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Biomedical subjects

A Jain

Publications and source records attributed to A Jain.

At least 235 records · Page 13Linked to original sources
PubMed1995

Absence of mutations in the MEN2A region of the ret proto-oncogene in non-MEN 2A phaeochromocytomas.

OBJECTIVE: To determine the presence of abnormalities of the MEN2A region of the ret proto-oncogene in phaeochromocytomas/paragangliomas (PHAEO) of different aetiologies. DESIGN: Total RNA was extracted from tumours and used as templates for reverse transcriptase polymerase chain reactions. A ret primer pair, which encompasses the region which is mutated in the germ-line of patients with MEN 2A, was used. The resulting 262-bp product was sequenced. PATIENTS: Ten PHAEOs were examined. Four tumours were from von Hippel-Lindau disease patients; five were sporadic, isolated tumours; one from a patient with multiple endocrine neoplasia type 2A (MEN 2A). The medullary thyroid cancer from the single MEN 2A patient was also examined. RESULTS: A heterozygous TGC to CGC mutation of codon 634 (cysteine to arginine) was found in the PHAEO and medullary thyroid cancer from the MEN 2A patient. The 262-bp ret fragment was not found in two tumours (one malignant PHAEO and one secretory paraganglioma), although the intra-cellular ret tyrosine kinase domain was detected in these tumours. The cysteine codons were normal in all other non-MEN 2A PHAEOs. CONCLUSION: Mutations of key cysteine codons of the ret proto-oncogene may be specific to MEN 2A.

Adrenal Gland Neoplasms↗
PubMed1995

Clinical pharmacokinetics of tacrolimus.

Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.

Drug Interactions↗
PubMed1995

Biometals in skin and sera of leprosy patients and their correlation to trace element contents of M. leprae and histological types of the disease; a comparative study with cutaneous tuberculosis.

The present study has provided information on the biometal contents of killed and dried Mycobacterium leprae as well as dermal granulomas induced by the invading mycobacteria in various histological types of leprosy patients. For comparison, the biometal contents of the contralateral leprosy-unaffected skin of the same patients also were measured. The study also reports changes of serum levels of the biometals in these patients which were compared with those in healthy control subjects and patients with skin tuberculosis. These data show that M. leprae is rich in zinc. During the course of the evolution of the disease there is gross alteration of the dynamics of the inflammatory cell population that infiltrates into leprosy granulomas, resulting in the alterations of trace element contents of the disease-affected skin lesions. Interestingly, the changes of the biometal contents in the granulomas of the patients with skin tuberculosis are similar to those in leprosy patients. It is postulated that the significant decrease of the contents of copper, zinc, iron, calcium and magnesium in the disease-affected skin in comparison to that of the contralateral healthy skin is a local effect, perhaps due to erosion or influx of biometal-deficient inflammatory cells into the affected skin with eventual loss of connective tissue of skin and mobilization of tissue-bound microelements into the vascular compartment. On the contrary, the changes in biometal levels in the sera of leprosy patients appear to be a general effect perhaps due to the release of interleukin-1, a product of inflammatory cells, causing hypercupremic, hypozincemic and hypoferremic responses in the hosts. Moreover, growth and multiplication of M. leprae, especially in polar lepromatous leprosy patients with a high bacillary load, demand essential biometals which may be mobilized into the bacterial bodies from the hosts. This perhaps results in the change in the homeostasis of the essential biometals in the hosts.

Adult↗
PubMed1995

Evaluation of antibody responses in Indian kala-azar by immunoblot.

When infected with Leishmania species, patients develop specific antibodies that constitute the basis of serodiagnosis. using Western blot analysis we studied the specificity of anti-leishmania donovani antibodies in patients with visceral leishmaniasis, healthy subjects living in an endemic and non-endemic areas, and patients of other infectious diseases like malaria, leprosy, tuberculosis and tropical splenomegaly. Sera from patients with kala-azar recognised numerous antigens that had a molecular weight of 150 KD, 145 KD, 120 KD, 92 KD, 87 KD, 72 KD, 65 KD, 56 KD, 50 KD, 40 KD, 26 KD, 21 KD, 14 KD, AND 12 KD. The 150, 145, 120, 92, 87, 81, 65, 25, 21, 14, and 12 KD antigens had the greatest specificity for kala-azar sera while the bands of molecular weights 72, 56, 50, and 40 KD were found to be cross reactive with sera of patients of other diseases.

Animals↗
PubMed1995

A study of autonomic neuropathy in diabetes mellitus in relation to its metabolic control.

50 Patients of diabetes mellitus (both IDDM and NIDDM) were selected with typical symptoms, signs and positive bed side tests of autonomic neuropathy. All the patients were followed for three months during which strict metabolic control was achieved by routine treatment with oral hypoglycaemic agents and/or insulin, simply by change in their previous treatment dosages and better attention to diet and physical activity. 22% patients showed significant improvement in symptoms of autonomic neuropathy. 42% showed partial improvement and 36% patients did not show any improvement. Improvement in objective test score was significant in 18%, partial in 46% and insignificant in 36%. Improvement in neuropathy did not correlate with HbA1C levels. 36% patients did not show any subjective or objective improvement in autonomic neuropathy inspite of good glycaemic control as indicated by normal HbA1C levels in them.

