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Tuesday, 30 May 2017

Septicemia and Shock: Pathogenesis and Novel Therapeutic Strategies

Septicemia and Shock: Pathogenesis and Novel Therapeutic Strategies
   Authored By
Beharampore, Murshidabad, West Bengal, India
2] 7/51 Purbapalli PO -Sodepur District 24 Parganas(north) West Bengal Kolkata-70001 India
[3] Swamiji Road , South habra District 24 Parganas(north) West Bengal Kolkata-70001 India
 [4]  B K Mitra Palliative care unit  Barrackpore District 24 Parganas(north) West Bengal Kolkata-70001 India 
Email-:  profpkb@yahoo.co.in     Mobile -9231510435


 Abstract and  research data/ result and analysis not given for this article here much intentionally to prevent plagiarism unless and untill  published in a high index journal
 [ NEJM] sent and in review process now t 

 The overall mortality in patients with sepsis is approximately 30%; this figure increases to 50% or greater in patients with septic shock, and sepsis continues to be seen as a major clinical challenges in ITU  or ICU or CCU .  Sepsis is usually associated with exacerbated production of both pro- and anti-inflammatory cytokines, which are detectable within blood .These “half-angel/half-devil” properties are fully illustrated in sepsis. While the cytokines are a prerequisite to fight infection, their overzealous production is also deleterious for patients. The highest levels of cytokines  are found in plasma of non-surviving patients from sepsis : can they be markers and causative agents of poor outcome in severe sepsis? . Only, the level of the chemokine “RANTES” is inversely considered as  associated with the APACHE II score and with poor outcomes. The link, interplay and network of cytokines taking place during sepsis are illustrated by the correlations between the levels of most pro- and anti-inflammatory cytokines. Excessive release of anti-inflammatory cytokines may be according to myself  associated  also with the immune dys-regulation observed in sepsis. However, despite the presence of huge amounts of anti-inflammatory cytokines and molecules targeting specifically interleukin-1 (IL-1) (i.e. IL-1 receptor antagonist) and tumor necrosis factor (TNF) (i.e. soluble TNF receptors), there is no indication that their levels are sufficient to fully counteract these pro-inflammatory cytokines. TNF was initially thought to be the “hub of the cytokine network”. Although TNF contributes to favor the production of many other cytokines within a complex cascade, there are numerous examples, which illustrate that its presence is not a prerequisite for these productions.     It is acknowledged that severe sepsis/ or septic shock is a major problem in clinical  bed side medicine,  and yet the extent of the problem and its basic immunology remains poorly defined to us. The problem of sepsis is further complicated by the remarkably diverse spectrum of illness encompassed under the term “sepsis”. Sepsis may  range in severity from mild systemic inflammation without significant clinical consequences to multi system failure(MODS)  as in septic shock with an exceedingly high mortality rate. Sepsis also connotes a clinical syndrome that may occur in any age group, in markedly different patient populations, and in response to a multitude of microbial pathogens from multiple different anatomic sites within the human body.
Although protocols could be tailored by each hospital, all the protocols a required to include a 3-hour bundle consisting of receipt of the following care within 3 hours: obtaining of a blood culture before the administration of antibiotics, measurement of the serum lactate level, and the administration of broad-spectrum antibiotics. Protocols are also required to include a 6-hour bundle, consisting of the administration of a bolus of 30 ml of intravenous fluids per kilogram of body weight in patients with hypo tension or a serum lactate level of 4.0 mmol or more per liter, the initiation of vasopressors for refractory hypotension, and the re measurement of the serum lactate level within 6 hours after the initiation of the protocol.  An association between time to treatment and outcome among patients with sepsis or septic shock treated in the emergency department during a state wide initiative mandating protocolized care.  It is found that a longer time to completion of a 3-hour bundle of care for patients with sepsis and the administration of broad-spectrum antibiotics were each associated with higher risk-adjusted in-hospital mortality.  A recent meta-analysis of 11 observational studies, however, showed no significant mortality benefit of the administration of antibiotics within 3 hours, as compared with after 3 hours, after triage in the emergency department (odds ratio, 1.16; 95% CI, 0.92 to 1.46) or within 1 hour after the recognition of shock (odds ratio, 1.46; 95% CI, 0.89 to 2.40).[1]. There  may be several biologic explanations for the association between the time to completion of a 3-hour treatment bundle and outcome of sepsis. First, more rapid the administration of antibiotics it reduces pathogen burden, modifies the host response, and could reduce the incidence of subsequent organ dysfunctions. Second, clinicians who decide more quickly to measure the serum lactate level may identify heretofore unrecognized shock and are more prepared to deliver lactate-guided resuscitation than clinicians who are slower to measure the serum lactate level — a strategy that may improve outcome in randomized trials.[2]  Third, physicians have broad variation in how they identify sepsis, even when they are presented with similar cases.[3] Fast delivery of sepsis treatment, even within the structure of mandated protocols, requires a prompt clinical suspicion of both infection and worsening organ dysfunction.
 Broad spectrum Antibiotics are essential to the treatment of bacterial sepsis as they reduce the bacterial burden. The impact of bacterial resistance found to be very important in a range of conditions. Resistance to antibiotics can be defined genotypically, phenotypically and clinically through pharmacokinetic/pharmacodynamic studies and their correlations with clinical outcomes. Although the kinetics of antibiotics has been shown to be favorably altered in sepsis, a range of studies in sepsis has revealed that for most pathogens resistance contributes to significant increases in mortality. This has been clearly demonstrated in bacteraemia, including community- and hospital-acquired infections, and with bacteraemia caused by vancomycin-resistant enterococci, methicillin-resistant staphylococci, and extended-spectrum producing gram-negative bacterias. Significant mortality increases have also been seen with ventilator-associated pneumonia and serious infections requiring admission to intensive care. Gentotypic and phenotypic resistance in coagulase-negative staphylococci causing bacteraemia, and in invasive pneumococcal disease has not shown differences in mortality. In the latter case, dosage regimens have to date been adequate to overcome laboratory-defined resistance. Early indications are that de-escalating therapy from broad-spectrum initial coverage after results of cultures and susceptibility tests become available does not jeopardise outcomes, and further prospective studies are warranted. There is now convincing evidence that broad-spectrum initial therapy to cover the  likely pathogens and their resistances pending culture results is mandatory in sepsis to minimise adverse outcomes.

