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Tuesday, 20 February 2018

Is Idiopathic Pulmonary Fibrosis - is Environmental or Genetic Disease – an old wine in a new bottle of Treatment

Authors-
 Pranab kumar Bhattacharya1,  Sumana Mukherjee2, Upasana Bhattacharya1, Rupak Bhattacharya3, Ritwick Bhattacharya3, Rupsa Bhattacharya3, Dalia Mukherjee3, Ayishee Mukherjee3, Debasis Mukherjee3, Hindole Banerjee3, Subhadeep Panda4.
Affiliation of authors-
1) Professor , Dept. of Pathology, Murshidabad Medical College, Berhampore Station Road,  Berhampore Court. Murshidabad, West Bengal, India.

2) Associate Professor, Dept. of Pathology, Calcutta School of Tropical Medicine, 108, C.R. Avenue,  Kolkata-73, West Bengal, India.

3)7/51 Purbapalli; PO: Sodepur; Dist-24parganas(North),Kolkata-110, West Bengal, India.
4)D.C.P student, Dept. of Pathology,Calcutta School OF Tropical Medicine, 108, C.R.Avenue Kolkata-700073, West Bengal, India.

Corresponding Author- Professor Dr. Pranab Kumar Bhattacharya, Professor of Pathology, Murshidabad Medical College, Rani Nagar, Gora Bazar, Berhampore Station Road,  Berhampore Court. Murshidabad, West Bengal
Email- profpkb@yahoo.co.in, Mobile -9231570435.
Copyright- Belongs to Professor Dr. Pranab  Kumar Bhattacharya as per Copyright Laws of Intellectual Property Right  


Key-words-Idiopathic Pulmonary Fibrosis

 Manuscript
Abstract-Idiopathic Pulmonary Fibrosis is a chronic progressive(IPF) and fibrotic lung disease, where healthy lung is replaced by a altered extra cellular matrix, alveolar architecture is gradually destroyed, with gradual increase of fibrosis due to deficient fibroblasts activation and proliferation and all these leads to decreased lung compliants and disrupted gas exchange , ultimately respiratory failure and death. It was previously known as most common type of Idiopathic Interstitial Pneumonia and treatment of choice was before 2000  prednisolone or prednisolone with  azathioprine  or acetylcysteine and or warfarin with poor prognosis and median survival time was then for 2 to 4 years time after diagnosis. But in less than 10 years time the landscape of idiopathic pulmonary fibrosis its pathophysiology, diagnostic modality, pathology and treatment had been transformed. Many people no longer consider IPF to be idiopathic rather interactions between casual factors including genetic polymorphism,  aging,  environmental exposures, which culminate in a melaptine repair process.

Introduction: Idiopathic Pulmonary Fibrosis(IPF) is a chronic inflammatory lung disorder; which gradually process to establish fibrosis. This condition is found more commonly in men, but is rarest in younger than age 50 years and median age of diagnosis is about 65 years.(1)
Although the disease course is variable, unpredictable (some patients progress rapidly, other quite slowly and others have sudden worsening after periods of stability with nintedancib)
The median survival time is 2-4years after diagnosis. Though the incidence of this disease is low in India (0.5). and in the Asian countries(4.2) per 1 lac population per year, the incidence is very high in European and north American countries, Canada etc and its incidence there is between 2.8-18 per 1 lack population per year. Anti-Inflammatory therapies with prednisolone, or prednisolone with immunosuppressive agents  azathioprine for long years did not improve the outcome rather was putative and subsequent meta analysis with prednisolone or prednisolone with azathioprine or acytyl cysteine or warfarin or everolemus was proved to be potentially harmful therapies. Treatment  by bosenten, imatinib , mactraintan or sidenafil was also attempted since 2010-2015 but were considered potentially ineffective therapies for IPF that are accepted worldwide- A tyrosine kinase inhibitors(rho-rho kinase pathway inhibitors) nintedanib and anti fibrogenic agent  Pirfenidone(TGFB2 inhibitors). IPF is now generally regarded as a consequence of multiple interacting genetic and environmental risk factors with repetitive local micro injuries to aging alveolar epithelium. These micro injuries stimulate fibroblast proliferation, produces extra cellular matrix expansion and altered matrix composition and biomechanics, induces matrix produces myofibroblast and aberrant remodeling of lung interstitium.

