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Influenza, HIV, Coronavirus: Limited/Incomplete Sustained Response to Therapy?

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DOI: 10.31038/MIP.2020115

 

The three viruses addressed in this opinion/review have in common that their genetic material is RNA and is single stranded.  Viral taxonomists do not consider HIV an RNA virus, as it has a DNA intermediate in its replication cycle and it is therefore referred to as a retrovirus.  Generally, RNA viruses have exceedingly high mutation rates compared to DNA viruses because the enzyme required for polymerization — RNA polymerase —does not possess the proofreading capability of DNA polymerase.  Because of this fallibility it is difficult to make effective vaccines for diseases caused by RNA viruses.  Retroviruses, in specific HIV, possess a high mutation rate even though their DNA intermediate is subject to host DNA proofreading as errors during reverse transcription are associated with both strands of DNA before integration.

For each of these viral entities, transmission through an intermediate animal host has been required to develop human disease.  In the case of influenza — bird or pig; for HIV — monkey; and for the newest COVID agent (SARS-CoV-2) a civet.  For influenza, annual vaccines (sometimes biannual) are available based upon the previous year’s activity.  Their effectiveness varies from year to year and recipient age, ranging between 40-60%. Typically, inactivated influenza vaccines rely on antibody response to achieve protection, while DNA vaccines can effectively interact with humoral and cell-mediated responses.  DNA vaccines for influenza have been in design since the 1990’s but have been slow in development. An advantage of DNA vaccines is that they forego the necessity of live virus reproduction and can be rapidly designed and upscaled to meet ever-changing seasonal variations.  More contemporary seasonal vaccines provide little to no protection against novel pandemic viruses of animal origin.

In the case of individuals who have not been vaccinated against influenza there are four FDA-approved anti-viral drugs recommended by the Centers for Disease Control (CDC).  These antivirals work best when taken within 48 hours of onset of illness to reduce the duration of infection and potentially prevent severe flu complications.

For HIV there are several FDA-cleared anti-retroviral agents (ARTs) and these have the capability to markedly reduce the viral load of infected individuals and extend the life of AIDS patients but they do not eliminate the virus.  HIV can persist at undetectable levels in blood and cryptic tissue sites of infected patients.  Although ARTs were developed early in the investigation of the disease, vaccines were considered the path to follow for eliminating AIDS.  Yet, after more than 30+ years, no vaccine has been developed and trialed with acceptable performance to warrant marketing. In fact, the HIV vaccine study known as ”HVTN 702” which began in October 2016 and was expected to show hints of working was stopped early for absence of efficacy.

For the recently diagnosed severe acute respiratory syndrome labelled COVID-19 caused by coronavirus-2 (SARS-CoV-2) it is too early to reference any effective anti-infective agent or vaccine.  In fact the problem has been complicated by diagnosis and diagnostics – that is a limited supply of viral test kits which are based on the polymerase chain reaction (PCR) to identify individuals with the disease.  Synthetic antibody tests are also in development.  These will do little to diagnose individuals with the disease, i.e. acute cases, but will help clarify questions about the spread of the infection and become an inventory for reagents in vaccine development.

Although the genetic sequence of the virus is known, it will take at least one year to design and trial an effective vaccine and several pharmaceutical companies are working to develop and deliver a vaccine to NIH for early testing.  Currently there is no approved antiviral agent for SARS – CoV-2, although the nucleotide analog, remdesivir has shown antiviral activity against other coronaviruses, namely MERS and SARS.

Clearly, the near universal and lifelong protection that vaccines have achieved with bacterial infections is absent with the three viral agents discussed here. It will require additional research initiatives and monetary investment to reach that goal.

Coronavirus Pandemic: Could Nature’s Bounty Combat the Disease and Other Similar Infections

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DOI: 10.31038/MIP.2020114

 

As the coronavirus epidemic in China continues to spread to other parts of the world, so far infecting at least 98,000 and killing over 3,000 people (6 March 2020; source: www.cbsnews.com), scientists and clinicians all over the world are racing against time to find a treatment. People infected with the novel coronavirus, named COVID-19, have not received a treatment specific to this virus since none yet exists. In-fact, so far no treatment has been approved for any of the coronaviruses known to infect humans. Rather, infected subjects are treated symptomatically with respiratory support, fever reduction, and rehydration; as well as, managing associated complications [1].

Coronavirus infection symptoms range from fever, cough and struggling to breath, to the much more serious cases of acute respiratory distress syndrome, pneumonia, kidney failure and death [2]. People with an already compromised immunity and elderly are considerably at more risk of getting infected with coronavirus and developing severe disease according to the USA Center for Disease Control and Prevention (CDC). A human-to-human transmission occurs through personal contact with an infected person, sneezing, coughing, touching contaminated surfaces and secretions of the mouth, nose or eyes. In very rare cases, transmission via fecal spread may take place. CDC recommends basic hygiene techniques for respiratory viruses such as washing hands regularly, sanitizing surfaces constantly, coughing into one’s arm or a tissue, keeping yourself hydrated and avoiding contact with one’s face or anyone who is sick. Moreover, wearing proper masks, gloves and gowns when dealing with a suspected or infected person.

Viral infections are usually difficult to treat. This is because viruses are very diverse, with unique characteristics, allowing for constant genetic mutations that can impart resistance to available antiviral drugs. Targeting the viruses while not harming human cells can be challenging, since viruses use human cellular mechanisms to form proteins that help it to reproduce [3, 4]. Although some pharmaceutical companies are already working on various possible anti-viral therapies to treat the new coronavirus, it is going to take some time for such drugs to be tested and approved.

Herbal remedies have been documented to cure infectious diseases for almost 2,000 years (5), with more than 10,000 herbal medicines and 100,000 recipes recorded in ancient literatures [6], giving us a very rich source to screen for pharmacological activities. Herbal products have especially been used to treat and inhibit viral respiratory infections (VRI) [5]. Rhinovirus, coronavirus, meta- pneumovirus, para-influenza, adenovirus, enterovirus, respiratory syncytial virus (RSV) and influenza viruses are the major causes of VRI [5]. Herbs tend to exhibit less side-effects and mild cured process as compared to other anti- infection drugs [7]. The benefits of herbs having integral immune-stimulating and inflammation-modulating influence means that they can help inhibit immune over-reaction (cytokine storm) to VRI while still helping the immune system manage better with the infections [8].

Generally, no single herb’s constituent is a solution to VRI, but instead a range of components with diverse actions are needed. Perhaps most important among those are herbs working against the invading viruses directly and improving human immune-system against infections. As such, it seems the circulation and expression of cytokines and their receptors are monitored by various immune connected cells under the stimuli of herbs [9]. For centuries, roots of Pelargonium sidoides have been used for treating diverse illnesses including infections of the airways in the southern Africa region [10–12]. In Germany and some Middle East countries, Pelargonium sidoides extract products such as EPs® 7630 and Plerus®, have been approved and marketed as a therapy for the treatment of acute bronchitis. It prevents the replication of multiple respiratory viruses including respiratory syncytial virus (RSV), seasonal influenza-A virus strains, parainfluenza virus, human coronavirus and coxsackie virus. The underlying beneficial effects of the Pelargonium sidoides extract in bronchitis patients are postulated to include immune-modulatory and cyto- protective effects, prevention of interaction between the infectious agent and host cells and increase of ciliary beat frequency on respiratory cells [10, 12].