Monocytes/macrophages play  also a key role in host defense mechanism  by phagocytosing invaded pathogens, or in  presenting antigens to immune cells, and producing numerous inflammatory  cytokine mediators. Expression of many proteins and genes  is  up regulated  in activated human monocytes, a whole picture of pathophysiologic function of activated human monocytes has not yet been drawn. Serial analysis of gene expression (SAGE) procedure when  are used  to lipopolysaccharide (LPS)-stimulated human monocytes  more than 12,000 different transcripts can be sequenced. In addition, the Long SAGE can be used in LPS-stimulated monocytes to increase the accuracy of corresponding gene identification. Comparison of gene expression profile with that of resting monocytes revealed the whole LPS-inducible gene expression profile. The functional classifications of LPS-inducible genes( greater than 8 fold increase compared with resting monocytes) in monocytes showed that 25% of inducible genes were identified to encode cytokines and chemokines, followed by proteins related to metabolism (11%), cell surface antigens (9%), nuclear proteins (8%), proteases (6%), proteins related to extracellular transport (4%) and intracellular transducers (4%). Moreover, 14% of LPS-inducible genes still encode proteins with unknown function.
HMGB1 is a member of the high mobility group protein super family that had been widely studied as nuclear proteins that bind DNA, stabilize nucleosomes, and facilitate gene transcription. Surprisingly, a series of recent discoveries revealed a cytokine activity of HMGB1, that when secreted into the extracellular milieu, mediates downstream inflammatory responses in endotoxemia, arthritis, and sepsis. HMGB1 is properly defined as a "cytokine" because it stimulates pro inflammatory responses in monocytes/macrophages, is produced during inflammatory responses in vivo in standardized models of systemic and local inflammation, mediates delayed endotoxin lethality, and is required for the full expression of inflammation in animal models of endotoxemia, sepsis, and arthritis. HMGB1 is either actively secreted by monocytes/macrophages or passively released from necrotic cells from any tissue. These pathways are central for the biology of HMGB1 as a cytokine, since they provide key mechanisms that integrate the inflammatory response to infectious and non-infectious cell injuries. Receptor signal transduction of HMGB1 occurs in part through the receptor for advanced glycation end-products (RAGE) expressed on monocytes/ macrophages, endothelial cells, neurons, and smooth muscle cells. HMGB1 is a “late-acting” cytokine, because it first appears in the extracellular milieu 8-12 hours after the initial macrophage response to pro-inflammatory stimuli. Knowledge of the cytokine role of HMGB1 has implications for understanding "downstream" cytokine cascades, regulation of delayed innate immune responses, and targeting treatment towards these processes. Effectiveness of delayed treatment with HMGB1 blockade up to 24 hours after induction of experimental sepsis offers a unique window of opportunities to allow rescue from lethal sepsisHMGB1 is a member of the high mobility group protein super family that has been widely studied as nuclear proteins that bind DNA, stabilize nucleosomes, and facilitate gene transcription. Surprisingly, a series of recent discoveries revealed a cytokine activity of HMGB1, that when secreted into the extracellular milieu, mediates downstream inflammatory responses in endotoxemia, arthritis, and sepsis. HMGB1 is properly defined as a "cytokine" because it stimulates proinflammatory responses in monocytes/macrophages, is produced during inflammatory responses in vivoin standardized models of systemic and local inflammation, mediates delayed endotoxin lethality, and is required for the full expression of inflammation in animal models of endotoxemia, sepsis, and arthritis. HMGB1 is either actively secreted by monocytes/macrophages or passively released from necrotic cells from any tissue. These pathways are central for the biology of HMGB1 as a cytokine, since they provide key mechanisms that integrate the inflammatory response to infectious and non-infectious cell injuries. Receptor signal transduction of HMGB1 occurs in part through the receptor for advanced glycation end-products (RAGE) expressed on monocytes/ macrophages, endothelial cells, neurons, and smooth muscle cells. HMGB1 is a “late-acting” cytokine, because it first appears in the extracellular milieu 8-12 hours after the initial macrophage response to pro-inflammatory stimuli. Knowledge of the cytokine role of HMGB1 has implications for understanding "downstream" cytokine cascades, regulation of delayed innate immune responses, and targeting treatment towards these processes. Effectiveness of delayed treatment with HMGB1 blockade up to 24 hours after induction of experimental sepsis offers a unique window of opportunities to allow rescue from lethal sepsis
The recent success of several important trials has fuelled interest in further therapeutic developments. Here, I review the many different strategies that are being investigated, focusing in particular on those that are in late pre-clinical, or early clinical development. These can be broadly divided into three groups: strategies aimed at bacterial targets, strategies aimed at disorders of immune regulation in the host, and finally, other novel strategies based on modifying host response like super antigens . Which, if any, of these will prove successful in large clinical trials is unknown. Nevertheless, the fact that sepsis has finally proved tractable as a target for new drug development lends support to those who believe that at least some of the compounds identified in this paper will prove to have clinical benefit..........(continued  but not published in the blog for safety purpose)  

