for chemotherapy [5]. For this second case, this aetiology could also be retained because the left mastectomy and axillary dissection was done 15 days ago, with venous approach on the right.. The 2005 Lhoeststudy of the complications of breast surgery found a frequency of 1.58% of MD without specificity in relation to the type of surgery with patients who developed the symptomatology 10 to 15 days after the intervention as it was the case for our patient [3, 10].

The clinical symptomatology found in our two patients was similar to what was described in the literature [4]. We discovered a cord with the form of a groove, a rectilinear gutter or, on the contrary, a linear relief better visible during breast elevation or arm abduction.

The topography is variable depending on the venous involvement [12] (Figure 3)

IGOJ-3-1-1-g003

Figure 3. Superficial veins of the anterolateral chest wall
A: Lateral thoracic avein
B: Thoraco epigastric vein
C: Superior epigastric vein

1. If the lateral thoracic vein is thrombosed, there is an oblique cord in the SEQ running up and out towards the axillary hollow along the outer edge of the pectoralis major;

2. If the thoraco-epigastric vein is affected, the cord located in the lower quadrant takes a direction rather down and out;

3. Finally, if it is the upper epigastric vein, it takes a direction from the infero-internal quadrant below and inside.

The size of the cord is variable, from a few millimeters to several centimeters; it extends over 20 to 30 cm sometimes less and can touch the upper limb by contiguity. In our two patients, the clinical examination was sufficient to recognize the pathology, the ultrasound associated with venous Doppler confirmed the diagnosis. Several authors believe that ultrasound associated to venous doppler is currently the gold standard for the diagnostis. We found the usual signs of venous thrombosis (non-compressibility of the vein under the probe and hypoechogenicendoluminal image) [1,4,11]. However, since the link with breast neoplasia is still not clearly established; we will recommend a mammogram even an MRI in the follow-up, especially in cases where no risk factors have been found. For our first patient, we did a breast MRI and a mammogram to find out an etiology to the increase of breast volume  observed after the trauma.

Concerning care, wherever the MD is located, it is necessary to treat the cause or the predisposing factors if they are found to promote healing and avoid recurrence.  Generally it is recommended either to abstain from therapy, than a simple analgesic or anti-inflammatory treatment, especially in cases where the pain is very significant. In a study carried out by Shirah which tested two therapeutic modalities namely a treatment based on NSAIDs by oral and local way, he found that the local way traetment was more effective because of its speed of action [1]. Some authors have reported the efficiency of an anticoagulant therapy in the acute phase, but this remains controversial [1,4].

Our first patient had spontaneous recovery without treatment. For the second patient, due to the pain and the stress caused by contralateral breast neoplasia, treatment with oral NSAIDs was started, with symptoms disappearing in less than 10 days. This further confirms the benign nature of this affection.

Conclusion

Mondor’sDisease (MD) is a rare and benign affection. It is a venous vascular pathology most often affecting the vessels of the anterolateral chest wall. Its real incidence and its etiopathogenesis are still unclear due to the few cases described in the literature. The clinical examination is generally sufficient to make the diagnosis. It is a pathology which is most often spontaneously resolved within a few days even in the absence of treatment.

