Tony George Jacob

Focal segmental glomerulosclerosis in idiopathic membranous glomerulonephritis: a clinico-pathological and stereological study

BACKGROUND The phenomenon of focal segmental glomerulosclerosis (FSGS) in idiopathic membranous glomerulonephritis (IMGN) has not been adequately studied. There is also a paucity of detailed glomerular morphometric and stereologic analyses data on renal biopsy in this association. METHODS Twenty-three (23) patients with IMGN and superimposed FSGS were compared to 35 patients with IMGN alone with respect to the clinical and laboratory features, light microscopic findings and stereologic parameters (glomerular cross-sectional area and estimated glomerular volume). RESULTS In the clinical parameters, patients with IMGN-FSGS had a significantly higher incidence of hypertension, raised serum creatinine and microscopic haematuria. The mean 24-h urinary protein excretion was higher in the group with IMGN-FSGS (7.4 +/- 1.36 g) as compared to IMGN alone (3.85 +/- 0.7 g, P < 0.001, Mann-Whitney test). On light microscopy, biopsies with IMGN-FSGS frequently had mesangial hypercellularity and more extensive tubulo-interstitial disease than those with IMGN alone. Stereological analysis showed that the non-sclerosed glomeruli in biopsies with IMGN-FSGS had a higher mean cross-sectional area (185466.7 +/- 32493.3 micro(2)) and higher estimated volume (855200 +/- 152640 micro(3)) as compared to glomeruli in cases with IMGN alone (76000 +/- 14719.2 micro(2) and 576666.7 +/- 131233.3 micro(3), respectively). CONCLUSION The present study is probably the first systematic analysis of stereologic parameters in renal biopsies of IMGN with FSGS. Our results objectively demonstrate the glomerular enlargement in the non-sclerosed glomeruli in cases of IMGN with FSGS. This detection of enlarged glomeruli may serve to alert the renal pathologist to the possibility of coexisting FSGS, which is a poor prognostic factor in IMGN.

Electron-microscopic evidence of mitochondriae containing macroautophagy in experimental acute pancreatitis: Implications for cell death

BACKGROUND Dysfunctional autophagy and necrosis are characteristic features of severe acute pancreatitis. OBJECTIVE To unravel the cellular mechanisms underlying the pathogenesis of acute pancreatitis. METHODS We studied the ultrastructural pancreatic morphology using electron microscopy in experimental acute pancreatitis. The control group of animals received intraperitoneal injections of normal saline. Different severity of acute pancreatitis was induced by low and high doses of caerulein in Swiss albino mice. In the low dose group, pancreatitis was induced by 4 injections of caerulein given hourly [50 μg/kg/dose - total of 200 μg/kg] and in the high dose group by 8 injections given hourly (total of 400 μg/kg). The experiments were repeated in Na-taurocholate model of acute pancreatitis in rats. The pancreatic tissue was processed and studied by transmission electron microscopy for ultrastructural changes. RESULTS The acinar cells of the pancreatitis animals revealed autophagosomes that contained cellular organelles, including mitochondria. The animals that received a higher dose of caerulein had numerous cells showing a necrotic morphology, whereas the animals in the low dose group showed a predominantly apoptotic cell morphology. The Na-taurocholate model in rats also showed similar features of severe pancreatitis with cellular necrosis and macroautophagy. CONCLUSIONS Dysfunctional mitochondria in the injured pancreatic acinar cells are degraded by macroautophagy. These observations are not model specific. Mitochondrial dysfunction and consequent energy deficit in the cells might be causally related to cellular necrosis.

Duration of injury correlates with necrosis in caerulein-induced experimental acute pancreatitis: implications for pathophysiology

Pancreatic acinar cell necrosis is indicative of severe pancreatitis and the degree of necrosis is an index of its outcome. We studied whether the dose and duration of injury correlates with severity, particularly in terms of necrosis, in caerulein‐induced acute pancreatitis (AP) in Swiss albino mice. In addition to control group 1 (G1), groups 2 and 3 received four injections of caerulein every hour but were sacrificed at five hours (G2) and nine hours (G3) respectively, and group 4 received eight injections and was sacrificed at nine hours (G4). The severity of pancreatitis was assessed histopathologically and biochemically. The histopathological scores of pancreatitis in groups 3 and 4 were significantly higher than in groups 1 and 2 (4 vs. 1, 4 vs. 2, 3 vs. 1, 3 vs. 2; P < 0.05). TUNEL‐positive apoptotic cells were significantly higher in groups 2 and 3 compared with groups 1 and 4 (P < 0.05). Necrosis was significantly more in group 4 than other groups (37.49% (4.68) vs. 19.97% (1.60) in G2; 20.36% (1.56) in G3; P = 0.006 for G 2 vs. 4 and P = 0.019 for G 3 vs. 4). Electron microscopy revealed numerous autophagosomes in groups 2 and 3 and mitochondrial damage and necrosis in group 4. The pancreatic and pulmonary myeloperoxidase activity in group 4 was significantly higher than that in the other groups (P < 0.01). Hence, severity of pancreatitis is a function of the dose of injurious agent, while inflammation is both dose and duration dependent, which may also explain the wide spectrum of severity of AP seen in clinical practice.

