Fibrosis and bone marrow: understanding causation and pathobiology.

Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-ß, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.

Anti tissue transglutaminase antibody in idiopathic autoimmune haemolytic anemia.

BACKGROUND: In idiopathic autoimmune haemolytic anaemia (AIHA haemolytic antibodies are directed to every type of red cellsWestern blot studies have shown antibody positivity towards red cell anion channel complex which also includes band 4.2 a protein with similarities to tissue trans glutaminase. OBJECTIVE: Evaluation of AIHA for anti tissue transglutaminase antibody (Anti tTG). MATERIALS & METHODS: Twenty three AIHA patients were tested along with routine hamatogical work up, for a series of auto antibodies and red cell eluates and serum from the patents were tested against solubilised group O red cell ghosts on western blot. Other ancillary investigations were done to rule out complications and secondary causes of haemolysis. RESULTS: 11/23 patients (48%) were positive for anti tTG, Four, 3 and 8,7 patients were positive for anti thyroid, anti b2 glycoprotein, lupus anticoagulant and ANA respectively. One patient with anti tTG had biopsy proven celiac disease. Three patient developed DVT and all of them were lupus anticoagulant as well as b2 gp-1 antibody positive.17 had become Coombs test negative on treatment while 21/23 had positive western blot test. DISCUSSION & CONCLUSION: There is strong association of anti tTG antibody with idiopathic AIHA. Aetiological association of this finding needs exploration.

Medical Research in Medical College in India: Current Scenario and Ways to Improve it.

BACKGROUND: Medical colleges should be the engines of medical research in India however sadly it is far from that. MATERIALS AND METHODS: Articles published in English literature from 1990's were reviewed along with personal experience of more than 30 years of interacting with various medical institutions of India. RESULTS: Six to ten medical colleges publish more than 60% of research papers in indexed journals out of existing 450 medical colleges in India. There are many reasons why there is very little or poor quality research in medical colleges in India. Poor mentorship, severe patients load, lack of research interest, lack of funding and lack of multicentric co-ordinates research activity, lack of incentive for research, are some of the reasons. DISCUSSION AND CONCLUSION: Many of the reasons cited above for good quality research needs are correction. However generous funding should be available as a research fund to the medical colleges both by state and by central government. Both undergraduate and postgraduate curricula needs to be modified to reflect that good medical research is part of good medical practice.

Predictive Value of Preoperative ICG-R15 Testing in Post-hepatectomy Liver Failure Following Major Liver Resection: Indian Experience.

Surgical resection stands as the preeminent therapeutic approach for both primary hepatocellular carcinoma and metastatic liver malignancies. Its efficacy is contingent upon the attainment of a comprehensive excision while ensuring a sufficient future liver remnant (FLR). However, post-hepatectomy liver failure (PHLF) remains a significant challenge, particularly in patients with preexisting liver disease. The present study aims to investigate the predictive value of the preoperative indocyanine green retention test at 15 min (ICG-R15) in identifying patients at risk of PHLF following major liver resection. This retrospective review focused on patients who underwent the ICG-R15 test before major liver resection between August 2021 and January 2023. All patients underwent standard preoperative evaluation and staging. Patients with primary or metastatic liver cancer planned for major resection and undergoing ICG-R15 were included in the study. Patients with elevated serum bilirubin (> 3 mg/dl) and those not undergoing liver resection or minor liver resection (< 3 segments) were excluded from the study. PHLF was defined by the International Study Group of Liver Surgery (ISGLS) criteria. Follow-up was performed to identify 90-day morbidity. Using univariate and multivariate logistic regression analyses, we confirmed independent risk parameters that predicted postoperative major complications and severe PHLF. The study included 72 patients who underwent preoperative ICG-R15 testing prior to major liver resection. PHLF occurred in 28 patients (38.9%), with 24 patients (33.3%) classified as severity score B and 3 patients (4.16%) had severity score C. Univariate analysis revealed future liver remnant (FLR), ICG-R15, and blood transfusion as predictors of PHLF. Multivariate analysis confirmed FLR (p = 0.019) and ICG-R15 (p = 0.032) as significant predictors. Receiver operating characteristic curve analysis yielded an area under the curve of 0.642 for ICG-R15 in predicting PHLF. An optimal cut-point of 7.5 was determined. Our study highlights the importance of preoperative risk assessment of liver function evaluation using the ICG-R15 test, to predict the risk of PHLF following liver resection. Implementing appropriate interventions, especially in patients with borderline FLR, can improve surgical outcomes and enhance patient safety. Further research and prospective studies are essential to refine risk prediction models and improve rates of PHLF after liver resections.