References

  1. Shirah BH, Shirah HA, Alonazie WS(2017) The Effectiveness of Diclofenac Sodium in the Treatment of Mondor’s Disease of the Breast: The Topical Patch Compared to the Oral Capsules. The Breast Journal 23 : 395-400.[crossref]
  2. Zidani H, Foughali M, Laroche JP (2010) Superficial venous thrombosis of the penis: penile Mondor’s disease? A case report and literature review. Journal des Maladies Vasculaires35: 352-354.[crossref]
  3. Lhoest F, Grandjean FX, Heymans O (2005)Mondor’s disease: a complication of breast surgery. Annals of cosmetic plastic surgery50: 197-201.
  4. Quéhé P, Saliou AH, Guias B, Bressollette L (2009) Mondor’s disease in 3 cases and review of the literature. Journal of vascular diseases34 : 54-60.[crossref]
  5. Olarinoye-Akorede SA, Silas BT (2017) Mondor’s disease of the breast in a Nigerian woman previously treated for invasive ductal carcinoma in the contralateral breast: A case report. Niger J Clin Pract20:1040-1043.[crossref]
  6. Amano M, Shimizu T (2018) Mondor’s disease: A review of the literature. Intern Med 57: 2607-2612. [crossref]
  7. Pasta V, D’Orazi V, Sottile D, Del Vecchio L, Panunzi A et al (2015) Breast Mondor’s disease: Diagnosis and management of six new cases of this underestimated pathology. Phlebology30: 564-568.[crossref]
  8. Ouattara A, Paré AK, Kaboré AF, Yaméogo C, Botcho G et al. (2019) Subcutaneous Dorsal Penile Vein Thrombosis or Penile Mondor’s Disease: A Case Report and Literature Review. Case Reports in Urology. [crossref]
  9. Wong SN, Lai KL, Chan PF, Chao DVK (2017) Mondor’s disease:sclerosing thrombophlebitis. Hong Kong Med J23: 311-312.
  10. Goldman A, Wollina U.Mondor’s (2018) Disease after Aesthetic Breast Surgery: A Case Series and Literature Review. J Ctan Aesthet Surg11: 132-135.[crossref]
  11. Rountree KM, Barazi H, Aulick NF. Mondor Disease. [Updated 2019 May 19]. In: StatPearls [Internet]. Treasure Island (FL):StatPearls publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538282/.

Special challenges related to persecution and imprisonment for Woman in Syria – aspects of neglected problems in the support of survivors

DOI: 10.31038/AWHC.2020313

Abstract

Women are at present experiencing unique challenges in the war in Syria and in neighbouring countries with autocratic regimes, especially in two areas so far at least partly neglected in research and humanitarian interventions. Prisons especially in Syria and Iran are not only a risk factor for the present spread of the present Covid-19 pandemic, but have exposed women to torture, sexual violence, forced disappearances, and other traumatic events, that are further aggravated by factors such as separation, and impact on the family. Perpetrators usually go unpunished. In our paper, we discuss problems and health implication, the context of international human rights and humanitarian standards, and measures to address redress and rehabilitation based on women survivors initiatives qualitative research we had conducted in several countries.

Keywords

human rights, gender, torture, war, forensic medicine, torture, rehabilitation

Imprisonment

Women who are imprisoned because of actual crimes, false allegations or as in Syria and Iran frequently due to political abuse of the legal or prison system, are in an especially vulnerable situation. This is in spite of the fact, that the international community, specifically the UN, has created a framework of special guidelines to protect women. These guidelines are safeguarding women’s humanitarian and human rights during this critical times [1, 2], independent from the reason for their imprisonment. These special rules are in the latest version called the “Bangkok” rules (named after the place where they had been drafted during an international expert meeting). They should be seen as a framework for conditions in all places of detention of women and their accompanying children, in addition to the more general “Minimum Standard Rules for the Treatment of Prisoners” (in the latest, revised version called also the “Mandela rules”). The Bangkok rules include specific provisions for the psychological, physical and medical needs of women such as those related to menstruation, protection against sexual violence, and others, and do not replace but extend the provisions of important further standards such as the Mandela rules or the UN Convention against Torture. Compliance with these rules is supervised by international bodies and organizations, such as the International Committee of the Red Cross, the UN Committee against Torture and the UN Special Rapporteur on Torture. Local NGO networks [1] in Syria have reported seven thousand women detainees, including 435 children, that are detained after arrest or kidnapping. They give also an estimate of about 8 thousand prison survivors with children under 10 years.