Other herbal products have been used as adjuvants for medicinal enhancement. Polygala tenuifolia root extract has been reported to exhibit a robust mucosal adjuvant activity [13]. The active adjuvant substances were isolated and identified as onjisaponins A, E, F and G. Onjisaponins have been shown to enhance the levels of serum antibody and nasal anti-influenza virus IgA and IgG when co-immunized with vaccines for influenza virus compared to inoculation of vaccines alone. In addition, intra-nasal vaccination with onjisaponin F has been shown to reduce the activity of mouse-adapted influenza virus A/PR/8/34 (H1N1) in broncho-alveolar lavages of mice [13]. Another adjuvant remedy, 9S, 12S, 13S-trihydroxy-10E-octadecenoic acid (pinellic acid), which is isolated from the tuber of Pinellia ternate Breitenbach, has been shown as an effective oral adjuvant for the nasal influenza vaccine [14]. As a traditional herb against influenza, the compounds of Astragalus membranaceus have been well researched and the saponins extracted from Astragalus membranaceus significantly enhanced the proliferation of ovalbumin induced splenocyte and antibody titers of ovalbumin specific IgG, IgG1 and IgG2b in serum, demonstrating the effective adjuvant function of saponins [15].

In summary, more translational and clinical studies are required to explore the promising effects of herbal products in the treatment and prevention of viral infections particularly those affecting the respiratory system.

References

  1. McKimm-Breschkin JL, Jiang S, Hui DS, Beigel JH, Govorkova EA, Lee N (2018) Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. Antiviral Res 149: 118–142. [crossref]
  2. Chafekar A, Burtram C Fielding (2018) MERS-CoV: Understanding the Latest Human Coronavirus Threat. Viruses 10: 93.
  3. Fredric S Cohen (2016) How Viruses Invade Cells. Biophys J 110: 1028–1032. [crossref]
  4. White JM, Delos SE, Schornberg K (2008) Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol 43: 189–219. [crossref]
  5. Eric Yarnell (2018) Herbs for Viral Respiratory Infections. Alternative and complementary therapies. 24: 1.
  6. T Li, T Peng (2013) Traditional Chinese herbal medicine as a source of molecules with antiviral activity. Antiviral Research 97: 1–9.
  7. Shen B (2015) A new golden age of natural products drug discovery. Cell 163: 1297–1300. [crossref]
  8. Donkor PO, Chen Y, Ding LQ, Qiu F (2016) Locally and traditionally used Ligusticum species—A review of their phytochemistry, pharmacology and pharmacokinetics. J Ethnopharmacol 194: 530–548.
  9. Wang H, Actor JK, Indrigo J, Olsen M, Dasgupta A (2003) Asian and Siberian ginseng as a potential modulator of immune function: an in vitro cytokine study using mouse macrophages. Clin Chim Acta 327: 123–128.
  10. Brendler T, van Wyk BE (2008) A historical, scientific and commercial perspective on the medicinal use of Pelargonium sidoides (Geraniaceae). J Ethnopharmacol 119: 420–433.
  11. Kolodziej H (2008) Aqueous ethanolic extract of the roots of Pelargonium sidoides – new scientific evidence for an old anti-infective phytopharmaceutical. Planta Med 74: 661–666.
  12. Wang Xiaoguang and Liu Zejing (2014) Prevention and treatment of viral respiratory infections by traditional Chinese herbs. Chinese Medical Journal 127:1344–1350.
  13. Nagai T, Kiyohara H, Munakata K, Shirahata T, Sunazuka T, et al. (2002) Pinellic acid from the tuber of Pinellia ternate Breitenbach as an effective oral adjuvant for nasal influenza vaccine. Int Immunopharmacol 2: 1183–1193.
  14. Yang ZG, Sun HX, Fang WH (2005) Haemolytic activities and adjuvant effect of Astragalus membranaceus saponins (AMS) of the immune responses to ovalbumin in mice. Vaccine 23: 5196–5203.
  15. Shimizu T, Tomioka H, Sato K, Sano C, Akaki T, et al. (1999) Effects of the Chinese traditional medicine mao-bushi-saishinto on therapeutic efficacy of a new benzoxazinorifamycin, KRM-1648, against Mycobacterium avium infection in mice. Antimicrob Agents Chemother 43: 514–519.

Between Evolution, Science and Humanity

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DOI: 10.31038/MIP.2020113

 

The relations of living beings with each other and with nature are dynamic and volatile so that adaptations are an indispensable constant for the maintenance of life. Biological and biochemical beings and structures succumb while others are perfected in an ecological engineering model of highly competitive or collaborative performance according to the survival interests of each one. In this environment, it is more common that the pathogens persist and accumulate itself than be extinguished, demanding from us an increasing capacity to cope or live with these agents.

Since millennial Hansen bacillus to the new Coronavirus, through bubonic plague, Spanish flu and HIV, pathogens are constantly changing and adapting to new ways of life, environmental changes and new prophylactic and therapeutic resources. Thus, the more living beings and nature interact for survival, the more complex these interactions become and the more surprising their effects.

Therefore, even whit the scientific and social progress, we will always need to invest in applied research in microbiology, immunology and pathology. This investment will increasingly require the incorporation of technological progress. The path traveled from the descriptive epidemiology used by John Snow to control the cholera in the city of London in 1854 to the molecular epidemiology for the control of Coronavirus in 2020 proves this statement.

This path was inspired on the relationship model between living beings each other and with nature. It developed from the interaction between traditional epidemiology and molecular biology [1]. It resulted, therefore, in the molecular epidemiology of today, capable of deciphering, in short-term, pathogens involved in diseases outbreaks or in individual diseases, as well as the relationships between these pathogens and the immune system of their victims, and with the therapeutic resources applied against them. Thus, it allows the rapid development of strategies to face the changes and adaptations of the infectious agents that are harmful to humans and other animals.

By deciphering the origin, the phylogeny, the phylogeographic circulation and the potential of interaction of the infectious diseases causative agents among themselves and with the organisms that they infect, molecular epidemiology puts us again in a position to confront the novelties that the new microbiological world presents us. However, for making the technological and scientific advances to have maximum effectiveness and efficiency, it is important that ethnic, social, cultural, political and geographical boundaries are not applied to science and its products. More and more joint international efforts are needed to face the diverse microbiological problems that affect us with a novelty every day. These boundaries are human constructions that are not recognized by nature or by other living beings and can put us at a disadvantage.

This means that it is important to guarantee the access of all people and animals to the applied resource of scientific production through equity principles. Otherwise, we will waste technological advance, subtract efficiency from scientific investment and place ourselves again at a disadvantage in the environment of complex ecological engineering for survival.

References

  1. Honardoost M, Rajabpour A, Vakil L (2018) Molecular epidemiology; New but impressive. Med J Islam Repub Iran. 28: 32–53. [Crossref]

Internal Loop Recording of Prolonged (39 Second) Sinus Pause Causing Syncope

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DOI: 10.31038/JCCP.2020312

Abstract

Presentation: A 53 year old woman presented with a syncopal episode which occurred whilst sitting in bed reading, witnessed by her husband. She was unrousable for maybe half a minute. She had no other medical history, clinical examination was unremarkable, as were multiple investigations.

Diagnosis: A loop recorder was inserted without difficulty. A few weeks later she again blacked out. Her loop recorder showed asystole for 39 seconds, followed by a return to sinus bradycardia and then sinus rhythm, accompanied by recovery of consciousness.

Treatment: She went on to have a dual chamber pacemaker inserted. At review after six weeks, six months and one year she had had no further syncopal episodes.

Conclusion: This case reports one of the longest documented episodes of asystole with spontaneous recovery and serves as a reminder of the utility of internal loop recorders in the investigation of syncope.

Introduction

This case reports a patient with syncope in whom an internal loop recorder revealed one of the longest documented episodes of asystole with spontaneous recovery.