Circulating tumor plasma cells and peripheral blood measurable residual disease assessment in multiple myeloma patients not planned for upfront transplant.

Circulating tumor plasma cells (CTPCs) provide a noninvasive alternative for measuring tumor burden in newly diagnosed multiple myeloma (NDMM). Moreover, measurable residual disease (MRD) assessment in peripheral blood (PBMRD) can provide an ideal alternative to bone marrow MRD, which is limited by its painful nature and technical challenges. However, the clinical significance of PBMRD in NDMM still remains uncertain. Additionally, data on CTPC in NDMM patients not treated with transplant are scarce. We prospectively studied CTPC and PBMRD in 141 NDMM patients using highly sensitive multicolor flow cytometry (HS-MFC). PBMRD was monitored at the end of three cycles (PBMRD1) and six cycles (PBMRD2) of chemotherapy in patients with detectable baseline CTPC. Patients received bortezomib-based triplet therapy and were not planned for an upfront transplant. Among baseline risk factors, CTPC ≥ 0.01% was independently associated with poor progression-free survival (PFS) (hazard ratio [HR] = 2.77; p = 0.0047) and overall survival (OS) (HR = 2.9; p = 0.023) on multivariate analysis. In patients with detectable baseline CTPC, undetectable PBMRD at both subsequent time points was associated with longer PFS (HR = 0.46; p = 0.0037), whereas detectable PBMRD at any time point was associated with short OS (HR = 3.25; p = 0.004). Undetectable combined PBMRD (PBMRD1 and PBMRD2) outperformed the serum-immunofixation-based response. On multivariate analysis, detectable PBMRD at any time point was independently associated with poor PFS (HR = 2.0; p = 0.025) and OS (HR = 3.97; p = 0.013). Thus, our findings showed that CTPC and PBMRD assessment using HS-MFC provides a robust, noninvasive biomarker for NDMM patients not planned for an upfront transplant. Sequential PBMRD monitoring has great potential to improve the impact of the existing risk stratification and response assessment models.

Monoclonal antibodies used for the management of hemataological disorders.

INTRODUCTION: Monoclonal antibodies Ab (MoAb) are increasingly becoming part of therapeutic armamentarium for haematologists and haemato-oncologists. This review brings together commonly used antibodies in one place for brevity and novel understanding. AREAS COVERED: Pubmed and Scopus databases were explored focusing on MoAb in clinical haematological practice. Emphasis was given to current review articles. The data base was searched from 1997 till present. 24 different antibodies, most of which are in use were discussed. Antibodies are used for diverse conditions i.e. malignant and benign haematological conditions, treatment at various phases of stem cell transplantation. These antibodies were used both alone or in combination with various chemotherapy, targeted small molecules or as immunoconjugates. Some of the side effect profiles of these antibodies were common and some were unique. Unusual infections or organ dysfunctions were noted. Improved function of antibodies by protein engineering is also advancing rapidly. Dosage, frequency and route of administration depended on the convenience and condition for which the antibody is used. EXPERT OPINION: MoAbs are increasingly used in haematology practice either alone or in combination with other types of therapy for improved out come in various haematological conditions.

Monoclonal antibodies are antibodies produced on an industrial scale in vitro. These are proteins that are directed against many macromolecules in our body which have a pathogenic role in causing different diseases. By producing these antibodies in a large amount on an industrial scale and modifying them for better action by molecular engineering, a large portfolio of therapeutic antibodies has been produced. A large number of monoclonal antibodies are used in hematological practice. Some familiarity with them and their usage are required for all hematologists even if it is outside their own day-to-day practice and expertise. Moreover, how modern biotechnology and antibody engineering technology are changing the facet of this therapy is also worthy of understanding. The present review encapsulates this area of advancing application and research.

D-Dimer: an analyte with increasing application in Covid-19 infection.