Pathogenesis of Idiopathic Pulmonary Fibrosis:
1.(Environmental pollution)-: Particulate inhalation is responsible in initiation and progression of IPF. A history of cigarette smoking is associated with IPF in most patients. However multiple other environmental exposures including metals, stone dust, silica dust, fogs, agriculture, farming viruses are also common predisposing factors for IPF to develop after age of 60 yrs.
2.Genetic factors-: Genetic susceptibility in the development of IPF plays a significant role. Common genetic variant which accounts for 1/3rd risks for development of IPF are MUC5B, ATP11A,TOLIP(these genes are related with host defense alteration) and telomere maintains gene(TERT,TERC,OBFC)and epithelial barrier functions (DSP,DPP9). 3,4 The largest genetic to all these gene variants are MUC5B and dis- regulation of AEC2 (alveolar epithelial cell)stem cells.
3.MUC5B gene defect found both in familial and sporadic IPF cases .MUC5B encodes mucin 5B precursor protein that contribute to airway mucus production and play an important role in lung host defense. Patients with IPF with MUC5B gain of function variant might have then higher rate survival than those without these variant. If these mutated and altered MUC5B in brochiolar epithelium, there is increased protein concentration that may reduce mucociliary clearance or impede normal lung repair process. Pathological mechanism of fibrosis though very challenging one, it is probably due to dis regulation of type 2 alveolar cells (AEC2).These AEC2 are stem cells within lung that contribute to renewal of type1 alveolar epithelial cell during homeostasis and after lung injury. Loss of AEC1 and abnormal AEC2 are identified in IPF with fibroblastic foci typically located adjacent to hyper plastic or apoptotic alveolar cell.[ 5]
In IPF, premature shortening of AEC2 stem cell telomere is seen in mouse model .A study on 2016 showed that AEC2 from IPF have impaired renewal capacity consistent with AEC2 stem cell failure. Activated and abnormal AEC2 produces numerous fibrogenic  growth factors and cytokines including TGF1B,PDGF with aberrant epithelial mesenchymal cross talk driving the recruitment and activation of myofiboblast.[ 6]
These activated myofibroblasts  deposit an increased amount of altered extracellular matrix, which again destroy alveolar architecture and interferer gas exchange. Multiple sources of myofibroblasts  are proposed including residual mesenchymal cell proliferation, lung interstitium, pericytes, circulation fibrocytes, epithelial messenchymal transition and endothelial messenchymal cells .[7] Changes in extracellular matrix composition , altered cell behavior and interactions between fibroblast, deficient apoptosis of fibroblast and aberrant extracellular matrix, both promote fibrosis and lung stiffness. Here integrins plays a central role with mechano sensitive protein-protein interactions occurring with adhesion complex and these interaction of stimulation of TGFB and intrinsic mechanoreduction occurs via Rho-Rho Kinase pathway which promotes myofibroblast differentiation and nintedanib acts better than Imatinib possibly as disease modifying therapy.

Clinical Presentation, Sign and Symptoms: Patient of IPF usually present with exertional  dyspnea with or without dry cough. This presentations might initially be attributed to aging, COPD, emphysema or other cardiovascular diseases or obesity. Occasionally patients present with acute dyspnea worsening with days or weeks often accompanied by fever and influenza like symptoms. This acute exacerbation require careful diagnosis from other acute interstitial lung diseases on physical examination fine high pitched basilar inspiratory  crackels are heard by stethoscope and digital clubbing is present in 30% patient.

Diagnosis: Diagnosis of Idiopathic pulmonary fibrosis is on basis of both radiological and histopathological criteria without evidence of alternative diseases. Careful attention to signs of various connective tissue disorders are essential to rule out associated diseases. In established cases pulmonary function test identify restrictive lung diseases(reduced total lung capacity) and abnormal gas exchange (reduced capacity co diffusion) . Amongst differential diagnosis needs
1.known cases of Interstial Lung Disease(ILD) 2.Domestic and occupational exposures, 3.Connective tissue disease 4.drug toxicity 5.Chronic hypersensitive pneumonia

High resolution Computed Tomography (HRCT) of chest shows reticular opacities associated with bronchiectasis and clusters of sub-pleural, cystic air spaces of diameter 3-10 mm with honeycombing , in a predominantly bilateral, peripheral and basal distribution .These features are of typical of all types of ILD(interstial pneumonia pattern) whereas features such as mosaic attenuation ground glass abnormality and nodules suggest IPF. When HRCT are non diagnostic true cut or open surgical open lung biopsy is advised. Every patient before going for open surgical lung biopsy, careful consideration must be done about the potential benefit of this biopsy procedure for patient younger than 65yrs only. In elder patients those are with other co morbidities or has clinically significant impairment lung function test or in acute non elective procedure the lung biopsy must be avoided and the diagnosis should rest on HRCT.