Case Report

A 53 year old woman presented with a syncopal episode which occurred whilst sitting in bed reading, witnessed by her husband. She was unrousable for maybe half a minute. She was a non-smoker, on no medications. Her father had a pacemaker inserted in his 70s, for slow atrial fibrillation; there was no family history of sudden adult death. She had no other clinical history; specifically, nothing to suggest sarcoidosis, haemochromatosis or other deposition disorders. Clinical examination was unremarkable. Multiple investigations, including echocardiography, electroencephalography and Holter monitoring, were essentially normal, as was brain magnetic resonance imaging. A Medtronic Reveal LINQ™ loop recorder was inserted without difficulty. A few weeks later she awoke as usual, went to the toilet, micturated and returned to bed feeling fine. Whilst lying in bed, she again blacked out. She recovered consciousness a while later, and felt nauseated with a slight headache.  That morning she was contacted by the hospital and advised to come in directly. Her loop recorder showed prolonged asystole!  Figure 1. She had gradually developed sinus bradycardia and then sinus arrest. After 39.4 seconds she returned to sinus bradycardia and then sinus rhythm without any compensatory tachycardia. There was no ventricular escape rhythm, simply a sinus pause with no rescue. The next day she was brought to the operating room for pacemaker insertion under local anaesthetic. Just after left subclavian vein cannulation, she had another 20 second pause, though she recovered before external pacing could be initiated. She regained consciousness and went on to have a dual chamber pacemaker inserted, with good thresholds in the right ventricular apex and right atrial appendage. At review after six weeks, six months and one year she had had no further syncopal episodes.

JCCP-2020-303_G. Pate_F1

Figure 1. Internal loop recorder tracing of 39.4 second asystolic pause.

Discussion

Loop recorders have proved very useful in documenting previously unrecognized arrhythmias, particularly intermittent pauses [1]. Current guidelines recommend loop recorder insertion for any unexplained syncope [2]. In the event of documentation of any symptomatic pauses greater than 3 seconds, or nocturnal pauses greater than 6 seconds, pacemaker insertion is recommended [3]. Anything more than 10 seconds is described as a very long pause. Multiple papers have documented pauses of 10 seconds or more [4–7], including one of 44 seconds [8]. During a tilt table test one paper described asystole for 72 seconds [9], but this was a provoked pause and cardiopulmonary resuscitation was commenced so this cannot truly be described as spontaneous recovery of rhythm. Another consideration here was of artefact, a recognized issue with loop recorders [10]. However, the patient’s clinical picture was consistent with the observed pause, she had not been undertaking any activity that might have produced an artefactual pause, and the fact she had another witnessed pause of 20 seconds in the hospital confirm that the observed pause was real.

No cause was identified for her pauses. However, she did not have tilt-table testing, electrophysiological studies or cardiac MRI scanning prior to pacemaker insertion; regardless, management would still have involved pacemaker insertion. This case reports one of the longest documented episodes of asystole with spontaneous recovery and provides a very graphic reminder of the utility of internal loop recorders in the investigation of syncope.

References

  1. Maggi R, Rafanelli M, Ceccofiglio A, Solari D, Brignole M, et al. (2014) Additional diagnostic value of implantable loop recorder in patients with initial diagnosis of real or apparent transient loss of consciousness of uncertain origin. Europace 16: 1226–1230. [Crossref]
  2. Varosy PD, Chen LY, Miller AL, Noseworthy PA, Slotwiner DJ, et al. (2017) Pacing as a Treatment for Reflex-Mediated (Vasovagal, Situational, or Carotid Sinus Hypersensitivity) Syncope: A Systematic Review for the 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 70: 664–679. [Crossref]
  3. European Society of C, European Heart Rhythm A, Brignole M, Auricchio A, Baron-Esquivias G, et al. (2013) 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 15: 1070–1118. [Crossref]
  4. Mairesse GH, Marchand B (2003) Prolonged asymptomatic sinus pause indicated by implantable loop recording. Heart 89: 244. [Crossref]
  5. Zaidi A, Clough P, Mawer G, Fitzpatrick A (1999) Accurate diagnosis of convulsive syncope: role of an implantable subcutaneous ECG monitor. Seizure 8: 184–186. [Crossref]
  6. Deharo JC, Jego C, Lanteaume A, Djiane P (2006) An implantable loop recorder study of highly symptomatic vasovagal patients: the heart rhythm observed during a spontaneous syncope is identical to the recurrent syncope but not correlated with the head-up tilt test or adenosine triphosphate test. J Am Coll Cardiol 47: 587–593. [Crossref]
  7. Menozzi C, Brignole M, Garcia-Civera R, Moya A, Botto G, et al. (2002) Mechanism of syncope in patients with heart disease and negative electrophysiologic test. Circulation 105: 2741–2745.
  8. Kanjwal K, Karabin B, Kanjwal Y, Grubb BP (2010) A case of mistaken identity: asystole causing convulsions identified using implantable loop recorder. Int J Med Sci 7: 209–212.
  9. Leftheriotis DI, Theodorakis GN, Kremastinos DT (2003) Prolonged asystole during head-up tilt testing with clomipramine infusion. Europace 5: 313–315. [Crossref]
  10. Ali H, Sorgente A, Daleffe E, Cappato R (2014) Asystole detected by implantable loop recorders: true or false? Ann Noninvasive Electrocardiol 19: 595–597. [Crossref]

Bladder Necrosis Due to Septic Shock

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DOI: 10.31038/SRR.2020311

Abstract

Background: Chronic constipation leading to fecal impaction and stercoral perforation is an important cause of morbidity and mortality in the aging population. Gangrenous cystitis, an even more rare entity, previously reported primarily in obstetric cases, has not been reported in association with stercoral perforation until this report.

Summary: This case report details the clinical presentation and treatment of a 61-year-old female with history of end-stage renal disease and history of kidney transplantation who presented in septic shock with a positive urinalysis. She underwent an emergent computed topography scan of the abdomen and pelvis which demonstrated a perforation originating from the sigmoid colon. Damage control surgery was performed, the sigmoid colon was resected, and the intestine was left in discontinuity. The abdomen was left open with a temporary abdominal dressing and a catheter for direct peritoneal resuscitation. She returned for a “second look” laparotomy where ischemic bladder tissue was noted. A partial cystectomy was performed, and the bladder was reconstructed over a Foley catheter and her abdomen remained open for continued direct peritoneal resuscitation. Ultimately, the
family determined that this level of care was not consistent with the patient’s wishes and she was made comfort measures.

Conclusion: This is the first report of stercoral perforation of the sigmoid colon in association with gangrenous cystitis in the literature. This case report highlights the importance of a thorough evaluation of the pelvis during surgical management of stercoral perforation so as not to miss concurrent gangrenous cystitis.

Keywords

sepsis, sterocoral perforation, gangrenous cystitis

Introduction

Gangrenous cystitis is a rare condition that has only been reported in the literature a total of 240 times worldwide since 1934. It was once seen in obstetric cases, associated with labor and delivery, but is now most commonly secondary to pelvic radiation/surgery, chemotherapeutic agents, urinary retention, urosepsis, pelvic thrombophlebitis, and colovesical fistulae. The pathogenesis is unknown but is thought to be initiated by bladder ischemia that is then subject to microbial superinfection [1] . Fecal impaction secondary to chronic constipation can lead to Stercoral Perforation (SP) through pressure necrosis of the large bowel [2]. SP is a well-defined entity in the literature that is associated with significant morbidity and mortality and has also been associated with a prior history of renal transplantation [3]. This case report is the first to identify SP of sigmoid colon as a cause of gangrenous cystitis.