INTRODUCTION: D- Dimer levels from peripheral blood are increasingly used to assess various pathological conditions. Initially, an area for hematologists, now this analyte is evaluated more extensively from many specialties of medicine. Covid-19 infection has not only added a new dimension to D-Dimer level assessment in this disease but has also shed newer lights to the underlying pathophysiological mechanisms for its elevation in this disease. AREAS COVERED: Innate variability in measuring D- Dimer levels, Impact of various techniques in measuring D- Dimer, nonavailability of uniform controls and standards, molecular heterogeneity of the product, how it is produced. Reasons for raised D- Dimer in covid-19 infection. D- Dimer in other pathological states. Articles with relevant key words from 1990 searched in PubMed were utilized for review. EXPERT OPINION: : D-Dimer has important application in diagnosis, prognosis, management, and understanding various conditions. Its level can rise with increased coagulability of blood, sepsis, cytokine storm, snake bite, etc. Renal function, age influences its reference ranges. Units of measurement, its expression varies in different reports needing international standardization. In Covid-19 infection its levels correlate with stage of the disease, pathology, and complications.

Overcoming the challenges of treating hemophilia in resource-limited nations: a focus on medication access and adherence.

BACKGROUND: Hemophilia is a high cost low volume disease. Resource limited nations (RLN) usually spend very little on health budget and most of it is spent in dealing with common ailments. Clotting products constitute more than 90% of the total cost of hemophilia care. The manner in which these products can be made accessible for persons with hemophilia (PWH) and how its continuous supply and distribution can be maintained and improved is described in this review. AREAS COVERED: Number of PWH in the Resource Limited Nations (RLN); minimum amount of concentrate required to keep a PWH relatively free of bleeds; the different products available for management of PWH; means and ways to minimize and optimize the concentrate usage and purchase on a budget; nonfactor therapy; ways and means to improve the management and allow better quality concentrates in higher quantities for PWH in those countries; adherence as a challenge for RLN country and ways to manage them. The time covered is from 1980s till date. Pubmed was searched mainly for review articles with the key words hemophilia, RLN, concentrate access, alternative therapy. Cross references from these reviews as well as some of the abstracts from international conferences were read. EXPERT OPINION: Developing a patient's society and a bleeding disorder registry are the two most important actions toward ensuring adequate treatment material for PWH in RLN. Government should allocate a budget for hemophilia care depending on the number of PWH diagnosed and future projection of increased numbers of PWH. Population based product requirement may not work initially as only 10-20% of PWH in such a country has been diagnosed hence initial requirement of concentrates should be directed to these patients. Meanwhile efforts should be made to diagnose new cases. Antenatal diagnosis centers should offer antenatal diagnosis and prevent birth of severe hemophilia children. Self sufficiency in plasma based concentrates should be planned and aimed. A national tendering committee can get a good price on the concentrates on global tendering with annual rate contracts (prevents outdating). Avoiding wastage by outdating of the products in large denomination vials will help. Hoarding concentrates in unreasonable amounts should be avoided through good supply chain management. Regular physiotherapy, proper use of optimum amounts of concentrate will reduce per PWH consumption of the factor concentrates. Plasma derived intermediate purity factors, first/second generation recombinant clotting factors are safe and relatively cheaper as well as effective. Also concentrates which are close to their expiry date (>3 < 6 months) are equally effective and cheap. With proper supply chain management such products can be included in the portfolio. Primary prophylaxis with low/ intermediate dose of the concentrates is a cost-effective way to manage the patients and this also reduces inhibitor development. Adherence to therapy is not yet an important issue for RLN countries but will become one in future. With advancement and improvement the country can access alternative non factor concentrates and other newer products.

Recent advances in screening and diagnosis of hemoglobinopathy.

Introduction: Hemoglobinopathies are important causes of inherited disorders with substantial mortality and morbidity across the world. Therefore, proper utilization of available screening and diagnostic techniques are important for its diagnosis and management.Areas covered: In this review, the authors attempt to summarize clinical presentations, give a brief account of existing techniques, and discuss evolving and advanced techniques for detection and screening of the condition. As prevention of the disease condition is an important community measure to control the disease, techniques involving newborn screening, antenatal diagnosis, and point of care tests have been described in addition to more advanced molecular and protein diagnostics. The literature search in this area is covered between 1980 and 2018 with PubMed as the main source along with authors' own research in this area.Expert opinion: Screening and detection of hemoglobinopathy is best accomplished by a hierarchical approach with the optimum blend of old and newer techniques. Starting with point of care techniques through the commonly used HPLC and high voltage capillary electrophoresis, or modern and high throughput molecular biology and mass spectroscopic techniques can be used depending on specific situations. Every country needs to optimize its techniques depending on the frequency of the problem and available resources.