Torture is of course the probably most serious human rights offense, and is unfortunately highly common in prisons in many countries such as Syria [3] and Iran [4–6], in spite of an absolute prohibition of all forms of torture in all international standards (7). Torture is permitted under no circumstances whatever, even in national emergencies (such as war, “war on terror” or pandemics like Corona) and as such, the absolute prohibition of torture is a non “non-derogable” human right. Still, the reports of prison visits by the UN parties mentioned above and present scientific research have demonstrated that torture is frequently used [1], specifically to oppress women activists [8]. It frequently includes or is associated also with sexual violence [8], that has been demonstrated to have the most serious long-term psychological impact, in addition to additional physical sequels such as infections [9] or unwanted pregnancies that in turn again themselves lead to severe psychological suffering including increased suicide rates [10, 11]. Besides torture, witnessing atrocities including sexual abuse and torture, or the killing of other inmates, lack of access to health care with resulting chronic health problems, must be expected to contribute to both immediate and long-term physical and psychological suffering [7].

Psychological suffering is not only caused by these factors, but also by the indirect results such as awareness of the impact on the family, the inability to take care of one’s family members during imprisonment and the destruction of one’s professional career,- that is already difficult in many countries for women to maintain [8]. Survivors are also frequently stigmatized in their society and even in their families and in close relationships [7].

Medical doctors and other health care personnel in prisons are by their professional ethical standards obliged to recognize, document, report on and try to stop human rights violations such as torture or inhuman and degrading treatment, but are frequently unwilling or unable to do so [12,13]. This process is explained for example in a joint medical and legal standard by the United Nations, the Istanbul Protocol [14,15]. This task is obviously dangerous for health care professionals and is reportedly frequently neglected in Iran and Syria. In these countries doctors who dare to act are frequently persecute by the authorities [3, 12, 13, 16–19]. The present selective policy of releasing only non-political prisoners in a situation where the COVID 19 pandemic endangers especially prisoners under the adverse prison conditions in these countries must be seen as an aggravated form of persecution, especially as it affects especially political and women activists and imprisoned doctors as observed for example by Amnesty and by prominent Syrian human rights lawyer Anwar Al. Buni [1].

Survivors of human rights abuses but also their family members and communities and health care professionals who take care of them should keep in mind that psychological symptoms resulting from this long list of problems encountered by women in prison are in principal a normal reaction to an abnormal and abusive situation, and not a sign of weakness, stupidity or “madness” even if psychological symptoms in general are stigmatized in a society. The emotional and practical, unconditional support of survivors by their family members, partners and communities is therefore of crucial importance for the recovery of women prison survivors. Justice, redress and compensation, and the protection against future abuse are also important factors for psychological recovery (“therapeutic justice”), though in the face of the limited options of international bodies it might take a principal regime change to achieve this aims, that promoted by international organizations such as “Redress” in the UK.

In regard to psychological reactions, posttraumatic stress disorder (PTSD) related to specific events during imprisonment, such as torture, with intrusive memories, repeated nightmares, loss of normal sleep, anxiety, and avoidance of normal activities, is the most common specific reaction observed in many survivors [7, 11]. Depression [7] is also common, and both psychological reaction patterns can become illness with severe impact on the life of the survivor and indirectly also on other family members, which can mean that support might not be enough, but treatment by psychotherapy or for limited time by medication might be required. This would best be provided by specialized experts, in if possible multi-disciplinary treatment centers that have been set up in many countries. Chronic abuse of tranquilizers, pain medication, and, in some countries even alcohol or other drugs can be part of ill advised self help and are complications of the prison related reactive symptoms [7].

Further problems include chronic pain, especially in joints, as head-ache, or pain in the genital area, sexual problems especially after sexual violence or rape [6], and problems with blunt brain injuries after beatings, falls, or after having been pushed against walls and against objects [20–22].

Missing persons

The uncertain fate of those imprisoned and of other family members that frequently become “missing persons” forever, is an additional stress factor in this situation, also for those not imprisoned themselves that are “indirect victims”. Groups of persons listed as “missing” also of course include those abducted by both state actors as well as non-state actors, such as ISIS/DAESH, but also those killed in the war or (inter)national armed conflict.