Histopathology:
1.Usual  interstial pneumonia: It is characterized by
A. interstitial fibrosis with spatial heterogenecity and patchy involvement of lung parenchyma.
B.Areas of marked fibrosis
c.Alveolar  architecture  distortion
D. Microscopic honeycombing
E. Cystic airspaces lined by bronchiolar epithelium filled up with mucin

2.In IPF all these features usual interstitial pneumonia and along with aggregates of proliferating fibroblast and myofibroblast in the form of fibroblastic foci such fibroblastic foci are key histopathlogical diagnosis of IPF

 Is Genetic testing necessary ? In individual with a family history of ILD suggestive of interstitial pneumonia genetic testing for mononuclear cell telomere length testing from peripheral blood will be helpful in disease course prognostification and future lung transplantation for sporadic IPF usually genetic testing is not recommended at all.




References
1.Raghu.G, Collard H.R,Egan J.J for the ATS/ERS/RS/ALAT committee on Idiopathic pulmonary study group. an official ATS/ERS/RS/ALAT statement, Idiopathic pulmonary fibrosis :Evidence based guide line for diagnosis and management Am.J.Repair Crit care.Med 2011,183,788-824

2.Huthcinson .J Fogart;Hubbard.R;MC KEEVR.T” Global incidence and mortality from  Idiopathic pulmonary fibrosis ; a systematic review” Euro.respo J 2015;46;795-806

3.Fingulen TE;Murphy.E,Zhang.W” Genome wide association study identifies multiple susceptibility loci for Idiopathic pulmonary fibrosis
Nat.Genet.2013;45;613-20

4.Seivold;MA;wise AL;Speer MC et al “A common MUC5b  promotes polymorphism and pulmonary fibrosis” N.Engl.J.Med 2011;364;1503-12

5.Scl Men.m;King.T.E,Pardo.A “for the American thoracic study group ,European respiratory study group and American college of chest physician study groups”
“Idiopathic pulmonary fibrosis; prevailing and evolving hypothesis about its pathogenesis and implication for therapy” Ann Internal.med.2001;134;136-51

6.Horowitz.J.C;ThannickalVJ “Epithelial messenchymal interactions in pulmonary fibrosis” Semin Respir.Care.Med 2006;27;600-12

7.Hung.C;Linn G;Chow.OI.H. et al “Role of lung parasites and resident fibroblast in the pathogenesis of pulmonary fibrosis” Am.J.Respir.Crit.care.Med 2013;188;820-30

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 Diana  Maxwell ; Editorial manager  of International clinical Pathology Journal  USA agreed with Prof Pranab kumar Bhattacharya by her E mail   that she will never charge  for the article/ manuscript on dated 23.01.2018 if Professor Pranab Kumar Bhattacharya Sends article in IJPL as her letter tells  “



Thank you for your reply.

I apologise for the inconvenience caused from our end.

I do understand from your end and I assure you that we never compel you for any kinds of APC/ publication charges/ DOI charges. Moreover I would like to have at least 2 page editorial article from eminent editors like you for representing the each issue of our journal. As you might be aware of that within the short period of time we got ISSN for our journal and already listed in ICMJE ; Pub med, so with your eminent support will achieve more accomplishments.

Look forward to have your collaboration
Best Regards,
Diana Maxwell
Editorial Manager 
International Clinical pathology Journal 