Case History/Examination

The patient is a 61-year-old female with a history of End Stage Renal Disease (ESRD) and remote kidney transplantation, with recent admission to the hospital for intertrochanteric fracture after fall. She was subsequently discharged to a rehab facility after a surgical repair of the fracture. The patient presented to our hospital two weeks later in septic shock. On physical examination she had an altered mental status, she was in respiratory distress, and profoundly hypotensive. The abdominal examination was remarkable for a soft but distended abdomen and a palpable transplant kidney in the right lower quadrant with no peritoneal signs.

Investigations and Treatment

White blood cell count was 11,000 with 94% neutrophils and serum lactate was found to be 6.1 cells per cubic millimeter of blood. A Urinalysis (UA) was grossly positive Urinary Tract Infection (UTI) so the patient was transferred to the Medical Intensive Care Unit (ICU) for suspected urosepsis. The patient was intubated and fluid resuscitation along with empiric broad spectrum antibiotics were initiated. An emergent Computed Tomography (CT) scan of the abdomen and pelvis was obtained and showed radiological evidence of perforated viscous, most likely from the sigmoid colon (Figure 1).

SRR 20 - 101_Joshua A Bloom_F1

Figure 1. CT scan of the abdomen and pelvis showing significant stranding and multiple locules of air outside the bowel lumen in the left lower quadrant adjacent to the sigmoid colon and along the left paracolic gutter.

An emergent surgical consult was obtained and the patient was taken immediately to the operating room for exploratory laparotomy. Upon entry to the abdomen, there was foul smelling, turbid fluid and an ischemic, dilated proximal sigmoid colon was encountered. A stercoral perforation of the sigmoid colon on the mesenteric border into the retroperitoneum was noted. The left side of the retroperitoneum had a large amount of necrotic tissue extending into the pelvis.

A damage control surgery was performed. The sigmoid colon was resected, and the intestine was left in discontinuity. The left side of the retroperitoneum and pelvis were opened, and debridement of the necrotic retroperitoneal tissue was performed. A 19 Fr blake drain was placed intra peritoneally for direct peritoneal resuscitation [4, 5]. At the end of the case, the patient was transferred to the Surgical ICU for further resuscitation and correction of metabolic abnormalities.

Postoperatively, the patient’s hemodynamics improved transiently, and vasopressor requirement did decrease somewhat but her serum lactate level continued to rise. With a new elevation of serum lactate the patient was taken to the operating room for a “second look” laparotomy approximately 24 hours later. No further bowel ischemia or necrosis was noted. There was still a significant amount of retroperitoneal necrotic tissue, especially in the pelvis. Further dissection into the pelvis did reveal a 7 cm cystostomy with ischemic bladder tissue mostly on the left side with clear demarcation of ischemic changes. There was some ischemia of the right side of the bladder as well. A Urology and Transplant Surgery consultation were obtained due her history of kidney transplant.

Outcome and Follow-Up

A multidisciplinary discussion resulted in the decision to perform a partial cystectomy and not explant the donor kidney. All of the obvious necrotic tissue was then resected, and the bladder was reconstructed over a Foley catheter. Afterwards, since the patient still was in a profound state of shock, the patient’s bowel was left in discontinuity, the abdomen was temporarily closed, and the patient was transferred back to the Surgical ICU for further management.

The next day the patient underwent a planned relaparotomy with abdominal wash out and temporary abdominal closure. No further areas of bowel or bladder necrosis were noted. Due to the patient’s extensive comorbidities and lack of improvement over the following 48 hours as well as the extent of the care she would continue to require, the family felt this was not consistent with her wishes and elected to make her comfort measures. The patient passed away shortly thereafter.

Discussion

This is the first case report of bladder necrosis due to stercoral perforation of the sigmoid colon. With no literature to guide us, it is difficult to make absolute conclusions, but we believe that the stercoral perforation into the retroperitoneum led to an inflammatory reaction and local infection around the bladder leading to ischemia and gangrenous cystitis.

In the literature, there are numerous causes of bladder necrosis published, mostly in the pre-antibiotic era. These causes include prolonged labor, pelvic radiation, chemotherapy, urinary retention, urosepsis, and pelvic thrombophlebitis to name a few. In these published cases, the mainstay of treatment has been early antibiotic therapy and surgical treatment with extensive debridement of necrotic bladder and wide drainage [6, 7].

In this case report, we differed from the traditional management in that we performed a damage control laparotomy with temporary abdominal closure and direct peritoneal resuscitation. This strategy allowed for source control in the OR and rapid transfer to the ICU for further resuscitation and correction of metabolic abnormalities. This provided our patient with the best chance of survival. Ultimately, it was her wishes that she would not want to live if she were not guaranteed to return to her former quality of life, and she was made comfort measures. However, we believe that she most likely would have survived this hospitalization had this been in line with her wishes.

Conclusion

Whether this patient’s bladder necrosis was due to her stercoral ulcer or her septic shock remains unclear as the literature is equally vague regarding both topics. However, surgeons should be aware of this phenomenon and while operating on the bowel emergently for perforation, should take the time to assess the pelvis, especially in patients with a grossly positive urinalysis.

Lessons Learned

Stercoral perforation of the sigmoid colon leading to septic shock can be associated with gangrenous cystitis and necessitates a thorough evaluation of the pelvis while operating on this entity.

References

  1. De Rosa A, Amer T, Waraich B, Bello A, Parkinson R (2011) Gangrenous cystitis in a 42-year-old male. BMJ Case Reports  2011: 1–4. [Crossref]
  2. Chakravartty S, Chang A, Nunoo-Mensah V (2013) A systematic review of stercoral perforation. Colorectal Disease 15: 930–935. [Crossref]
  3. Dubinsky I (1996) Stercoral Perforation of the Colon: Case Report and Review of the Literature. Journal of Emergency Medicine 14: 323–325. [Crossref]
  4. Rai R, Sikka P, Aggarwal N, Shankaregowda SA (2015) Gangrenous Cystitis in a Woman Following Vaginal Delievery: An Uncommon Occurrence -A Case Report. Journal of Clinical and Diagnostic Reasearch 9: 13–14.
  5. Smith JW, Neal Garrison R, Matheson PJ, Harbrecht BG, Benns MV, et al. (2014) Adjunctive treatment of abdominal catastrophes and sepsis with direct peritoneal resuscitation: indications for use in acute care surgery. J Trauma Acute Care Surg 77: 393–398 [Crossref]
  6. Hinev A, Anakievski D, Krasnaliev I (2010) Gangrenous Cystitis: Report of a Case and Review of the Literature. Urologia Internationalis 85: 479–481. [Crossref]
  7. Piraprez M, Ben Chehida M, Fillet M (2017) Case Report: Emphysematous cystitis. Red Med Liege 384–387.

Bronchoscopy: A not-so-innocent invasive examination

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DOI: 10.31038/NAMS.2020311

Abstract

Bronchoscopy has for many years been the only invasive examination used to screen for bronchus in real time, remove objects that have entered the airway, healing properties, and finally a sample including missing tissue for biopsy for the right follow up medical evaluation and treatment. The usual examination is performed by a flexible bronchoscope which does not cause much discomfort to the patient and causes few complications, complications such as bleeding, cardiac arrhythmias, fever, pneumonia, death, introduction and exacerbation of infection, etc.

This short research is about to overturn this nice and enjoyable environment that has been created regarding the safety of this invasive examination that will eventually and happily very soon be replaced. The present short research is here to overthrow the benefits of bronchoscopy and present the reality as this has not been presented to patients before undergoing an invasive examination that may not eventually need to be done.

Dedication: This short research is dedicated to my Father Panagiotis, who recently died.

