PubMed Health⌕ Search

Biomedical subjects

J Varghese

Publications and source records attributed to J Varghese.

At least 19 recordsLinked to original sources
PubMed2006

Combined femoral and Chiari osteotomies for reconstruction of the painful subluxation or dislocation of the hip in cerebral palsy. A long-term outcome study.

In order to treat painful subluxation or dislocation secondary to cerebral palsy, 11 patients (12 hips) underwent combined femoral and Chiari pelvic osteotomies with additional soft-tissue releases at a mean age of 14.1 years (9.1 to 17.8). Relief of pain, improvement in movement of the hip, and in sitting posture, and ease of perineal care were recorded in all, and were maintained at a mean follow-up of 13.1 years (8 to 17.5). The improvement in general mobility was marginal, but those who were able to walk benefited the most. The radiological measurements made before operation were modified afterwards to use the lateral margin of the neoacetabulum produced by the pelvic osteotomy. The radiological migration index improved from a mean of 80.6% (61% to 100%) to 13.7% (0% to 33%) (p < 0.0001). The mean changes in centre edge angle and Sharp's angle were 72 degrees (56 degrees to 87 degrees; p < 0.0001) and 12.3 degrees (9 degrees to 15.6 degrees; p < 0.0001), respectively. Radiological evidence of progressive arthritic change was seen in one hip, in which only a partial reduction had been achieved, and there was early narrowing of the joint space in another. Painless heterotopic ossification was observed in one patient with athetoid quadriplegia. In seven hips the lateral Kawamura approach, elevating the greater trochanter, provided exposure for both osteotomies and allowed the construction of a dome-shaped iliac osteotomy, while protecting the sciatic nerve.

Adolescent↗
PubMed2003

VDAC is a conserved element of death pathways in plant and animal systems.

Programmed cell death (PCD) is very much a part of plant life, although the underlying mechanisms are not so well understood as in animals. In animal cells, the voltage-dependent anion channel (VDAC), a major mitochondrial outer membrane transporter, plays an important role in apoptosis by participating in the release of intermembrane space proteins. To characterize plant PCD pathways by investigating the function of putative components in a mammalian apoptotic context, we have overexpressed a rice VDAC (osVDAC4) in the Jurkat T-cell line. Overexpression of osVDAC4 induces apoptosis, which can be blocked by Bcl-2 and the VDAC inhibitor DIDS. Modifying endogenous VDAC function by DIDS and hexokinase II (HxKII) in Jurkat cells inhibits mitochondria-mediated apoptotic pathways. Finally, we show that DIDS also abrogates heat-induced PCD in cucumber cotyledons. Our data suggest that VDAC is a conserved mitochondrial element of the death machinery in both plant and animal cells.

Animals↗
PubMed2003

Caspase-3 activation is an early event and initiates apoptotic damage in a human leukemia cell line.

Many apoptotic pathways culminate in the activation of caspase cascades usually triggered by the apical caspases-8 or -9. We describe a paradigm where apoptosis is initiated by the effector caspase-3. Diethylmaleate (DEM)-induced apoptotic damage in Jurkat cells was blocked by the anti-apoptotic protein Bcl-2, whereas, a peptide inhibitor of caspase-3 but not caspase-9 blocked DEM-induced mitochondrial damage. Isogenic Jurkat cell lines deficient for caspase-8 or the adaptor FADD (Fas associated death domain) were not protected from DEM-induced apoptosis. Caspase-3 activation preceded that of caspase-9 and initial processing of caspase-3 was regulated independent of caspase-9 and Bcl-2. However, inhibitors of caspase-9 or caspase-6 regulated caspase-3 later in the pathway. We explored the mechanism by which caspase-3 processing is regulated in this system. DEM triggered a loss of Erk-1/2 phosphorylation and XIAP (X-linked inhibitor of apoptosis protein) expression. The phorbol ester PMA activated a MEK-dependent pathway to block caspase-3 processing and cell death. Constitutively active MEK-1 (CA-MEK) upregulated XIAP expression and exogenous XIAP inhibited DEM-induced apoptotic damage. Thus, we describe a pathway where caspase-3 functions to initiate apoptotic damage and caspase-9 and caspase-6 amplify the apoptotic cascade. Further, we show that MEK may regulate caspase-3 activation via the regulation of XIAP expression in these cells.