Friday, 19 January 2018

Health Inequity in India Published in Blogs.BMJ.com

In India, 63 million people sink into poverty yearly due to unaffordable health cost in paradoxical health care system, since independence 1947. In 1950, central government designed national health programme. Severe variations amongst states economic development, social & religious conditions, familial income inequities, political governance and willing led wide disparities in access to health services and population health. India initially accepted public sector led model, where services were free to all, emphasizing rural health care, when private sectors were limited to general practitioners and charity run hospitals . It was pyramidal structure connected PHCs to S-D to district to government run tertiary medical colleges. Since 1947 economic planning regarded health expenditure was non-productive, poorly recorded. Public health needs to meet health of expanding population particularly in areas of stroke, CVD, cancer, diabetes, respiratory diseases, mental illness, suicide, HIV, tropical and infectious diseases and other chronic diseases and stressed health system beyond their capacity and private sectors proliferated, large corporate hospitals opened in urban aggregation and non engagement with primary health care providers, do not provide basic essential health care to largest sections of rural, suburban population & these are centres of all kinds of malpractices. Un affordable for most Indians, with weak regulatory system, failing to set and enforce quality, cost standard inadequate, inappropriate, unethical care & cure. Health insurance available to small proportions of workers and when poverty level is very high i.e. 10% of health care expenditure is out of pocket spending.All these are because economist & policy makers do not recognize health as essential for economic development and health is not a legislated right in India. NRHM focuses on maternal & child health. No attention is even paid to communicable, non-communicable, tropical & mental diseases which lead to largest death & disability in India. In 2012-2017 planning Government of India focussed & recommended increased public finances from 1% of GDP to 2.5% of GDP through toy funding supplemented by ESI & EPJ & free provision of essential drugs & diagnostics and referral system. India must address the enactment of right to health through parliamentary legislation and allow the state what services that the right should translate into welfare scheme. India & West Bengal must engage community care instead of mushrooming growth of private care. Improvement of public care & cure, improvement of quality health care personnel, Generalists, Specialists, nurses, GDAs, shortfalls & more training institutions.HEALTH EXPENDITURE VALUE Per Capita (US $) 61 Percentage of GDP 3 Amount of pocket private health expenditure 86 Public services(% of total) 33 Percentage of population insured in 2015 17 (Government 12%+ employee 3%+ individual 2%) No of Physician per 1000 population in 2015 7 Life expentancy at birth 66 Annual no. of death per 1000 population 17 No. of infant death per 1000 live birth 8 No. of death per 1000 live birth in 2014 41 No.of maternal death per 100000 live birth in 2014 190

Please note  it very carefully that, The Copy Right of this article belongs only 
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 in chronological order  , as per copy right rules of IPR 1996 applicable in India-2006
 under sections 307/ 306/ 3D/107/2012 and PIP Acts of US 2012SPARC authors amended 
Copy Right rules-2006  of US  when & if accepted for any other blogs, as a reference, or publication  or Research  or  reference material  or published as paper or article in open access journals as a commissioned article  and then  also this article will be under RDF Copy Right rules of 
IPR of Prof PK Bhattacharya.
 No persons/  nor any Private care Hospitals/ nor any Nursing homes/ and their health care
 provider doctors nurses paramedical staffs from any states of  country India or any citizen of India or of Indian origin are for ever authorized by Professor Pranab kumar Bhattacharya to use  any  scientifically meaningful  syllables/words  /sentences/ new drugs/protocolos/  change of Health care by implementation from this  published blog article in the Blogs of Prof Pranab kumar Bhattacharya MD(cal) FIC path(ind.) in Blog spot.com  without  his / future copy right  owner ‘s written permission  &copy Right clearance, even for any
 one’s personal or for his/her fair use even/ treatment of his or her patients/ dissemination of  
any information( Will be considered  then as Plagiarism) , [except such all permission is always
 remain granted to other authors ,their first degree blood relatives in what ever manner they want 
to use this article  for ever from the date of publication in ProfPranab Kumars Bhattacharya 
MD(cal) FIC path(ind)  Blog at blog spot.com   or for digital preservation of  the article in National
 Level Science Library(NSDL) US or of other countries.- by declaration- 


Blogs of Professor(Dr.) Pranab Kumar Bhattacharyya MD(calcutta.Univ) Pathology; : The INDO SOCIO DEVELOPMENT ASSOCIATION ( www.isda....

Blogs of Professor(Dr.) Pranab Kumar Bhattacharyya MD(calcutta.Univ) Pathology; : The INDO SOCIO DEVELOPMENT ASSOCIATION ( www.isda....: The INDO SOCIO DEVELOPMENT ASSOCIATION (  www.isda.in  ) by a  letter of their Reference no -: ISDA/MEM/RPA/ 13 th March, 2018 of dat...