Keywords

bronchoscopy, hemoptysis, death, complications, pneumonia

Introduction

Very easily, mainly after a CT scan, a PET/CT has appeared in our lives to improve the quality of imaging data, also including the case but not always the lack of knowledge, recommend that patients undergo an invasive bronchoscopy. that the diagnostic process in short time will end, and the patient is transferred to the next stage of treatment, but if the patient never reaches the treatment stage and is instead hospitalized with complications? according to the literature, it is reported that bronchoscopy is performed by an experienced physician, how can the patient know if the physician is experienced or not?

How can the patient know if during the examination they will not contribute to the examination and trainees which is prohibitive in certain coexisting lung diseases where particular experience is required, such as a patient with bronchectasis, COPD, tec, who they need bronchoscopy from a very experienced physician. Is the procedure is followed of informing the patient prior to bronchoscopy about the pros and cons of the examination as well as their complications? Finally, is it worth doing a bronchoscopy which, depending on the clinical picture of the patient, may eventually have the opposite effect? bronchoscopy is not for everyone.

Analysis

Bronchoscopy is an invasive examination performed in public and private hospitals as well as in private diagnostic centers and clinics. Before conducting the examination blood tests are performed, including blood and cardiology tests, so, how many tests for a diagnostic examination that is considered safe? The complications that it presents contradict the advantages, advantages that in cases depending on the severity of the patient are disadvantages.

Advantages that become disadvantages when one of the following reasons are met.

  1. Inexperienced Invasive physician
  2. Bronchoscopy by trainees (depends on case).
  3. Inexperienced staff.
  4. Hygiene conditions.
  5. Disinfection, cleaning, and sterilization of a bronchoscope.
  6. The clinical picture of the patient.
  7. Consideration of medical examinations to avoid bronchoscopy.
  8. Inform the patient about the complications of bronchoscopy.

When one or more of the above is not observed, then the patient is at high risk, as the complications of the bronchoscopy examination can cause the patient even more serious damage than the disease itself led the patient to bronchoscopy. What safe examination are they talking about?

Is there a mortality rate of about 0.5% these patients were aware of the complications? Should they have done bronchoscopy? have the hygiene rules been adhered to or fallen into a category of the above 8 listed? Although international literature indicates guidelines for safe bronchoscopy examinations, does the patient know whether the guidelines are being followed?

One of the major complications of bronchoscopy is bleeding, ranges for example from low 10ml to 150ml which is very high. It is a serious complication that needs to be addressed immediately since its origin is complex, it can come from many areas such as pulmonary capillaries, pulmonary arteries, pulmonary veins, and finally large thoracic vessels. Bleeding is directly related to the biopsy, in most cases bronchoscopy is performed to obtain a biopsy, an experienced physician in a burdensome patient with a history who knows before, noted here the bronchoscopy requires the patient to hold already a CT, which will require a CT scan. is the one who will judge it must be done, if it is to be done, to pay attention, what requires observation, coexisted, possible complications, time of examination in relation to the severity of the patient, the participation of trainees or not, and how to get a sample.

There are two types of sample deficiencies: endobronchial and transobronchial biopsy, transobronchial biopsy causes the patient and most bleeding, here is a big question, in patients with bronchiectasis, or similar medical cases that usually occur in these medical cases colonies and bacteria such as pseudomonas aeruginosa that are usually resistant to antibiotics, a transobronchial biopsy is responsible for burdening the patient’s clinical picture? Thus, correlated the bleeding with the number of biopsies and how they were obtained. Considering the fact that patients with congenital diseases, medicines that are taken for various important reasons, a bleeding can reach or exceed 40% depending on the case of patients undergoing bronchoscopy. So why should they do a bronchoscopy? The treating physician should be able to judge the overall picture of the patient in order to be able to make a correct diagnosis, taking into account patients with a poor medical history considering the negative aspects of a bronchoscopy, however, bronchoscopy is an invasive risk examination depending on the patient’s physical condition and medical history. Bronchoscopy examination is not for everyone.

It is concluded that the bleeding of the patient after bronchoscopy implies with further clinical progress, although the incidence of sudden death is small as has been mentioned above. Small bleeding can be easily treated large bleeding to stop may require laser and even surgery, the patient must consider all options and exhaust all parameters. It is worth considering whether it is worth the effort, pain and risk to perform a bronchoscopy examination that no one can guarantee his or her physical situation after the examination is completed.

Most complications that have occurred during the examination or thereafter have to do with how to obtain and receive biopsy material. Such cases are brushes that have broken down or have not worked properly. Continuous aspiration during the examination may lead to hypoxemia and atelectasis. Pseudomonas aeruginosa is the most frequently transmitted organism from an inappropriate bronchoscope (see above 8 reasons) which has not been properly disinfected and cannot be used. Using such a bronchoscope is a criminal act against the patient. During bronchoscopy, patients have been observed to have increased blood pressure and increased heart rate, this is due to increased oxygen demand from the myocardium which may then lead the patient to arrhythmias and ischemia. Cardiac arrhythmias that occur after bronchoscopy confess hypoxemia. Particularly in COPD patients with hypercapnia hypoxia is contraindicated for flexible bronchoscopy. It is worth noting at this point that complications of bronchoscopy often occur when there are concomitant diseases such as pneumonia or tumor, as well as the type of forceps to be used, that is toothed or non-serrated forceps. In patients with chronic bronchiectasis, the physician should consider all indications for the overall picture of the patient and whether or not to perform the bronchoscopy. It is the physician that will analyze the patient’s respiratory function and the degree of criticality. It should also be borne in mind that some patients with infections will need antibiotics after bronchoscopy, these patients likely to need antibiotics that will be able to deal with germs and bacteria that are resistant. These patients are more likely to develop febrile episodes as well as critical respiratory function.

The physician is solely responsible for analyzing the pros and cons, it is the one who weighs the benefit of the risk. Patients with bronchiectasis should not be bronchoscopied by trainees or by physicians who rarely perform bronchoscopy. When these patients show haemoptysis, the detection of bleeding is crucial. Finally, bronchoscopy in COPD patients is particularly burdensome compared to non-COPD patients, COPD patients should be evaluated on the findings of their clinical trials together with medical evacuation before performing the bronchoscopy. Assessment of potential advantages over advantages must be evaluated.

Conclusion

Bronchoscopy is a conditional safe examination when all safety rules are met, medical evaluation is performed separately for each patient, each patient is different. Bronchoscopy is not for all patients, generally described as a safe invasive examination but with so many complications that there are people who have had a bronchoscopy and have not returned home, is this safe medical examination they say? it is not a safe medical examination, it is a safe conditional examination, evaluating the clinical picture of the patient in combination with the degree of experience of the physician and the clinical picture of the patient judging its effectiveness.

Patients with co-existing health problems should be assessed for the advantages of screening in conjunction with screening complications. Physicians should not be dragged into the altar of the rapid effect of detecting the problem by undergoing bronchoscopy in patients who are not allowed to do a bronchoscopy based on physical or medical pre-existing health conditions. It is a medical examination with uncertain complications sometimes simple, sometimes heavy and sometimes deadly.

Classical bronchoscopy has begun to come to a second myrrh as soon as virtual bronchoscopy is implemented and thus the complications of classical bronchoscopy will be eliminated. Bronchoscopy should be chosen as a medical examination after all other medical examinations and methods have been utilized and under conditions based on the clinical picture of the patient, in strict compliance with the hygiene guidelines.