Administration, Oral↗
PubMed1994

OEIS complex with craniofacial anomalies--defect of blastogenesis?

We report on a 31-week fetus with hydrocephalus, hypertelorism, microtia, short neck, vertebral and rib defects, scoliosis, omphalocele, exstrophy of bladder, absent external genitalia and pubic rami, imperforate anus, diaphragmatic hernia, defective lobulation of lungs, single kidney, bicornuate uterus, and flexion deformities of the limbs. Similar extensive anomalies in the rostral and caudal regions were described by Russell et al. [Pediatrics, 67:176-182, 1981] and Stewart et al. [Am J Med Genet, 45:426-429, 1993]. The patients described by them had a combination of the oculo-auriculo-vertebral sequence (OAV) and caudal deficiency sequence, whereas the patient reported here can best be described as a combination of OAV and OEIS (omphalocele, exstrophy of bladder, imperforate anus, spinal defects) complexes. The widespread malformations seen in our patient may be the result of an error during blastogenesis.

Abnormalities, Multiple↗
PubMed1994

Identification of two hydrophobic patches in the active-site cavity of human carbonic anhydrase II by solution-phase and solid-state studies and their use in the development of tight-binding inhibitors.

This paper describes inhibitors for human carbonic anhydrase II (HCAII, EC 4.2.1.1) that bind with nanomolar dissociation constants. These inhibitors were developed by exploiting interactions with hydrophobic "patches" in the lip of the active site of this enzyme. These patches are molecular surfaces presented by a phenylalanine on one face of the active-site cleft (Phe-131) and three adjacent hydrophobic residues on the opposite face (Leu-198 and Pro-201/202). Comparison of the affinities of molecules that can occupy either one or both of the two sites indicates that these hydrophobic interactions can contribute factors of 10(2)-10(3) to binding constants and that the strength of the interaction is relatively insensitive to the structure of the hydrophobic ligand. One of these inhibitors, the competitive inhibitor N-[N-[N-(4-sulfamoylbenzoyl)phenylglycyl]glycyl]glycine benzyl ester (17), has been studied by X-ray crystallographic methods in its complex with HCAII at 1.9-A resolution. The geometry of binding of the arylsulfonamide group of 17 is similar to geometries observed in other HCAII-arylsulfonamide complexes. The aromatic side chain of the phenylglycine residue of the inhibitor is inferred to pack against the hydrophobic Phe-131 face, and this interaction "steers" the peptide backbone of the inhibitor toward a region in the HCAII active site different from that occupied in the related triglycyl peptide. Attempts to design inhibitors capable of binding simultaneously to Phe-131 and Leu-198/Pro-201/202 did not lead to molecules that bound more tightly than those binding to these hydrophobic sites individually.

Amino Acid Sequence↗
PubMed1994

An unusual 30-kDa protein binding to the polyhedrin gene promoter of Autographa californica nuclear polyhedrosis virus.

Gel retardation assays using nuclear extracts from the Autographa californica nuclear polyhedrosis virus-infected Sf21 (Spodoptera frugiperda) insect cell line revealed a host factor (polyhedrin promoter-binding protein or PPBP) that binds to the polyhedrin gene promoter. A hexanucleotide sequence (AATAAA) within the promoter is important for binding in association with neighboring elements, some of which are contributed by the sequence TAAGTATT present at the transcription start point. PPBP was affinity purified and appears to be an unusual DNA-binding protein with respect to its stability (binding was obtained at NaCl concentrations and temperatures ranging from 0.2 to 2 M and 0 to 65 degrees C, respectively), high binding affinity (binding even in the absence of nonspecific DNA) with an apparent dissociation constant of approximately 3.7 x 10(-12) M, and high specificity (binding was unaffected in the presence of a 50,000 times excess of nonspecific DNA). From UV cross-linking and Southwestern analyses the molecular mass of PPBP was estimated to be approximately 30 kDa. PPBP is phosphorylated and may have a regulatory function because dephosphorylation abolished DNA binding activity. Differences in PPBP characteristics between nuclear extracts from Sf21 and from Bm5 (Bombyx mori) cell line suggested that additional factors may be involved in the interaction of PPBP with the polyhedrin promoter.

Animals↗
PubMed1994

Protein simulations using techniques suitable for very large systems: the cell multipole method for nonbond interactions and the Newton-Euler inverse mass operator method for internal coordinate dynamics.