History of Teaching Anatomy in India: From Ancient to Modern Times

Safe clinical practice is based on a sound knowledge of the structure and function of the human body. Thus, knowledge of anatomy has been an essential tool in the practice of healthcare throughout the ages. The history of anatomy in India traces from the Paleolithic Age to the Indus Valley Civilization, the Vedic Times, the Islamic Dynasties, the modern Colonial Period, and finally to Independent India. The course of the study of anatomy, despite accompanying controversies and periods of latencies, has been fascinating. This review takes the reader through various periods of Indian medicine and the role of anatomy in the field of medical practice. It also provides a peek into the modern system of pedagogy in anatomical sciences in India. Anat Sci Educ 6: 351–358.

The human trochlear and abducens nerves at different ages - a morphometric study.

The trochlear and abducens nerves (TN and AN) control the movement of the superior oblique and lateral rectus muscles of the eyeball, respectively. Despite their immense clinical and radiological importance no morphometric data was available from a wide spectrum of age groups for comparison with either pathological or other conditions involving these nerves. In the present study, morphometry of the TN and AN was performed on twenty post-mortem samples ranging from 12-90 years of age. The nerve samples were processed for resin embedding and toluidine blue stained thin (1µm) sections were used for estimating the total number of myelinated axons by fractionator and the cross sectional area of the nerve and the axons by point counting methods. We observed that the TN was covered by a well-defined epineurium and had ill-defined fascicles, whereas the AN had multiple fascicles with scanty epineurium. Both nerves contained myelinated and unmyelinated fibers of various sizes intermingled with each other. Out of the four age groups (12-20y, 21-40y, 41-60y and >61y) the younger groups revealed isolated bundles of small thinly myelinated axons. The total number of myelinated fibers in the TN and AN at various ages ranged from 1100-3000 and 1600-7000, respectively. There was no significant change in the cross-sectional area of the nerves or the axonal area of the myelinated nerves across the age groups. However, myelin thickness increased significantly in the AN with aging (one way ANOVA). The present study provides baseline morphometric data on the human TN and AN at various ages.

Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis

BACKGROUND Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP. METHODS Consecutive patients with AP were included in a prospective cohort study at a tertiary care center. Serum levels of IL-6, TNF-α, IL-10, MCP-1, GM-CSF and IL-1β were measured at day 3 of onset of AP. Variables such as age, co-morbidity, etiology, SIRS, and cytokines were modeled to predict severe AP by multivariable regression analysis. Genotyping was done to correlate IL-6, TNF-α and MCP-1 gene polymorphisms with cytokine levels. RESULTS Of 236 patients with AP, 115 patients admitted within 7 days of onset formed the study group. 37 of the 115 (32%) patients developed organ failure. Independent predictors of organ failure were persistent SIRS (OR 34; 95% CI: 7.2-159) and day 3 serum IL-6 of >160 pg/ml (OR 16.1; 95% CI:1.8-142). IL-6 gene (-174 G/C) GG genotype was associated with significantly higher levels of IL-6 compared to CC/CG genotype. Serum IL-6 >160 pg/ml increased the positive predictive value of persistent SIRS from 56% to 85% and specificity from 64% to 95% for predicting OF without compromising its sensitivity and negative predictive value. CONCLUSION Serum IL-6 of >160 ng/ml added significantly to the predictive value of SIRS for severe AP.

Comparison of unbiased stereological estimation of total number of cresyl violet stained neurons and parvalbumin positive neurons in the adult human spiral ganglion