 Reference
1] Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med 2015;43:1907-191
2] Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752-761
3] Rhee C, Kadri SS, Danner RL, et al. Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case vignettes. Crit Care 2016;20:89-89

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Monday, 29 May 2017

Save Women from Cervical Cancer in Low Middle Income Countries and Middle Income Countries


Professor of Pathology, Murshidabad Medical College, India
Received: April 29, 2015 | Published: May 01, 2017
*Corresponding author: Pranab Kumar Bhattacharya, Professor of Pathology, Murshidabad Medical college, (university of Calcutta) FIC path, Berhampore station road, Berhampore Court, District -Murshidabad, West Bengal, India, Tel: 9231510435; Email: 

Abbreviations

HICS:Incidences Rate Between High; LICS:Low Income Countries; LMICS:Low Middle Income Countries; VIA: Visual Inspections with Acetic Acid; ISH: In Situ Hybridization; IHC: Immunohistology; UN: the United Nations; NCD: Non Communicable Diseases

Editorial

No women should die of cervical cancer in this day and age and yet each year more than 2,60,000 women world wide in Low and middle income countries die of this cancer only. There is dramatic disparity in the incidences rate between high (HICS) and low income countries (LICS) and this disparity is likely to be due to differential access to screening of cervical pre cancerous lesions, treatment facilities available in primary level and taking preventive measures with new HPV-9 vaccines- as use of Human papilloma virus vaccinations continues to be lag in the low middle income countries (LMICS). Dramatic benefits were observed from vaccinations of HPV and early cervical pre- cancerous lesions [1]. The new HPV-9 vaccine which includes 9 or more HPV types there is good chance after several decades cervical cancer screening may no longer be warranted. But that is for the high income countries. What about for LMICS and MICS like India or in West Bengal Province of India? Hundreds and millions of women are already beyond the age of adolescence and age of vaccination and remains without screening and preventive treatment due to lack of human resources like trained pathologists & laboratory technicians as resource personals and this author apprehends that some 25 millions women will die of cervical cancer by next 25 years in MICS and LMICS.
We and government know that successful methods that could reduce the incidence of cervical cancer are Pap smear, colposcopy and biopsy and new 9 HPV vaccines. But women in LMICS has almost nil access to biopsy & Pap smear due to lack of adequate trained pathologists in rural, urban, suburban districts, sub divisional, and state general level public hospitals. The basic tools for cervical screening already exists and getting better and better(new Bethesda classification -2014 thin prep smear fluid based cytology and HPV detection) in high income countries but still out of reach for millions of women in LMC and MICS like India only due to lack of human resources and budgetary allotment by the government.
 One notable advances in screening methods is visual inspections with Acetic Acid (VIA) which allows trained health workers to spot cervical abnormalities with just a speculum examination available even at primary health center (primary care level) of West Bengal , India The high cost bearing but highly sensitive molecular tests by In situ Hybridization (ISH) or by Immunohistology (IHC) that detect HPV infections- is not accessible for remote villages urban semi urban hospitals except in some Medical colleges of West Bengal state as it needs sophisticated laboratory infrastructure like thin prep, monoclonal primary and secondary antibodies or PCR or FISH technology and trained pathologists. However both Visual inspections with Acetic Acid (VIA) and Molecular identifications of HPV are now acceptable screening methods by WHOM also. There has been much improvement in preventive treatment using technologies such as Cryo pen and thermal coagulation and conventional cryotherapy. Advances in the uses of mobile