References

  1. Kovaleva J, Peters FT, van der Mei HC, Degener JE (2013) Transmission of infection by flexible gastrointestinal endoscopy and bronchoscopy. Clin Microbiol Rev 26: 231–254. [Crossref]
  2. Pereira W Jr, Kovnat DM, Snider GL (1978) A prospective cooperative study of complications following flexible fiberoptic bronchoscopy. Chest 73: 813–816. [Crossref]
  3. Kreider ME, Lipson DA (2003) Bronchoscopy for atelectasis in the ICU: a case report and review of the literature. Chest 124: 344–350. [Crossref]
  4. Trouillet JL, Guiguet M, Gibert C, Fagon JY, Dreyfuss D, et al. (1990) Fiberoptic bronchoscopy in ventilated patients. Evaluation of cardiopulmonary risk under midazolam sedation. Chest 97: 927–933. [Crossref]
  5. Hanson RR, Zavala DC, Rhodes ML, Keim LW, Smith JD (1976) Transbronchial biopsy via flexible fiberoptic bronchoscope; results in 164 patients. Am Rev Respir Dis 114: 67–72. [Crossref]
  6. Da Conceiçao M, Genco G, Favier JC, Bidallier I, Pitti R (2000) Fiberoptic bronchoscopy during noninvasive positive-pressure ventilation in patients with chronic obstructive lung disease with hypoxemia and hypercapnia. Ann Fr Anesth Reanim 19: 231–236. [Crossref]

Relationship between polycystic ovarian syndrome (PCOS) and fatty liver disease

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DOI: 10.31038/EDMJ.2020413

Abstract

Background – Polycystic ovarian syndrome (PCOS) and fatty liver disease are considered to be off-shoots of insulin resistance. However, the link between the two disorders have recently been found to be variable.

Objective – To explore the association of fatty liver disease with PCOS and to model the association of hyperandrogenism, obesity and insulin resistance indices among subjects with or without PCOS and fatty liver disease.

Methodology – This study was carried out between Jan-2018 to Aug-2019 at PNS HAFEEZ hospital. Odds ratio (OR) for having PCOS with fatty liver disease were calculated. We utilized general linear model (GLM) by keeping hyperandrogenism, abdominal volume index (AVI) and insulin resistance as dependent variables against PCOS and fatty liver disease as independent factors.

Results – OR for having PCOS in subjects with fatty liver disease was 1.34(95%CI: 1.34(0.868-2.065). Using Free Androgen Index(FAI) as dependent variable and fatty liver and PCOS as fixed factors in a GLM analysis, the group wise differences are depicted as: Group-1: No Fatty liver+No PCOS=2.37(+1.30),n=97), Group-2: No PCOS+Fatty Liver=3.35(+2.23),n=66), Group-3: PCOS+No Fatty Liver=6.08(+5.05),n=88), and Group-4: PCOS+Fatty Liver=6.83(+4.70),n=80).(p<0.001). Abdominal obesity was not associated with PCOS (p=0.980), but was significantly associated with fatty liver disease (p<0.001).

Conclusion – Presence of fatty liver disease in females can lead to slightly higher frequency of PCOS. Biochemical and clinical hyperandrogenism were associated with presence of PCOS, while abdominal obesity and insulin resistance were linked with fatty liver disease.

Keywords

Polycystic ovarian syndrome (PCOS), free androgen index (FAI), modified Ferriman-Gallwey score (mFG score), fatty liver and Rotterdam PCOS criteria.

Background

Lipids are considered as the mainstream culprits in pathogenesis of development of polycystic ovarian syndrome (PCOS) and fatty liver disease. [1, 2] Therefore the probability based upon the famous “Common Soil Hypothesis” dealing in directly with metabolic syndrome suggest a common linkage between the two pathogenic disorders. [3] Both PCOS and Fatty liver disease amounts to multiple complications. PCOS has been shown to result in hirsutism and reproductive issues. [4], while fatty liver disease is associated with acceleration liver damage leading to cirrhosis and hepatocellular carcinoma (HCC). [5]

While the mechanism seems more understandable in terms of extra fat accumulation within liver but some evidence indicates PCOS phenotype variability does allow differential association with fatty liver disease. Macut et al have shown that subjects having higher serum testosterone, a hallmark of PCOS are associated with a two-fold increased risk of fatty liver. [6] Rocha et al in their systematic review from 2007 to 2017 highlighted that prevalence of PCOS with NAFLD remains variable, but the combined presence of PCOS and NAFLD results in higher degree of clinical and biochemical hyperandrogenism than the female subjects only demonstrating PCOS with former category more associated with metabolic derangements. [7] Contrary to that there is evidence where both fatty liver disease and PCOS are associated and attributed to common pathogenesis. The research work by Vassilatou et al have demonstrated that lipid based abnormalities are central to the development of PCOS and NAFLD; however, he categorized data from PCOS patients as either being obese or otherwise. [8] Similarly, Kauffman et al have demonstrated that PCOS and NAFLD can occur due to common pathogenic mechanisms including androgen excess and insulin resistance. [9, 2]

So, the obvious question arises as to how fat accumulation or associated metabolic defects differentially affect the two organs? While PubMed data search indicates both fatty liver disease /NASH/NAFLD and PCOS both being the off-shoots of insulin resistance, [10] still there are both genetic and epigenetic  mechanism at work which can probably change the overall phenotype of metabolic syndrome and related diseases. In this regard a study from Poland had identified GG genotype variation to result in higher frequency of NAFLD in PCOS than PCOS subjects without Cannabinoid Receptor-1 gene polymorphism thus highlighting genetic predilections towards PCOS-fatty liver occurrence. [11] Similarly, Jones et al have identified higher risk of fatty liver disease with hyperandrogenism associated PCOS in comparison to female subjects having reduced hyperandrogenism independent of insulin resistance. [12] Bruce et al by highlighting the concept of “Metabolic Circadian Clock System” have attempted to highlight epigenetic factor from environmental triggers which change the phenotypic presentation of metabolic syndrome, and thus can be interpreted indirectly as the effect of regional effects or ethnic triggers. [13] Another aspect of this is the adipocyte size which has been shown to result in variability in hepatic steatosis [14], which have been smaller but with increase adipocyte area in Asian population than Caucasians and so the affect could be due to specific racial reasons [15]. So racial differences due to variability adipocyte area, genetic factors and epigenetic influences need to be considered and may probably be different in whatever has been observed elsewhere. Based upon these newly emerging evidence a compelling need was therefore felt to learn the association between the PCOS, fatty liver disease and androgenicity which were supposedly to be associated due to common trigger i.e., insulin resistance.

A study is therefore planned to explore the association of fatty liver disease, PCOS and hyperandrogenism by estimating the hirsutism, anthropometric, biochemical and endocrine differences (Free androgen index) between subjects with fatty liver associated PCOS and non-fatty liver PCOS.

Methods

We planned a cross-sectional analysis among reproductive-age female subjects after formal approval of hospital’s ethical review committee of PNS HAFEEZ Hospital. The study involved department of radiology, pathology, obstetrics and gynecology. The duration of study was 18 months from Jan-2018 to Aug-2019. Females in reproductive age post 2 years of menarche were initially included as target population. Patient selection was based non-probability convenience mode of sampling. Females who some acute or chronic conditions including pelvic inflammatory disease, metabolic diseases like hypertension, diabetes and ischemic heart disease, autoimmune disorder, on any medication, fertility treatment, or other unknown drugs were excluded from the study. Subjects who could not complete all testing formalities for any reason were excluded from the study. Finally selected females were formally requested to visit pathology department on 2nd day of menstrual cycle Subjects who finally followed up for study in medical fasting were formally

explained about study design, requirements and were asked to sign a consent form. Further clinical evaluation included history, evaluation of hirsutism as per modified Ferriman-Gallwey scores [16], anthropometric measurements, vital signs measurements and a generalized clinical examination for any signs of chronic disease. They were questioned about duration of menstrual cycle for presence or absence of oligo/anovulation as per criteria utilized by Kollmann et al. [17]

Radiological and laboratory analysis: 10 ml (approx.) of blood was collected for fasting plasma glucose, ALT, HbA1c, total testosterone, Sex Hormone Binding Globulin (SHBG) and serum insulin and lipid profile. Following sample collection, females were requested to go for radiological examination for evaluation of reproductive tract examination for presence or absence of polycystic ovarian syndrome as per Rotterdam criteria [18]

Lab analysis and measurements: Fasting plasma glucose, total cholesterol and triglycerides were measured on Selctra-ProM (Clinical chemistry analyzer) by GPO-PAP, CHOD-PAP and GPO-PAP method. LDL-cholesterol and HDL-cholesterol were measured by direct enzymatic methods using accelerator selective detergent on Selectra-proM. ALT was measured by IFCC method at 370C. Total testosterone, SHBG, glycated hemoglobin were analyzed by using chemiluminescent microparticle Immunoassay (CMIA) on ARCHITECT (iSystem) developed by Abbot Diagnostics. Serum insulin was measured on Chemiluminescence method on Immulite® 1000 analyzer. Internal and National External Quality Assurance Program are in place to monitor inter and intra lab imprecision along with internal QC management for precision and accuracy by documented trouble shooting on instrument generated charts as per Westgards’s standard protocols.