Apoptosis↗
PubMed2002

Prospective comparison of MRA with catheter angiography in the assessment of patients with aortoiliac occlusion before surgery or endovascular therapy.

AIM: The purpose of this study was to evaluate the usefulness of gadolinium enhanced 3D magnetic resonance (MR) angiography (CE MRA) as an alternative to translumbar or brachial angiography in the pre-operative work-up of patients with aortoiliac occlusion. MATERIALS AND METHODS: Nineteen patients (14 men and five women; age range 45-77 years; mean 62 years), not suitable for perfemoral angiography (aortoiliac occlusion, n = 18; infected femoro-femoral graft with femoral artery pseudoaneurysm, n = 1), underwent pre-operative CE MRA and catheter angiography (translumbar, n = 5; brachial, n = 14). CE MRA was performed using a 3D fast spoiled gradient-recalled pulse sequence during the intravenous injection of 40 ml of gadolinium DTPA and a 32-s breath-hold. All patients subsequently underwent surgical (n = 13) or percutaneous transluminal (n = 6) treatment for their vascular disease. The accuracy of CE MRA was determined compared with the findings at catheter angiography taken as the gold standard. RESULTS: CE MRA gave accurate information about the occlusion, inflow and distal run-off in the majority of patients. CE MRA revealed occlusions with an accuracy of 94.7% in the aortic segment, 98.7% in the iliac segment, and 100% in the common femoral segment. The arterial segments distal to the common femoral artery were not completely visualized in four patients but CE MRA provided sufficient information to plan either surgical or percutaneous transluminal therapy in all but one patient. CONCLUSION: CE MRA is highly accurate in showing the presence and extent of aortoiliac occlusions. In our study group, CE MRA gave sufficient information in the pre-operative evaluation of aortoiliac occlusion.

Aged↗
PubMed2002

Predictive value of benign percutaneous adrenal biopsies in oncology patients.

PURPOSE: Percutaneous CT guided biopsy is accepted as a safe procedure for the diagnosis of indeterminate adrenal masses in oncologic patients. The purpose of this study was to evaluate the accuracy of a 'negative for tumour' adrenal biopsy in the oncologic patient population by assessing subsequent outcome including clinical course, size and imaging characteristics of the adrenal lesions on follow-up imaging studies and pathological findings at re-biopsy or following adrenal mass resection. MATERIALS AND METHODS: Retrospective analysis of 225 oncological patients (FM, 128;87; age range 33-87 years, mean age 66 years) who had undergone CT guided biopsies of an adrenal mass over a 5-year period was performed. Those patients with a report consistent with 'negative for malignancy' were evaluated by reviewing the medical records for patient demographics, primary malignancy, histology of adrenal tumour, subsequent surgical interventions, repeat adrenal biopsy under image guidance, by open surgery or at autopsy, subsequent abdominal imaging in which the adrenal gland was imaged, and long-term outcome including hospital admissions, or death. RESULTS: Of the 225 CT-guided adrenal biopsies performed, 41 (18%) were negative for neoplasm. The primary neoplasm in these 41 patients included lung cancer (n=32), breast (n=5), renal cell carcinoma (n=2), bladder (n=1), and prostate (n=1). The size of the adrenal lesions ranged from 2.8-5 cm. Of the 41 biopsies, which were negative for tumour; 10 were identified as adenomas and the rest showed benign adrenal cortical cells or hyperplasia on cytopathology and histopathology. Repeat biopsies were obtained in 13/41 (31%) patients; whereas 2/41 (5%) had their adrenal gland analyzed on post mortem examination. None of these 15 repeat evaluations yielded tumour. CONCLUSION: In oncological patients, pathological analysis of tissue samples obtained by CT-guided percutaneous biopsy, suggesting benign aetiology, is reliable and predicts a benign course on long-term follow-up. A negative or benign pathology result for a CT guided percutaneous adrenal biopsy can be regarded as a true negative evaluation in oncological patients with no necessity to repeat the biopsy.