phones for tracking health information and reaching patients and the explosive growth of their availability in MICS and LMICS is another opportunity to improve cervical cancer prevention. So a state or a country must have political will to take advantages of knowledge and technologies to provide sufficient human resources (here pathologists, technicians, health workers) training. Providing budget for in situ hybridization or immunohistology or immunocytochemistry and extending even to primary care or community care. Fortunately in 2017 Government of India included it as national health program in 2017 declared. The United Nations (UN) summit on non communicable diseases (NCD) held in 2011 and listing WHO for screening and treatment of cervical pre-cancerous lesions to prevent cervical cancer is a feasible proposition for LICS and MICS.
Why the LICS are not much interested in the effective cervical, Lung cancer, breast cancer screening diabetes, hypertension, stroke, prostate cancer screening in the national health program? They are enable to in funding in many health issues like eradications of malaria ,dengue, polio, wide spread treatment of HIV –AIDS, 5% reduction of mortality of children, and tobacco control program, malaria dengue vaccine development program when signs of global commitments are emerging in 2015 as five years initiative “ taking cervical cancer Prevention: Protecting all women and girls”.
  1. According this author for the MICS like India has to build
  2.  Efficient screening services and in India and west Bengal provinces of India there is much shortage of Pathologists, laboratory technicians and health workers.
  3. In India the health system is week and both private and public mixed type and private care health system never participate in national health program as there is no profit in this system.
  4. In adequate health information system.
  5. Tracking individual patients is lacking.
  6. Monitor program performance is lacking.
  7. Vaccination campaign in adolescent girls to be done.
  8. Proper training of pathologists to identify pre cancerous lesions in low resource setting if possible by VIA.
 Of course molecular testing like HPV and its sub typing using cervical or vaginal smears form sophisticated laboratories in cities and Medical colleges( all medical colleges do not have this facility yet) after collecting it from rural sub divisional districts hospitals even by self collections from homes or communities by health workers possible and providing HPV 9 vaccinations [9VHPV – a new Vaccine 0,5 ml contains 30ug HPV-6, 40ug HPV 11, 60ug HPV 16, 20ug, HPV 18 virus like particles and 20ug HPV 31, 21ug HPV 33, 20ug HPV 45, 20ug HPV 58 virus like particles] for those who are positive for HPV types 11, 16,18,31 in India is the most effective ways in closing the burden but probably will not be enough effective one because
  1. pathologists/cytopathologists will not be opting for it to work as it becomes too much burden for a pathologists to screen every day hundred slides of Pap cervical smears [from self experiences].
  2. Technicians will not perform ISH and IHC as it takes DNA based technology and time consuming dedicated monoclonal antibody staining requires somewhat like 4-5 hours time unless there is automated immuostainers are provided.
  3. There will be cultural barrier for women to test PaP smear and biopsy.
  4. Enhancing accuracy, yields and efficient screening remain absent due to lack of adequate training amongst pathologists/cytopathologists (for liquid based cytology of cervical smears and vaginal smears as per Bethesda classification 2014[2].
  5. HPV vaccine may cause some harm to some few people but balance between benefits and harms suggests vaccinations.
 So this author considers that if MICS and LMICS can provide equalities access to rural women and poor or poorer women screening by PaP smear liquid based cytology with HPV testing more than once and screening of older women at least for once can expect greater disease burden reduction by effective treatment for those who are positive for Pap smear or HPV 11, 16 & 18 in west Bengal and in India.