Calculated parameters – Free Androgen Index (FAI) was measured as: FAI = (Total testosterone/SHBG) x 100. FAI > 5%was greater than 5% was termed as biochemical hyperandrogenism as per Al Kindi et al. [19] Homeostasis Model Assessment of Insulin resistance (HOMAIR) was measured using Mathew’s et al mathematical model. [20]

Data analysis – We used SPSS-version 24 for statistical analysis. Age was calculated as per mean and SD by descriptive statistics. Descriptive statistics for frequency of PCOS, hirsutism and fatty liver disease % were calculated for subjects with or without fatty liver disease. Inferential statistics involved calculation of Odds Ratio for presence of PCOS as per Rotterdam criteria in subjects with or without fatty liver disease. We utilized General linear models (GLM) where we evaluated sequentially FAI, mFG scores for hirsutism, abdominal volume index (AVI) and insulin resistance (HOMAIR) as dependent variables against presence or absence of PCOS and fatty liver disease as fixed factors.

Results

Mean age among subjects with Rotterdam defined PCOS was (26.71+ 6.99, n=168) and without PCOS was (29.07+ 8.11, n=163). Similarly subjects who had fatty liver had a mean age of (30.95+7.10, n=146) in comparison to females without fatty liver [25.45+7.17, n=185). 236 females in our data set were married, while 95 were non-married. Hirsutism was diagnosed in 157 females while 174 were having a modified FG score of less than 8. 88/185 (47.57%) of the cases without fatty liver disease were diagnosed with PCOS, while 80/146 (54.79%) of cases diagnosed to have fatty liver disease had PCOS indicating no statistically significant association between presence of PCOS and fatty liver disease in our regional data set. Odds ratio (OR) for having PCOS in subjects with fatty liver disease is 1.34 but not statistically significant. (Table-1)

Table 1. Odds ratio for presence of PCOS as per Rotterdam criteria in subjects with fatty liver disease (p=NS).

PCOS

Odds Ratio

(Rotterdam criteria)

(95 % CI)

NO

YES

Fatty liver diagnosed

Fatty liver not

97

88

185

on ultrasonography

diagnosed

1.34

Fatty liver

66

80

146

(0.868-2.065)

diagnosed

Total

163

168

331

Keeping free androgen index (FAI) as dependent variable with PCOS and fatty liver disease as fixed variables indicates a definite increase in FAI due to presence of PCOS which get slightly worsened with the presence of fatty liver depicted as: Group-1: No Fatty liver + No PCOS= 2.37 (+ 1.30), n=97), Group-2: No PCOS + Fatty Liver = 3.35(+

2.23), n=66), Group-3: PCOS + No Fatty Liver = 6.08 (+ 5.05), n=88), and Group-4: PCOS + Fatty Liver = 6.83 (+ 4.70), n=80). Figure-1 shows a General Linear Model (GLM) with FAI being a dependent variable is evaluated against independent variables i.e., presence or absence of PCOS (p<0.001) and fatty liver disease (p=0.035) demonstrating that PCOS presence is more associated with increase in biochemical hyperandrogenism than fatty liver disease. (Overall Model significance<0.001). Similarly, hirsutism as measured by mFG scores was not significantly related to fatty liver disease but was associated with presence of PCOS. [Figure-2] Abdominal Volume Index (AVI) as a measure of abdominal obesity was not associated with PCOS, but was significantly associated with fatty liver disease. [Figure-3] Furthermore, insulin resistance as a dependent variable was seen to rise more with the presence of fatty liver in comparison to PCOS. [Figure-4]

Sikandar EDMJ_f2

Figure 1. General Linear Model (GLM) where FAI being a dependent variable is evaluated against independent variables i.e., presence or absence of PCOS (p<0.001) and fatty liver disease (p=0.035). (Overall Model significance<0.001).

Sikandar EDMJ_f3

Figure 2. General Linear Model (GLM) where mFG score as surrogate markers for hirsutism being a dependent variable is evaluated against independent variables i.e., presence or absence of PCOS(p <0.001) and fatty liver disease(p=0.820). (Overall Model significance<0.001).

Sikandar EDMJ_f4

Figure 3. General Linear Model (GLM) where Abdominal Volume Index (AVI) as a marker for abdominal obesity being a dependent variable is evaluated against independent variables i.e., presence or absence of PCOS (p=0.980) and fatty liver disease (p<0.001). (Overall Model significance<0.001).

Sikandar EDMJ_f5

Figure 4. General Linear Model (GLM) with insulin resistance as dependent variable and presence or absence of PCOS (p=0.157) and fatty liver disease (p<0.001) as independent variables (Overall Model significance<0.001).

Discussion

Polycystic ovarian syndrome (PCOS) and fatty co-occurrence in study subjects was slightly higher than subjects with having one of the pathology, implying a very weak association between the two entities. Though the OR for presence of PCOS in subjects with fatty liver disease was above i.e., 1.34 but it was not statistically significant. Our data identified free androgen index and hirsutism to be more associated than fat deposition within liver as factors in contributing polycystic ovarian pathology. Furthermore we identified increase in AVI i.e., as a surrogate for abdominal fat deposition and insulin resistance to be more associated with presence of fatty liver disease than with PCOS. The trend, hence identified a strong link for insulin resistance in causation of fatty liver disease and hyperandrogenism for PCOS. Contrary to our findings the data from some studies have highlighted a stronger link between obesity an insulin resistance markers with as common culprits in associating fatty liver and PCOS. [7, 8, 10, 11].

Macut et al have also identified a much higher combination diagnosis of PCOS and fatty liver disease than presence of a single pathology in Serbian population. [21] Coming to our data in terms of finding a weaker link it is important to understand that lean PCOS types are well-recognized in sub-continental population. [22] More so as Pande et al evaluated obesity and insulin resistance indices in these lean category of PCOS and observe them to be dissimilar than obese PCOS subjects, where the latter group were found to have more metabolic derangements.

[23] Similar to that Chinese have results quite similar to ours, where BMI and NAFLD were minimally associated with PCOS females. [24] Even some European studies have found a higher percentage of up to 40% lean-PCOS in their studies. [25] However, if we study the western population a contrast appear where insulin resistance and higher trunk fat mass clearly supersedes the Asian PCOS phenotype. [26] Therefore regional differences and possible epigenetic triggers can be attributed to the differential or minimal relationship between fatty liver disease and insulin resistance in subjects with PCOS.