Taking care of the surviving relatives of missing persons, mothers, wives, siblings and children, is a special challenge to be addressed especially in regions with a high number of missing persons such as Syria. Information on those who have been killed under torture, or died because of factors related to bad prison conditions, including COVID-19, by extra -legal executions, or also in war action, is frequently seen as an important supportive factor to provide psychological closure, and numerous forensic projects have been implemented to provide forensic evidence of persons killed, especially by the International Committee of the Red Cross. This is substantially supported by recent developments in DNA analysis [23] and new databases [24]. The special services of “naming the dead” of course also are a basis for accountability of perpetrators, and for the recovery of community history [25]. The identification of those killed and the circumstances of their deaths play an important role in transitional justice. This last process is often necessary to address and make public what has happened, and find a solution to offer justice to victims in the face of the often large numbers of perpetrators present in the aftermath of widespread human rights violations such as in Rwanda, Iran, or Syria.

In qualitative research we have conducted through focus groups with altogether 80 survivors in countries such as Peru and Uganda(26), three factors (categories) have been identified that surviving family members of those killed in prisons or massacres describe as helpful in psychological healing:

  1. confirmation, that it actually happened (which is important, as responsible governments or parties frequently deny that abuses ever happened, and in turn blame family members for false allegations of the government being responsible for disappearances),
  2. confirmation, that the action leading to the death was incorrect and not justified,
  3. Confirmation, that all steps will be taken, that it doesn’t happen again (which might include persecution of the perpetrators and an end to impunity).

International organizations such as the International Committee of the Red Cross (ICRC) have at least since the second world war developed strategies for the forensic identification of those missing persons killed, but also for those still alive, and recently have made use of the Internet and social networks to collect and distribute information on living survivors [1] bringing families and loved ones together again even in disorganised situations such as the war in Syria. While the identification of victims killed and discovered for example in mass the action leading to the death was incorrect and not justified in fact be an important factor in recovery and closure, psychological support should always be offered in addition to notification of victims identified on their manner of death. It must take into consideration that the process of mourning is usually a longer and complex one and re-confrontation with this type of information is not helpful in all steps of this process.

In general, mutual support and solidarity between direct and indirect survivors, is probably the most efficient supportive tool to be provided, as exemplified in the historical movement of the “mothers” (“madres de la plaza mayo”) (now grandmothers) in Argentine [27]. Similar organizations have now been set up by women prison survivors in Syria [2] to provide information, testimony and other forms of support in a critical situation. This has the benefit of reconfirming an active identity that does not depend on help received from third parties, well intentioned as it that might be. Further, new strategies such as “Universal Jurisdiction” have been developed, that provide for the option that criminal charges against perpetrators will be brought to third countries courts, for example in Europe, in a situation where a fair process, investigation or an international court cannot yet be implemented in a country where atrocities happened, as presently in Syria or Iran [28]. This process is intended to address the issues of impunity, redress, and serve the prevention of further abuses [29–31].

Conclusions

Imprisonment of women, especially of political activists and human rights defenders, should be closely monitored by independent bodies.

In cases where it constitutes part of political persecution, it should be stopped immediately especially in countries like Syria and Iran, where violations of human rights standards are common or even extreme.

Consistent support and protection for individuals but also survivor NGOs are a task also for the international community, especially in a situation where those imprisoned are suffering from sexual abuse and torture, and further are in prison endangered by selective exposure to COVID-19 pandemic. A comprehensive understanding of the problems and solutions as outlined in this article should in our opinion guide this process.

Acknowledgement

We are grateful to the Syrian Women’s International Initiative (Detained women’s) initiative for advice and information on the situation in Syrian prisons and to Nobel woman’s initiative for additional input.