Adenoma↗
PubMed2001

Inhibition of p38 kinase reveals a TNF-alpha-mediated, caspase-dependent, apoptotic death pathway in a human myelomonocyte cell line.

TNF-alpha transduces signals of survival or death via its two receptors, R1/p55/p60 and RII/p80/p75. The role of caspases as effectors of cell death is universally accepted, although caspase inhibitors may potentiate TNF cytotoxicity in some instances. In conditions when macromolecular synthesis is blocked, caspases are part of the machinery that executes TNF-triggered apoptotic death in U937, a human myelomonocyte cell line, and in the Jurkat T cell line. However, inhibition of p38 mitogen-activated protein kinase (p38 MAPK) triggered TNF cytotoxicity in U937 cells and murine splenic macrophages, but not the Jurkat cell line. TNF induced expression of the antiapoptotic protein c-IAP2 (cytoplasmic inhibitor of apoptosis protein 2), and was blocked in the presence of a p38 MAPK inhibitor, which also induced caspase-dependent, TNF-mediated apoptosis in U937 cells. Thus, inhibition of p38 MAPK resulted in the activation of caspase 9 and cleavage of the adaptor molecule BH3 interacting domain death agonist, and blocked NF-kappaB-mediated transactivation, without affecting the nuclear translocation of NF-kappaB. Collectively, these data show that activation of p38 MAPK is critical to cell survival by TNF in U937 cells, and demonstrate lineage-specific regulation of TNF-triggered signals of activation or apoptosis.

Active Transport, Cell Nucleus↗
PubMed2001

Sialidase inhibitors related to zanamivir. Further SAR studies of 4-amino-4H-pyran-2-carboxylic acid-6-propylamides.

SAR investigations of the 4- and 5-positions of a series of 4-amino-4H-pyran-2-carboxylic acid 6-carboxamides are reported. Potent inhibitors of influenza A sialidase with marked selectivity over the influenza B enzyme were obtained when the basic 4-amino substituent was replaced by hydroxyl or even deleted. Modifications at the 5-position exhibited a tight steric requirement, with trifluoroacetamide being optimal.

Antiviral Agents↗
PubMed2001

The role of calpain in caspase activation during etoposide induced apoptosis in T cells.

T cells treated with the drug etoposide undergo apoptotic death characterized by early evidence of nuclear damage followed by loss of mitochondrial integrity and cell lysis. Calpains and caspases are cytoplasmic proteases and there is increasing evidence of cross-talk between these proteases in death pathways. In this study we have investigated the role of calpain, in etoposide-triggered apoptosis in the 2B4 murine T cell hybridoma. Cell permeable inhibitors of calpain, ALLnM, E64 and calpeptin that block Fas ligand-Fas-mediated death in T cells, blocked etoposide-induced nuclear damage, loss of mitochondrial integrity and cell lysis. A broad spectrum peptide inhibitor of caspases, ZVAD-fmk, partially blocked nuclear damage but poorly inhibited mitochondrial damage or cell lysis triggered by etoposide. Etoposide-induced expression of the cleaved, proteolytically active form of caspase 3, and DEVD-ase activity, detected prior to nuclear damage, were blocked in the presence of calpain inhibitors. Collectively, these data describe a role for calpain in regulating etoposide-induced apoptosis via a caspase-dependent pathway in T cells.

Animals↗
PubMed1999

Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory factor (NIF) in the Fischer 344 rat.

1. Recombinant neutrophil inhibitory factor (NIF) is a glycoprotein. Its amino acid sequence remains constant and has a molecular weight of 28.9 kD. However, approximately 40% of the total molecular weight consists of glycans with variable structure. 2. The pharmacokinetics of 11 different NIF batches with varying extents and patterns of sialylation have been investigated in the Fischer 344 rat following intravenous administration. These data indicate that reducing the extent of NIF sialylation reduces the half-life of the molecule due to an increase in the systemic clearance. Also, an increase in the number of unsialylated or neutral glycans may increase the volume of distribution of NIF, although this effect is marginal. 3. Isolated perfused rat liver (IPRL) investigations have shown that sialylated NIF has a low hepatic extraction (< 1%), while asialo NIF has an extraction that is > 20-fold higher. Co-administration of asialo NIF with asialo fetuin (a protein cleared by hepatic asialoglycoprotein receptor (possibly galactose)-mediated uptake reduced the hepatic extraction of asialo NIF. 4. These data suggest that NIF molecules that have free sugar moieties (possibly galactose) interact with an asialoglycoprotein receptor (possibly galactose-mediated) in the liver (parenchymal cells/hepatocytes). Interaction with this receptor leads to cellular internalization and degradation.