Two new methods developed for molecular dynamics simulations of very large proteins are applied to a series of proteins ranging up to the protein capsid of tomato bushy stunt virus (TBSV). For molecular dynamics of very large proteins and polymers, it is useful to carry out the dynamics using internal coordinates (say, torsions only) rather than Cartesian coordinates. This allows larger time steps, eliminates problems with the classical description of high energy modes, and focuses on the important degrees of freedom. The resulting equation of motion has the form. [formula: see text] where for T is the vector of generalized forces, M(theta) is the moments of inertia tensor, theta is the vector of torsions, and C is a vector containing Coriolis forces and nonbond forces. The problem is that to calculate the acceleration vector theta from M, C, and T requires inverting M(theta), an order N3 calculation. Since the number of degrees of freedom might be 300,000 for a million atom system, solving these equations every time step is impractical, restricting internal coordinate methods to small systems. The new method, Newton-Euler Inverse Mass Operator (NEIMO) dynamics, constructs the torsional accelerations vector theta = M-1 (T-C) directly by an order N process, allowing internal-coordinate dynamics to be solved for super larger (million atom) systems. The first use of the NEIMO method for molecular dynamics of proteins is presented here. A second serious difficulty for large proteins is calculation of the nonbond forces. We report here the first application to proteins of the new Cell Multipole Method (CMM) to evaluate the Coulomb and van der Waals interactions. The costs of CMM scales linearly with the number of particles while retaining an accuracy significantly better than standard nonbond methods (involving cutoffs). Results for NEIMO and CMM are given for simulations of a wide range of peptide and protein systems, including the protein capsid of TBSV with 488,000 atoms. The computational times for NEIMO and CMM are demonstrated to scale linearly with size. With NEIMO the dynamics time steps can be as large as 20 fs (for small peptides), much larger than possible with standard Cartesian coordinate dynamics. For TBSV we considered both the normal form and the high pH form, in which the Ca2+ ions are removed. These calculations lead to a contraction of the protein for both forms (probably because of ignoring the RNA core not observed in the X-ray).

Algorithms↗
PubMed1994

Predictors of restenosis: a morphometric and quantitative evaluation by intravascular ultrasound.

Despite advances in catheter-based interventional techniques, restenosis remains a major complication of angioplasty. Recently, intravascular ultrasound imaging (IVUS) has provided new insight into plaque composition and geometric distribution inside the vessel. To investigate if IVUS-defined parameters can predict restenosis in patients after coronary angioplasty, we performed IVUS in 33 patients (33 lesions) after balloon angioplasty (n = 25) or directional atherectomy (n = 8). Qualitative analysis included assessment of plaque composition, plaque eccentricity, plaque fracture, and presence of dissection. In addition, minimal luminal diameter, percent diameter stenosis, percent area stenosis, plaque burden, and elastic recoil were quantitatively analyzed. Follow-up data were obtained 1, 2, and 6 months after angioplasty and were available for 30 patients. Angiographic restenosis occurred in 11 patients (group 1), and no restenosis occurred in 19 patients (group 2) by clinical (n = 10) or angiographic (n = 9) assessment. Plaque fracture was noted in 30% of group 1 patients and 74% of group 2 patients (p = 0.04). Major dissections were more frequent in group I than in group II (78% vs 10%, p = 0.009). Of the quantitative parameters analyzed, plaque burden was significantly higher in group 1 than in group 2 (0.50 +/- 0.05 vs 0.34 +/- 0.05, p = 0.0001). In 78% of the patients with plaque burden of > 0.40, restenosis developed. Thus, of the various parameters analyzed, the absence of plaque fracture, the existence of a major dissection, and greater plaque burden were associated with increased incidence of restenosis. Our results indicate that IVUS can identify a subset of patients in whom restenosis is likely to develop. Information about the morphologic features of the atheroma and its composition may be used to modify the interventional strategy and thus optimize lumen size and possibly reduce the chance of restenosis.

Aged↗
PubMed1994

Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency.

A 45-month-old girl with 5-oxoprolinuria (pyroglutamic aciduria), hemolysis, and marked glutathione depletion caused by deficiency of glutathione synthetase was followed before and during treatment with ascorbate or N-acetylcysteine. High doses of ascorbate (0.7 mmol/kg per day) or N-acetylcysteine (6 mmol/kg per day) were given for 1 to 2 weeks without any obvious deleterious side effects. Ascorbate markedly increased lymphocyte (4-fold) and plasma (8-fold) levels of glutathione. N-Acetylcysteine also increased lymphocyte (3.5-fold) and plasma (6-fold) levels of glutathione. After these treatments were discontinued, lymphocyte and plasma glutathione levels decreased rapidly to pretreatment levels. Ascorbate treatment was extended for 1 year, and lymphocyte (4-fold) and plasma (2- to 5-fold) glutathione levels remained elevated above baseline. In parallel, the hematocrit increased from 25.4% to 32.6%, and the reticulocyte count decreased from 11% to 4%. The results demonstrate that ascorbate and N-acetylcysteine can decrease erythrocyte turnover in patients with hereditary glutathione deficiency by increasing glutathione levels.

Acetylcysteine↗