References

  1. Sawasdipanich N, Puektes S, Wannasuntad S, Sriyaporn A, Chawmathagit C, Sintunava J, et al. (2018) Development of healthcare facility standards for Thai female inmates. Int J Prison Health. 14: : 163–74.
  2. Paynter MJ (2018) Policy and Legal Protection for Breastfeeding and Incarcerated Women in Canada. J Hum Lact 34: 276–81.
  3. Torture and ill treatment in Syria’s prisons. Lancet 388(10047): 842.
  4. Dehghan R (2018) The health impact of (sexual) torture amongst Afghan, Iranian anad Kurdish refugees: A literature review. Torture 28: 77–91.
  5. Busch J, Hansen SH, Hougen HP (2015) Geographical distribution of torture: An epidemiological study of torture reported by asylum applicants examined at the Department of Forensic Medicine, University of Copenhagen. Torture 25: 12–21.
  6. Mirzaei S, Hardi L, Wenzel T (2011) How to combat torture if perpetrators are supported by a religious “justification”. Torture 21: 173–7.
  7. Wenzel T (2007) Torture Curr Opin Psychiatry. 20: 491–6.
  8. Alsaba K, Kapilashrami A (2016) Understanding women’s experience of violence and the political economy of gender in conflict: the case of Syria. Reprod Health Matters 24: 5–17.
  9. Todrys KW, Amon JJ, Malembeka G, Clayton M (2011) Imprisoned and imperiled: access to HIV and TB prevention and treatment, and denial of human rights, in Zambian prisons. J Int AIDS Soc 14: 8.
  10. McColl H, Higson-Smith C, Gjerding S, Omar MH, Rahman BA, Hamed M, et al. (2010) Rehabilitation of torture survivors in five countries: common themes and challenges. Int J Ment Health Syst 4: 16.
  11. Wenzel T, Griengl H, Stompe T, Mirzaei S, Kieffer W (2000) Psychological disorders in survivors of torture: exhaustion, impairment and depression. Psychopathology 33: 292–6.
  12. Torture in Syria’s hospitals. Lancet 378(9803): 1606.
  13. Jones P (2019) Medical involvement in torture in Syria. Torture 29: 77–9.
  14. Robertson BW, Berger CE (2019) Interpreting Evidence of Torture. Med Law Rev 27: 687–95.
  15. R JH, Lin J, Modvig J, Nee J, Iacopino V (2019) The Istanbul Protocol: A global stakeholder survey on past experiences, current practices and additional norm setting. Torture 29: 70–84.
  16. Iran denies medical care to quell dissent (2012) Lancet. 379(9827): 1691–2.
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  20. Keatley E, d‘Alfonso A, Abeare C, Keller A, Bertelsen NS (2015) Health Outcomes of Traumatic Brain Injury Among Refugee Survivors of Torture. J Head Trauma Rehabil 30: E1–8.
  21. Mollica RF, Chernoff MC, Megan Berthold S, Lavelle J, Lyoo IK, Renshaw P (2014) The mental health sequelae of traumatic head injury in South Vietnamese ex-political detainees who survived torture. Compr Psychiatry 55: 1626–38.
  22. Keatley E, Ashman T, Im B, Rasmussen A (2013) Self-reported head injury among refugee survivors of torture. J Head Trauma Rehabil 28: E8-E13.
  23. Turingan RS, Brown J, Kaplun L, Smith J, Watson J, Boyd DA, et al. (2019) Identification of human remains using Rapid DNA analysis. Int J Legal Med.
  24. Hofmeister U, Martin SS, Villalobos C, Padilla J, Finegan O (2017) The ICRC AM/PM Database: Challenges in forensic data management in the humanitarian sphere. Forensic Sci Int 279: 1–7.
  25. Ubelaker DH, Shamlou A, Kunkle AE (2019) Forensic anthropology in the global investigation of humanitarian and human rights abuse: Perspective from the published record. Sci Justice 59: 203–9.
  26. Wenzel Tea (2020) Tools in transitional justice in human rights violations In: Wenzel T, Alksiri, R., editor. Women, safety and health in Asia. Cambridge Scholars Press: Newcastle
  27. MGB (2002) Revolutionizing Motherhood: The Mothers of the Plaza de Mayo. London: Rowman & Littlefield Publisher
  28. Wenzel T, Alksiri, R (2020) Folter und Menschenrechte im interdisziplinären Rahmen. In: Six-Hohenbalken M, editor. Vulnerabilität in Fluchtkontexten. Wien: Verlag der Akademie der Wissenschaften