The INDO SOCIO DEVELOPMENT ASSOCIATION ( www.isda.in ) by a suddenly sent letter of their Reference no -: ISDA/MEM/RPA/ 13 th March, 2018 of dated 21.01.2018 told that they selected Dr.Pranab Kumar Bhattacharya , Professor of Department of Pathology ; Calcutta School of Tropical Medicine, West Bengal "RASHTRIYA PRATIBHA AWARD"( For Most Talented Personality In India) to be conferred on him on a fixed date 13 th March ,2018 at New Delhi ,India


The INDO SOCIO DEVELOPMENT ASSOCIATIONwww.isda.in ) by a  letter of their Reference no -: ISDA/MEM/RPA/ 13 th March, 2018 of dated 21.01.2018 told that they selected Dr.Pranab Kumar Bhattacharya , Professor of Department of Pathology ; Calcutta School of Tropical Medicine, West Bengal "RASHTRIYA PRATIBHA AWARD"( For Most Talented Personality In India) to be conferred on him on a fixed date 13 th March ,2018 at New Delhi ,India
Indo Socio Development Association - is a non profit voluntary registered organisation with government of India aimed at contributing to the economic growth and social development of country. ISDA has been co- coordinating the sincere efforts of individuals as well as institutions and organizations to take the Indian nation to newer height with each passing days............
The Society will honor individuals, organizations and institutions with Awards for outstanding contributions and achievements in their respective field. These include economic development in industry, finance and business. Awards will also be given in the fields of education, health, medical treatment and ho
Add caption An Picture of Awards Session Rashtriya Pratibha Award in New Delhi -2016 
Add caption     Rashtriya Pratibha Awards” 2018 ( For Talented Personality in India) of  Indo Socio Development Association of address \v195, Street No 15A Near SgerShadan Mondir Vijay park , Maujpur New Delhi 110053 (www.isda.in) selected Professor Pranab Kr Bhattacharya as an awardee (letter of selection as awardee of  Rashtriya Pratibha Awards” 2018

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Tuesday, 16 January 2018

Prevalence of proteinuria and abnormal urinary cytology in HIV +ve asymptomatic patients

Date of Web Publication11-Jan-2018
   
   Abstract
How to cite this article:
Mukherjee S, Bhattacharya PK, Hazra S, Das S. Prevalence of proteinuria 
and abnormal urinary cytology in HIV +ve asymptomatic patients.
 Ann Trop Med Public Health 2017;10:1496-9


How to cite this URL:
Mukherjee S, Bhattacharya PK, Hazra S, Das S. Prevalence of proteinuria
 and abnormal urinary cytology in HIV +ve asymptomatic patients.
 Ann Trop Med Public Health [serial online] 2017
 [cited 2018 Jan 16];10:1496-9. 
Available from: http://www.atmph.org/text.asp?2017/10/6/1496/222656

Please note  it very carefully that, The Copy Right of this article belongs only 
to Professor Pranab kumarBhattacharya MD(cal) FIC path(Ind) and other authors
 in chronological order  , as per copy right rules of IPR 1996 applicable in India-2006
 under sections 307/ 306/ 3D/107/2012 and PIP Acts of US 2012SPARC authors amended 
Copy Right rules-2006  of US  when & if accepted for any other blogs, as a reference, or publication  or Research  or  reference material  or published as paper or article in open access journals as a commissioned article  and then  also this article will be under RDF Copy Right rules of 
IPR of Prof PK Bhattacharya.
 No persons/  nor any Private care Hospitals/ nor any Nursing homes/ and their health care
 provider doctors nurses paramedical staffs from any states of  country India or any citizen of India or of Indian origin are for ever authorized by Professor Pranab kumar Bhattacharya to use  any  scientifically meaningful  syllables/words  /sentences/ new drugs/protocolos/  change of Health care by implementation from this  published blog article in the Blogs of Prof Pranab kumar Bhattacharya MD(cal) FIC path(ind.) in Blog spot.com  without  his / future copy right  owner ‘s written permission  &copy Right clearance, even for any
 one’s personal or for his/her fair use even/ treatment of his or her patients/ dissemination of  
any information( Will be considered  then as Plagiarism) , [except such all permission is always
 remain granted to other authors ,their first degree blood relatives in what ever manner they want 
to use this article  for ever from the date of publication in ProfPranab Kumars Bhattacharya 
MD(cal) FIC path(ind)  Blog at blog spot.com   or for digital preservation of  the article in National
 Level Science Library(NSDL) US or of other countries.- by declaration-