Estimation of total number of neurons in the spiral ganglion (SG) at various ages and their functional status is important as these neurons are constantly exposed to noise and other environmental factors that may lead to neuronal loss with aging due to excitotoxic damage. Parvalbumin (PV) is a calcium-binding protein (CBP), found in highly metabolically active neurons. It helps in buffering cytosolic calcium, which is essential for neurotransmitter release. The neurons in the adult human SG express PV more strongly than other CBPs like calbindin and calretinin. These CBPs can be used as signatures to recognise neurons. In the present study, we quantified the number of neurons expressing PV by unbiased stereology and compared it to the number of neurons stained by cresyl violet (CV), which is a Nissl stain, in the adult human SG. Five adult human cadaveric temporal bones were obtained from the forensic science mortuary, after due clearance from the institute ethics committee. Independent CV stained and PV immunostained sections were used to estimate the total number of neurons (optical fractionator), with StereoInvestigator (SI) software. The estimated total number of SG neurons was 27,485±3251 and 26,705±1823 in the PV and CV stained sections, respectively. There was no significant difference between the estimates (p=0.552). Therefore, CV staining is simpler and more cost effective when estimating neuronal number. Although PV stains spiral ganglion neurons (SGNs) with a greater intensity and provides a functional status, its tedious protocol limits its use for quantification.

Evidence of continuity of mesentery from duodenum to rectum from human cadaveric dissection - video vignette

Standard dissection techniques have not resolved uncertainties about the continuity of the peritoneal fold, also termed the mesentery, which attachesthe intra-abdominal gut tube to the posterior abdominal wall. [1, 2]. This is readily observed in jejunum, ileum, and the transverse and sigmoid colon. In contrast, the fold is less obvious in duodenum, ascending and descending colon. This article is protected by copyright. All rights reserved.

Fast-track medical course and its implications.

To the Editors, Anatomical Sciences Education Recently, the New England Journal of Medicine published a point-counterpoint on the shortening of the medical curriculum in the United States of America (Abramson et al., 2013; Goldfarb and Morrison, 2013). There was a well-nuanced debate as to whether a shortening of the medical curriculum would be a step to enhance the number of general practitioners entering the health care system that is facing a shortage of physicians or is it hampering the quality of medical graduates (Abramson et al., 2013; Goldfarb and Morrison, 2013). The side for the curtailment of the course argued that this would not only reduce the debt-burden on the student but also increase the number of productive years as a physician in practice, since the average age of entry into medical school in the United States is 24 years and they join the workforce in their 30s (Abramson et al., 2013). Whereas, the side against such a move cited the failure of such an attempt in the 1970s and how with expanding medical knowledge the physician, as the leader of the medical team, should be better equipped, not only with pre-clinical and clinical knowledge, but also with areas such as ethics, medical technology, and research methodologies (Goldfarb and Morrison, 2013). I feel that these trends would also affect the medical education system in India, where following the international trends the pre-clinical course, including anatomy, was drastically reduced from 18 months to 12 months (Jacob, 2013). The three-year medical curriculum in the United States, which would produce physicians on a fast-track mode, would be attractive to Indian policy makers due to the acute shortage of doctors in the public health system, in order to achieve Universal Health Coverage by 2022 (Singh, 2013). But there are a few differences that should be factored in. In India, a student usually enters medical school after secondary school, usually at the age of 18 years (Diwan et al., 2013). They undertake a graduate course in medicine and surgery after which they re-appear in an entrance examination to join a post-graduate course of three years in the specialty of their choice. Hence, the Indian medical graduate can join the workforce either at the age of 23 years (average) as a graduate or 26 years as a post-graduate, if all goes well and in time (Supe and Burdick, 2006). But a large number of these students prefer to work in urban areas instead of rural ones, where there is actually a crunch of trained medical practitioners (Subba et al., 2012). In addition, there is a skewed distribution of specialists in the various states, some having more than others (Ananthakrishnan et al., 2012). The only word of caution that we can sound here is that the policy makers of medical education in India weigh the options according to the needs of the country while tailoring the system. It should not follow international trends just to keep up with the Jones’. It would always be better to have well-trained physicians capable of independent decision making and taking on leadership roles (Goldfarb and Morrison, 2013) rather than improved figures in national statistics.

Changing Population of Neurons and Glia in the Human Cochlear Nucleus During Aging

The human cochlear nucleus (CN) is composed of dorsal and the ventral subdivisions. Neurons of this nucleus are unique because they respond to specific impulses arising from the cochlea. This nucleus and the neurons of the cochlea are continuously exposed to external stimuli and can degenerate with aging. This may be one of the causes of presbycusis—an age related hearing loss. One of the therapeutic interventions for this condition is a brainstem implant. An understanding of the morphology of the CN with aging changes will help making better implants for these patients. In the present study we have investigated the qualitative and quantitative changes in the neuronal and glial population of various sub-divisions of human CN at different ages. Forty one (1st to 9th decade) CN were processed for morphometry and stereology. Although the volume of the nucleus does not change with aging, neuronal number showed significant changes with aging. The data from the current morphometric report may facilitate in understanding the physiology of prebycusis, provide insight for cochlear nuclear implantation and eventually help clinicians to rehabilitate geriatric patients with hearing loss.