Online Resources

https://www.unodc.org/documents/justice-and-prison-reform/Bangkok_Rules_ENG_22032015.pdf

https://www.ohchr.org/Documents/Publications/training8Rev1en.pdf

https://www.penalreform.org/issues/prison-conditions/standard-minimum-rules/

An Uncommon Cause of Bilateral Pulmonary Nodules in a Long-Term Smoker

DOI: 10.31038/IMROJ.2020512

Abstract

Pulmonary Langerhans Cell Histiocytosis (LCH) in adults is a rare disease and no precise epidemiological data are available concerning its prevalence. Bilateral diffuse nodular infiltration without cystic changes could be one of the Langerhans Cell Histiocytosis (LCH) presentation depend on the stage of evolution of the process. We are reporting in this case an early possible manifestation of LCH that can mimic other wide deferential diagnosis especially among smokers.

Keywords

Smoking related lung disease, Interstial lung disease, Langerhans cell histiocytosis, Smoking

Case Report

58-year-old Irish male with previous medical history of psoriasis, which is controlled on topical treatment, was referred by his GP for Chronic cough and abnormal chest Xray. Patient gave history of chronic dry cough for the last 2 years. No dyspnea or wheezing and his mMRC score was Zero. Review of system was negative for weight loss, hemoptysis, joint pain or night sweat. Significant history of 80 pack-year smoking. Negative exposure to TB or asbestoses.

On examination, his temperature was 36.9°C, his blood pressure was 121/82 mmHg and his oxygen saturation was 97% in room air. There was no evidence of clubbing. No palpable lymphadenopathy. Normal breath sound.

Initial chest Xray showed multiple nodular densities in the both lungs. All his blood tests were normal, including: liver, renal function, calcium, white cell count, hemoglobin, platelet count, Anti-Nuclear Antibody (ANA), Anti-Neutrophil Cytoplasmic Antibodies (ANCA), Erythrocyte sedimentation rate (ESR) and ACE level. Quantiferon was negative.

Pulmonary Function test showed: FEV1: 92% (2.95L), 106% (4.2L), FEV1/FVC: 68%. Lung volumes: RV 116%, TLC 104%. DLCO 82% Kco 88%.

Urgent CT chest (figure 1a) showed: Innumerable predominantly less than 1cm pulmonary nodules in both lungs. The largest nodule in the left lower lobe 7mm.No significant hilar or mediastinal lymph nodes.

IMROJ-5-1-502-g001

Figure 1a. CT chest View.

Given his extensive smoking history, the likelihood of these abnormalities representing metastatic solid organ malignancy was very high. Other differential diagnoses to be considered include: multiple abscesses, septic emboli, fungal infection, non-inflammatory conditions like sarcoidosis, pneumoconiosis and inflammatory conditions like rheumatoid arthritis.

Bronchoscopy with BAL was done and that was negative for bacterial and MTB culture with normal differentials.

After Respiratory MDM discussion, CT guided biopsy of 7mm nodule in the left lower lobe was done. The core biopsy showed foci of perivascular and peribronchiolar interstitial cellular infiltrate of histiocytic cells with moderate amounts of pale cytoplasm and irregular nuclei. Also present were prominent eosinophils and some small lymphocytes. The large histiocytic cells were strongly positive for S100 and CD1a (figure 1b) and for Langerin confirming the morphological impression of Langerhan’s Cell Histiocytosis.