Possible understanding of authors on this minimally existent relationship between PCOS and fatty liver disease in our data subjects is being explained below: Firstly, we described in the introduction that adipocyte size variation between Asian and Caucasian population, so possibly smaller adipocyte among Asians with capacity to accumulate more fat led to lesser abdominal volume indices and fatty liver disease in our data of female subjects. [15, 24] The argument therefore can be made that these most often obese-PCOS phenotypes females had higher insulin resistance due to increase fat mass and least contributed by hyperandrogenism. [26] However, we as author feel more interventional trials can clarify the real causation of PCOS and in specific its relation with abdominal and hepatic steatosis. Secondly, what impact the weather, environment and lifestyle could lead to aforementioned variation of PCOS patterns? We highlighted earlier the findings of

Bruce et al who described the role of environment in causing variable PCOS phenotypes. [13] A Spanish study by Concha et al evaluated the epigenetic marks by analyzing miRNAs and histone methylation in various body fluids and tissues to conclude a very strong impact of environmental triggers in association

with development of PCOS. [27] Pursuant and related directly to epigenetic mechanisms Monniaux et al was able to demonstrate in ovine fetuses that over exposure of follicular and uterine tissues may lay the foundation stone for a possible PCOS phenotype. [28] Finally, dietary patterns may be a significant contributor to PCOS as studies on gut microbiome had a different phylogenetic type along with lower density than control female subjects. [29] Thus shifting diet patterns from traditional and more natural food consumption to refined and high caloric diets could be an add on, if not causative factor in leading to PCOS development. We, therefore believe with globalization and mixing of people and in specific adopting western style diets and life styles the disease pattern may change overtime tilting more in favor of obese-phenotype. [30]

Certain limitations regarding our cross-sectional analysis needs to be taken into account: Firstly, we did this study in hospital-setting and our findings must be extrapolated to an epidemiological level to understand PCOS and its phenotype prevalence within our community. Secondly, we feel certain cultural barriers persist in our community due to lack of basic medical education and history. Provided our questionnaire format was structured and no language barrier was there still we interpret and this aspect to cause some degree of bias.

This study has important clinical implication especially in backdrop of wide regional and racial variation PCOS phenotypes. Taken the study setting and cross-sectional design the study can be further replicated to validate phenotypes of PCOS prevailing at broader level. Thus more data should follow this study project. However, this article does provide a broader guideline in terms of interpreting and segregating PCOS phenotypes within our population, which can help treating physicians to specify their treatment options in a more personalized manner. On a national scale the data also highlights the need for local guidelines for our community using this data and evidence from surrounding regions.

Conclusion

Presence of fatty liver disease in females can lead to slightly higher frequency of PCOS. Biochemical and clinical hyperandrogenism were more associated with presence of PCOS than with fatty liver disease, while abdominal obesity and insulin resistance were more often than not associated with fatty liver disease in comparison to PCOS.

Declarations

  • The data sets and SPSS outputs used and/or analyzed during the current study are available from the corresponding author on formal request.
  • Ethical approval – The study “Relationship between polycystic ovarian syndrome (PCOS) and fatty liver disease” was approved by ethical committee of the hospital. All participants were volunteer and provided “written consent” for the study.
  • Author’s contributions – SHK: (Author for all Correspondence) Study plan, Involved in study plan, involved in sampling, methodology, lab analysis, data analysis, manuscript writing. SA: History collection, data analysis, and contributed towards discussion. RS: Radiological diagnosis of PCOS, Defining PCOS as per criteria, manuscript writing. RM: Initial patient history collection and examination, defining oligo/anovulation, data analysis, manuscript writing. RA: Patient examination, history writing, anthropometric measurements, manuscript writing. TC: Study plan, methodology, manuscript writing. Final manuscript was approved by all authors.
  • Consent for publication: Signed consent was sorted from all study participants.
  • Competing interests – There are no competing interests to declare.
  • Data funding – The study had no funding source to disclose.
  • Acknowledgements – The authors acknowledge the work of Miss Huma, and Lab technician Ibrahim and Iftikhar for the support.

Abbreviations

Fatty liver disease, Polycystic ovarian syndrome (PCOS), Free Androgen Index (FAI), Homeostasis Model Assessment for Insulin Resistance (HOMAIR), Modified Ferrimen Gellwey (mFG) score, Abdominal Volume Index (AVI).

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Effect of Glucose Oxidase on the Cytokine Profile and Cholesterol of Monocytes in Liver Cancer

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DOI: 10.31038/MIP.2020112

Abstract

Introduction: Cancer has an extremely important human and socio-economic impact. It is due to several cellular disturbances causing uncontrollable proliferation, which stimulate immune system elements including monocytes that can play a dual role either in the elimination or progression of cancer cells [1], these disturbances affect a variety of functions such as glucose metabolism [2].

Keywords

Liver cancer, Monocyte, GOx, Cytokines. Cholesterol

Objectives

This work hopes to investigate the effect of glucose oxidase at the level of the monocyte on the tumor growth thus determining its impact on the glycolysis activity and on the mitochondrial metabolism.

Aim: The aim of this study is to show the role of GOx in the polarization of monocytes in contact with tumor cells.

Materials and methods

Monocytes isolated from the blood of the cancer patient were co- cultured with the tumor epithelial cells isolated from a biopsy of the liver cancer, in a culture medium supplemented or not with GOx.

Results

GOx induced an increase in the INF-γ and decrease of IL-10 as well as in NO and Arginase in the presence of Glucose oxidase compared to thus without GOx, the Cholesterol in microenvironment was decreased in presence of GOx.

Conclusion

In conclusion, our results showed an pro-inflammatory effect was reported in monocytes in contact with liver tumor epithelial cells.

References

  1. Elliott LA, Doherty GA, Sheahan K, Ryan EJ (2017) Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity. Front Immunol 8. [Crossref]
  2. Annibaldi A, Widmann C (2010) Glucose metabolism in cancer cells. Curr Opin Clin Nutr Metab Care 13: 466-470. [Crossref]

Biomarkers of Oxidative with Colorectal Cancer

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DOI: 10.31038/MIP.2020111

Abstract

The number of   colorectal cancer increases regularly every year in Algeria and precisely in Tlemcen. It is a disease involving several genetic, hormonal, professional, environmental, but also behavioral factors, namely nutrition, the objective is to evaluate the nutritional and lipid profile on the one hand and some oxidative parameters of And to determine the relationship that may exist between nutritional factors and oxidative stress in patients with this type of cancer.

Keywords

Oxidative Stress, Colorectal Cancer

Materials and Methods

Thirty-three patients with newly diagnosed colorectal cancer were recruited from the Department of Gastroenterology, C.H.U. (CL, HDL-LC, LDL-CL, TG) and the oxidative status (ORAC, Catalase, Vitamin C, MDA) of Tlemcen and thirty-five healthy controls.

Results

A very significant difference was observed for patients with liver cancer compared to ORAC controls (1, 143 ± 0.121) (0, 4197 ± 0.0456) p <0.000; MDA (0, 2400 ± 0.0492) (0, 083 ± 0.0275) P <0.008; Catalase (1.385 ± 0.162) (0, 588 ± 0.219) p <0.008; LDL-CHOL (0.4300 ± 0.0239) (1. 0692 ± 0.0627 p <0.000, on the other hand no difference was observed for Vitamin C (0.221 ± 0.0465) (0, 1947 ± 0.0889) p <0.615 HDL-CHOL (0.4300 ± 0.0322) (0.466 ± 0.031) p <0.355.

The balance of the oxidizing / antioxidant status is a primary factor in oncology. The free radicals can lead to the appearance of mutations and, conversely.

References

  1. Golbidi S, Laher I (2010) Antioxidant therapy in human endocrine disorders. Med Sci Monit 16: 9–24.
  2. Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol 1: 173–179. [Crossref]