Animals↗
PubMed1998

Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B.

The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, whereas in type B enzyme, significant distortion of the protein is observed. The results suggest that the decreased affinity in enzyme from influenza B is directly correlated with the small changes that occur in the amino acid residue interactions accompanying ligand binding. Molecular dynamics calculations have shown that the tendency for salt-bridge formation is greater in influenza A sialidase than influenza B sialidase and that this tendency is a useful descriptor for the prediction of inhibitor potency.

Acetamides↗
PubMed1998

Abdominoscrotal hydrocoeles: little place for conservatism.

Abdominoscrotal hydrocoeles (ASH) are infrequently reported in children. The presence of bilateral ASH is even rarer, with fewer than five cases reported to date. ASH are present at birth and tend to be progressive in nature. Spontaneous resolution has not been documented. The pathogenesis is uncertain and their presence in the neonatal period suggests a preformed abnormality of the processus vaginalis. Diagnosis is suspected on clinical examination and confirmed by ultrasonography, which is a reliable diagnostic tool. Undescended testes frequently coexist. Early surgery is the preferred management, and complications are frequent if left unattended. Surgery is simply an extension of a hernia operation, without the need for a laparotomy.

Cryptorchidism↗
PubMed1998

The efficacy, tolerability and safety of diethylcarbamazine-fortified salt in the treatment of the microfilaraemias of brugian filariasis: an open, hospital-based study.

Cooking salt fortified with diethylcarbamazine (DEC) has been successfully used to control lymphatic filariasis in several parts of the world. The kinetics and efficacy of DEC-fortified salt in clearing microfilaraemias of Brugia malayi and the salt's tolerability and safety are examined in this study. Twenty individuals with B. malayi microfilaraemias (pre-treatment levels of 108-6358 microfilariae/ml; median = 309/ml) consumed DEC-fortified salt (0.2%, w/w) with their food for 1 year, initially in hospital (for 1 week) and later at home. The mean daily intake of DEC was 21.4 mg (range = 9.0-39.4 mg). Even on the first day of consuming the salt, there was a decrease in the microfilarial levels of 14 patients and a sharp increase in six patients. Microfilarial levels tended to fluctuate thereafter but there was a progressive, general decline. At the end of the study year, eight patients were amicrofilaraemic and microfilarial clearance was > 95% in 58% of the patients. Eight patients did not develop any adverse reactions. Lymph-node tenderness and enlargement were seen in eight patients (40%), and dilated, inflamed lymphatic channels standing out as cords ('string sign') were seen in another five patients. These reactions were transient and did not require any specific treatment. The DEC-fortified salt was well accepted by the study population. The DEC content of fortified salt and the duration of its use for the control of brugian filariasis need to be re-examined. Health education should include messages that mild, self-limiting, adverse reactions are likely to occur even with the use of such salt.

Adolescent↗
PubMed1997

Estimation of ASO titer as an indicator of streptococcal infection precipitating acute adenolymphangitis in brugian lymphatic filariasis.

Recurrent episodes of acute adenolymphangitis (ADL) are important clinical manifestations of lymphatic filariasis which contribute significantly to the progression of lymphedema. It is increasingly being recognized that secondary bacterial infections play an important role in the etiology of ADL. We examined the role of streptococcal infection as a precipitating factor of ADL in brugian filariasis, by determining the anti-streptolysin O (ASO) titers and by isolating the causative organism wherever possible. The study population consisted of 30 patients with filariasis related ADL (Group A), 30 patients with chronic filarial edema (Group B) and 60 age and sex matched healthy adults (Group C). ASO titer was estimated by the latex agglutination method at the time of entry into the study, at the 15th day and at 3, 6 and 12 months. ASO titers were persistently elevated in 90% of patients in Group A and a portal of entry for bacterial infection was detected in all of these patients. In Group B only six patients had persistently elevated ASO titers. These patients had grade III lymphedema and three of them had monilial infections in the affected limb. In the control group none had persistently elevated ASO titers. The elevated ASO titers and the detection of a site of entry for bacteria in patients with ADL supports a streptococcal etiology for this condition.