IMROJ-5-1-502-g002

Figure 1b.The histiocytic cells are positive for CD1a which also highlights the perivascular distribution of the infiltrate.

Discussion

Pulmonary LCH in adults is a rare disease and no precise epidemiological data are available concerning its prevalence. Pulmonary involvement with LCH can be observed in patients of any age. Systemic forms of the disease are usually seen in infants and children and pulmonary involvement is often not a prominent feature [1]. In contrast, isolated pulmonary LCH occurs predominantly in young adults with a peak frequency between 20 and 40 years of age. Patients with pulmonary LCH also tend to be heavy smokers [2, 3]. Approximately two thirds of patients present with respiratory symptoms, usually a dry cough, often associated with dyspnea on exertion [4].

The abnormalities seen on the chest radiograph are generally bilateral and symmetrical .More commonly, bilateral widespread cystic lesions may be identifiable.

The most striking characteristic on HRCT of this patient was bilateral diffuse nodular infiltration without cystic changes. That raises another presentation of pulmonary LCH depend on the stage of evolution of the process. Serial studies of individual patients with pulmonary LCH indicate that the lesions evolve as follows: nodules in early stage, cavitary nodules, thick walled cysts then thin walled cysts in late stages [5, 6].

References

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Does a commensal relationship exist between coronaviruses and some human populations?

DOI: 10.31038/JMG.2020323

Abstract

Coronaviruses enter lung tissue via the ACE2 receptor, which varies structurally among human populations. In particular, the Chinese population has fewer variants that bind weakly to the coronavirus S-protein. This global variation suggests that the ACE2 receptor has coevolved with different environments, some of which have favored susceptibility to infection of lung tissue by coronaviruses. It has been argued that respiratory viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases, like tuberculosis, pneumonia, and pneumonic plague. This preventive effect has been shown withother viral pathogens, notably γherpesvirus 68 and cytomegalovirus. Some human populations may have therefore gained protection from severe respiratory infections by becoming more susceptible to mild respiratory infections, such as those normally caused by coronaviruses. This commensal virus-host relationship would have been especially adaptive wherever respiratory pathogens could easily propagate, i.e., in crowded environments, where manypeople live in proximity not only to each other but also to animal sources of infection. In regions that have long had crowded environments, natural selection may have favored susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly pulmonary diseases.

Keywords

ACE2, China, coronaviruses, respiratory viruses, tuberculosis


Coronaviruses were not considered highly pathogenic until the emergence of SARS in 2002. Although previous strains could be highly infectious, the infection itself was normally mild, i.e., a common cold. The current “novel” strain has raised concern because it is as contagious as the common cold but much more pathogenic.

Coronaviruses infect lung tissue via the ACE2receptor. This receptor varies structurally among human populations, notably in its ability to bind to such viruses and facilitate their entry into lung tissue. A study of 1,700 alleles in the ACE2 gene region found major differences in allele frequency not only between Asians and other human groups but also between different Asian groups. In particular, the Chinese population has fewer alleles that code for weak binding to the coronavirus S-protein [1]. Different ACE2 alleles are also associated with differences in susceptibility to diabetic retinopathy, an eye disease with a distinct global pattern of prevalence: 22% in Italy, 23% in China, 30% in the United Kingdom, and 40% in the United States [2].

Chinese lung tissue may therefore be especially susceptible to coronavirus infection, although the evidence remains controversial. One study, after identifying certain cells with high concentrations of the ACE2 receptor, showed that such cells were over five times more numerous in the lung tissue of an Asian donor than in the lung tissue of Euro American or African American donors; however, the entire sample had only one Asian donor [3]. Another study failed to find significant differences in ACE2 gene expression between Asian and Caucasian lung tissue [4]. Both studies suffer from the broadness of the term “Asian,” which covers a wide range of populations that differ from each other in many ways, notably in the structure of the ACE2 receptor.