Strongyloides stercoralis septicaemia following steroid therapy for eosinophilia: report of three cases.

Three apparently immunocompetent patients died in the intensive care unit at Loni Hospital, Ahmednagar, Maharashtra, India, between 2001 and 2006 due to multiorgan failure and Strongyloides stercoralis septicaemia following a short course of corticosteroid (prednisolone) therapy of 6-17 days for peripheral blood eosinophilia associated with urticaria and angioneurotic oedema, bronchospasm, and generalised aches and pains, respectively. None of the patients had any obvious lymphoproliferative disorder, solid tumour or HIV 1+2 infection as an underlying immunosuppressive condition. These three patients highlight the extreme caution that must be exercised in administering a moderate dose of oral corticosteroid even for a short period of time as well as the high degree of suspicion that needs to be maintained if there is clinical deterioration following corticosteroid therapy.

Ischemia Modified Albumin Test to Detect Early Diabetic Complications.

BACKGROUND: The objective of this study was to assess the albumin cobalt binding (ACB) test in a cohort of type 2 diabetes patients. The ACB test is a simple, inexpensive, sensitive and robust test that could have important clinical application in detecting complications of type 2 diabetes mellitus. MATERIALS AND METHODS: We tested patients with type 2 diabetes without any clinically detectable complications or without any other comorbid conditions for serum ACB levels along with an equal number of age- and sex-matched healthy control subjects. ACB levels were compared after the patients with diabetes were investigated for various complications using standard statistical tests of significance. RESULTS: A total of 100 patients with type 2 diabetes were studied with age- and sex-matched healthy control subjects. Of the 100 patients, 78 had different complications on detailed laboratory testing. The patients with complications had significantly higher ACB test results when compared to the patients with diabetes without complications and to that of the control subjects (0.62 ± 0.04, 0.42 ± 0.07, 0.30 ± 0.05absorbance units (ABSU)/mL, respectively. P < 0.001). All values in diabetics were significantly higher than that of controls. CONCLUSIONS: The serum ACB test is a sensitive indicator of complications developed in type 2 diabetes mellitus. Patients may be followed up with ACB results to detect early complications in this disease.

Albumin Cobalt Binding or Ischaemia Modified Albumin: a Test of Great Prognostic Value in Malaria.

BACKGROUND: We evaluated albumin cobalt binding (ACB) assay also known as Ischaemia Modified Albumin (IMA) assay as a prognostic marker for severe malaria in a medical college setting. METHODS: Consecutive adult patients admitted with both vivax and falciparum malaria were evaluated with ACB assay at the time of admission. Detailed work up and individual patient directed management were instituted in addition to immediate artemisin based antimalarial therapy. RESULTS: 100 consecutive patients (50 with vivax and 50 with falciparum malaria) were evaluated. The reference range for ACB assay was established using 50 adult healthy (25 male and 25 female) individuals. 16 out of 50 p. Falciparum-Infected developed complicated malaria. None of the P Vivax patients developed complicated malaria. All malaria infected patients had high ACB levels (P<0.0001). There was a stepwise increase in ACB levels from healthy volunteers to different categories of malaria (P<0.0001) without any overlap. CONCLUSION: ACB has the potential to be used as a robust simple and inexpensive prognostic marker for organ dysfunction in severe malaria even if an evaluation at multiple sites with a bigger number of patients should be initiated for final recommendation.

Management of Haemophilia in Developing Countries: Challenges and Options.

There are significant challenges in managing haemophilia patients in developing countries. These challenges are (i) Lack of proper health care infrastructure and human resources suitable for haemophilia care (ii) Competing health care priorities of the government. (iii) Lack of penetrance of medical insurance in the population. (iv) Lesser visibility of the haemophilia patients in health care system (v) Low awareness across the medical profession, population and the policy makers about the condition (vi) Non availability of factor concentrates (vii) Inadequate utilization of knowledge for reducing factor concentrate use. (viii) Inadequate pain relief (ix) Challenges due to inhibitor developing (x) Viral hepatitis & (xi) Lack of research publications relevant to the country are some of the challenges faced by PWH for their management in developing country. The solutions are not easy but development of a strong patient organization with linkages with World Federation of Haemophilia is an important initial step. Following that internal and international twinning, use of internal sources, strong advocacy programme targeting government, doctors, opinion makers will solve many of the challenges in the time to come.