References

  1. Markowitz LE , Liu G , Hariri S, Steinau M , Dunne EF, et al. (2016) Prevelance of HPV after introduction of vaccination on program in the united states. Pediatrics 137(3): 1-9.
  2. Nayar R, Wilbur DC (2015) The Pap Test and Bethesda 2014 Cancer Cytopathol 123(5): 121-132
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Friday, 12 May 2017

The Cosmic Web, the Seed of Galaxies- are also made of Warm Intergalactic Medium(WHIM) and Dark Energy

Authors affiliation : BSc(Calcutta University ), MSc (Jadavpur Univ), of residence 7/51Purbapalli, Sodepur, Dist 24 Parganas(north), Kol 110,West Bengal, India. Free lancer Theoretical Physicist.Author σ: Professor, MD(Calcutta Univ) ; FIC Path(India), Professor of department of Pathology(detailment), Calcutta School of Tropical Medicine,108, C.R Avenue; Kolkata-73, West Bengal, India. Author ρ: Student, Mahamayatala, Garia, kol-84, only daughter of Prof.PK Bhattacharya.
 Author Ѡ: B.com(Calcutta Univ). Author ¥: MSc (PUSHA New. Delhi, India) of residence7 /51 Purbapalli, Sodepur, Dist 24 parganas(north), Kolkata-110, West Bengal, India, Author χ: Calcutta Univ, Swamiji Road, South Habra, 24 Parganas(north) West Bengal, India. Author ν: BHM( IGNOU).Author Ѳ: Student. Author ζ: Bsc(Calcutta Univ) of Residence Swamiji Road, South Habra, 24 Parganas(north), West Bengal, India. Author £: of residence7/51 Purbapalli, Sodepur, Dist 24parganas(north), Kolkata-110,West Bengal, India. Author €: MA (Calcutta University) BK Mitra Palliative care unit Barrackpore North 24 parganas West Bengal India.
Now published in
Global Journal of Science Frontier Research A Physics and Space Science Volume XVII Issue V ersion I Year 2017 page 57-68

of the PDF Please go at page 74 to 85 GJSFR-A 
Classification: FOR Code: 029999
This is a research/review paper, distributed under the terms of theCreative Commons Attribution-Noncommercial 3.0 Unported License http://creativecommons.org/licenses/by-nc/3.0/), permitting all non commercial use, distribution, and reproduction in any medium, provided the original work is properly cited]
Abstract- Universe consisted of mysterious Dark energy (70%), Dark matter(25%) and that makeup now 95% of matter in the universe which revel it self as gravity. Enormous filaments andblobs of dark matter in early universe condensed as universe condensed. Within the cosmicwebs, all galaxies, stars, planets were next created. Galaxies are not dotted randomlythroughout universe but are generally either concentrated in groups or in clusters, which areconnected again by multitude of filaments and voids. These filamentary distributions of galaxiesexplained by vast quantities of dark matter enveloping galaxies and filamentary cold gas flowingwithin them, responsible for star formation within them and the dark matter ISM is the dominantmass in the universe. Galaxies over passing time, clumped itself in a filamentary networks
click at URL https://globaljournals.org/GJSFR_Volume17/E-Journal_GJSFR_(A)_Vol_17_Issue_1.pdf