Ethnic differences are also suggested by data on the prevalence of bronchiectasis, which is often caused by respiratory viruses [5]. In the United States, the prevalence is 2.5 to 3.9 times higher among Asian Americans than among Euro or African Americans [6]. Again, the term “Asian” is problematic. A high prevalence has likewise been found in Korean adults [7].

While it is not surprising that some human populations have adapted to the presence of certain pathogens by becoming more resistant, the population in this case has become less resistant, as if it actually benefits from infection by respiratory viruses. Some immunologists have suggested that such viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases, like tuberculosis, pneumonia, and pneumonic plague [8]. This preventive effect has been shown with other viruses. When mice are infected with γherpesvirus 68, which is similar to Epstein-Barr virus, there is production of large quantities of IFN-γ and activation of macrophages that protect against subsequent infection by Listeria monocytogenes, Mycobacterium tuberculosis, and Yersinia pestis [9,10]. Infection with cytomegalovirus likewise protects against Listeria monocytogenes and Yersinia pestis [9]. Other viruses may have similar commensal relationships with human hosts, but little is still known about the benefits the host would gain from their presence [11,12]. Recent work suggests that commensal viruses contribute to intestinal health [13].

Some human populations may have therefore gained protection from severe respiratory infections by becoming more susceptible to infection by coronaviruses, which are normally mild in their effects. This commensal virus-host relationship would have been especially adaptive wherever respiratory pathogens posed a major threat to health. As one team of researchers suggested: “human γHV-infection may be an important but unrecognized factor which modifies TB [tuberculosis] outcome, particularly in high TB burden countries where most children acquire EBV [Epstein-Barr virus] by 3 years of age” [10].

Tuberculosis has historically caused much mortality, particularly in crowded social environments:

Crowd diseases are generally highly virulent and depend on high host population densities to maximize pathogen transmission and reduce the risk of pathogen extinction through exhaustion of susceptible hosts. Many crowd diseases emerged during the Neolithic Demographic Transition (NDT) starting around ten thousand years ago (kya), as the development of animal domestication increased the likelihood of zoonotic transfer of novel pathogens to humans, and agricultural innovations supported increased population densities that helped sustain the infectious cycle. The marked expansion of MTBC [Mycobacterium tuberculosis complex] during the NTD, but not during earlier human expansion events, suggests that the success of this pathogen was primarily driven by increases in human host density, which is typical of crowd diseases [14].

Tuberculosis became prevalent at an early date in China, approximately six to eleven thousand years ago [14]. This time frame is consistent with China’s expansion of agriculture, domestication of animals for food, and emergence of large communities. In a crowded environment, where many people live in proximity not only to each other but also to animal sources of infection, natural selection would favor different ways to boost the immune response of lung tissue. One way would be to increase susceptibility to mild respiratory infections, such as those normally caused by coronaviruses. This commensal relationship may explain why China was less affected by the Spanish flu of 1918-1920 [15]. Since that time, the Chinese population may have unknowingly become less resistant to severe respiratory infections because mild respiratory infections have become less prevalent, through improvements in public health and reduction of household size.

This kind of gene-culture coevolution probably happened not only in China but also in other regions with a long history of animal domestication and crowded environments, such as the Indo-Gangetic Plain, the Fertile Crescent of the Middle East, and the Mediterranean Basin [16]. In all of these regions, natural selection may have increased susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly respiratory pathogens.

Perhaps this commensalism explains why COVID-19 has been more severe in southern Europeans than in northern Europeans. One might expect the opposite: the severity of infection would increasewith increasing latitude. After all, arespiratory virus should be more contagious under conditions of lower temperature, lower humidity, and lower solar UV. Northern Europeans, however, have coevolved with animal domestication and crowded environments for a shorter time.The virus may be more contagious among them, but its entry into lung tissue is not facilitated to the same extent.

References

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  4. Cai G. (2020) Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov.medRxiv2020.02.05.20020107
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