Acute Disease↗
PubMed1996

Large scale purification process for recombinant NS1-OspA as a candidate vaccine for Lyme disease.

A purification process was developed for the manufacture of NS1-OspA as a candidate vaccine for Lyme disease. NS1-OspA was expressed as a soluble recombinant protein in E. coli from 50 and 200 liter fermentations. A multistep bench scale procedure, including detergent treatment, sonication, Q-Sepharose chromatography, dialysis, and SP-Sepharose chromatography, was used to effectively purify NS1-OspA from E. coli to > 90% purity with a 35% yield. This procedure was subsequently modified and specific steps eliminated to create a manufacturing scale process for the purification of NS1-OspA. Continuous flow centrifugation, mechanical lysis, QA-52 anion exchange chromatography, acid induced precipitation, and cross flow filtration gave a final purity of > 75%, a recovery of > 70%, and measured endotoxin levels of < 5 micrograms/mg of protein. Unique features of this process include using unclarified lysates and a single use (disposable) resin for the batch chromatography step. This simple, cost effective production process provides a recombinant protein with the yield and purity suitable for use as a subunit veterinary vaccine.

Animals↗
PubMed1994

Evaluation of a novel hydrophilic derivatized capillary for protein analysis by capillary electrophoresis-electrospray mass spectrometry.

A new type of hydrophilic derivatized capillary has been used to enable the on-line capillary electrophoresis separation and electrospray mass spectrometric detection of a mixture of proteins containing bovine cytochrome c, tuna cytochrome c and horse heart myoglobin. Less than 40 fmol of each compound were loaded into the capillary. Baseline resolution of components was achieved, as were accurate assignments of molecular masses. The hydrophilic derivatized capillaries were taken through extensive testing procedures to characterize their performance and capabilities for protein analysis. A mixture of six proteins (cytochrome c, ribonuclease A, alpha-chymotrypsinogen, myoglobin, carbonic anhydrase II and alpha-lactalbumin) in acetic acid-sodium acetate buffer was used to delineate the relationships between migration time and pH, along with migration time and buffer concentration for each protein. The variations in capillary efficiency as a function of pH and as a function of buffer concentration were also characterized for the same six proteins in the acetic acid-sodium acetate system. A pH of 4.8 was found to offer an excellent compromise between separation efficiency (up to 500,000 theoretical plates) and analysis time. Capillary efficiencies were also found to be very good when employing a Tris.HCl electrolyte adjusted to pH 4.8. Lastly, electropherogram reproducibility and capillary durability were examined with the finding that little deterioration of the capillary occurred over the course of 400 injections (200 h run time). This represents a notable improvement over previously documented derivatization procedures designed to reduce protein adsorption to fused-silica capillary walls.

Animals↗
PubMed1994

Secondary hyperparathyroidism, and not beta 2-microglobulin amyloid, as a cause of spontaneous tendon rupture in patients on chronic hemodialysis.

Spontaneous bilateral rupture of the extensor mechanisms of the knees, without significant history of trauma, has been reported rarely, generally in association with chronic metabolic disorders, such as chronic renal failure and secondary hyperparathyroidism. We report spontaneous tendon rupture in two patients on chronic hemodialysis for 4 and 11 years, with documented severe secondary hyperparathyroidism. One patient had spontaneous bilateral rupture of his quadriceps and partial avulsion of the left triceps tendons. The other patient had spontaneous rupture of his right quadriceps tendon. Both patients had markedly elevated serum intact parathyroid hormone and moderately elevated serum beta 2-microglobulin levels. Pathologic examination revealed diffuse immunohistochemical staining for beta 2-microglobulin but negative Congo-red staining of the ruptured tendon specimens. These cases and the previous reports in the literature suggest that secondary hyperparathyroidism may play a role in the pathogenesis of this clinical entity.

Adult↗