Biomedical subjects
Publications and source records attributed to R Shah.
Noninvasive techniques have been used to demonstrate a specific pattern of impaired vasoactive response in the normal brachial artery of patients with clinical atherosclerosis. This is a physiologic reflection of the systemic nature of atherosclerosis and may be useful as a marker for identifying patients with preclinical atherosclerotic disease.
Thoracic outlet syndrome (TOS) associated with congenital clavicular pseudoarthrosis is rare in adults and often misdiagnosed. In this case report, we describe an adult female who was found to have thrombosis of the subclavian and axillary arteries with embolization documented by invasive angiography. This unusual vascular manifestation of TOS should remind physicians that anatomic derangements may predispose to upper extremity ischemia.
Rat T cells reactive against myelin basic protein (MBP) are exclusively, CD4+ CD8- CD45RC-, inevitably produce abundant IFN-gamma, and appear to correspond to members of the Th1 CD4+ T cell subset characterized in mice. To ascertain the basis of the pathogenic activity of these cells, we studied their pattern of cytokine expression in response to activation by distinct TCR ligands. Using RT-PCR and Northern blot assays to quantify cytokine gene production and cytokine production from intact cells, we show that (i) rat MBP-reactive T cells express IL-2, IFN-gamma, and TNF-alpha as well as IL-5 and IL-10; (ii) cytokine production is not an all or nothing phenomenon, but rather varies according to the type and dose of TCR ligand, leading to variation in the pattern of cytokine production, or dissociation between cytokine production and cell proliferation; and (iii) nonencephalitogenic T cells do not differ appreciably from their encephalitogenic counterparts in ability to produce major cytokines.
Morphological plasticity of medium-sized spiny neurons of the striatum was examined in Long-Evans hooded rats reared in complex or individual cage environments. Rat pups, aged 28-32 days, were housed either individually in standard laboratory cages or as a group in a large toy- and object-filled environment for 30 days. The spine density on dendrites of medium-sized spiny neurons in the dorsolateral striatum was then examined using the Golgi-Cox method. Rats reared in the complex environment displayed an increase of approximately 30% in spine density relative to those reared individually. These results demonstrate experience-dependent changes in neural structure in the striatum and suggest that the mechanisms for information storage in response to experience may be more widespread in the forebrain than previously believed.
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Normal volunteers received subcutaneous injections of recombinant human interleukin-3 (rhIL-3) on 4 consecutive days to characterize toxicity, pharmacokinetics, and hematopoietic effects. Dosages were 2.5, 5.0, and 7.5 micrograms/kg/day (n = 6 subjects per group). Adverse effects consisted predominantly of flu-like symptoms such as fever and headache. Mean area under the serum concentration-time curve and maximum serum concentration were linearly related to dose. Serum clearance was not apparently related to dose. Clearance increased slightly but significantly between days 1 and 4. Rapid but modest elevations in neutrophil and eosinophil counts were observed during treatment. Mean platelet counts rose modestly, peaking on day 10. Increases of CD34+ cell counts were correlated with increases of colony-forming unit-granulocyte macrophage (peak, day 7).
A swine model was developed to study quantitatively the pharmacokinetics of hepatic extraction and clearance of doxorubicin (DOX). Systemic and hepatic artery infusions of DOX (0.5-9 mg kg-1) were administered to 34 pigs. Pharmacokinetic analysis was simplified by use of a double-balloon catheter in the inferior vena cava to collect hepatic venous effluent. During hepatic artery infusion only, DOX in hepatic venous blood was extracted using activated carbon filters to prevent drug recirculation. Hepatic extraction and clearance of DOX were independent of dose and route of administration. Extraction ratios varied from 0.75 to 0.91 during hepatic artery infusion and from 0.50 to 0.72 during systemic infusion. Clearance results were analogous. After cessation of drug infusions, hepatic extraction and clearance of DOX was negative, suggesting that the liver serves as a drug reservoir during DOX infusion and subsequently is a net source of unmetabolised drug. Liver extraction and clearance of DOX in pigs are substantial. During either systemic or hepatic artery infusion of DOX, the liver serves as a drug reservoir. Subsequent mobilisation of this hepatic pool of DOX may cause prolonged systemic exposure to drug.
Ejaculates from 25 patients with severe asthenozoospermia (all spermatozoa immotile or only non-progressively motile) were studied to identify individually the cause of impaired motility. Multiple tests were performed, viz. light and electron microscopic studies and sperm function tests. An objective scoring was applied to both the routine and the functional analyses. Three categories of samples were identified: (1) necrozoospermia (n = 9), where sperm viability was very poor; (2) structural tail abnormality as seen by light microscopy (n = 4); and (3) ultrastructural abnormality (n = 12). In the last category, one case showed absence of dynein arms; this was associated with mitochondrial abnormalities. Mitochondrial abnormality with normal tail components was observed in the majority (n = 7) and accessory fibre abnormality in four cases. The scoring system revealed that, functionally, all samples were abnormal whereas routine analysis showed 15 samples to be subnormal and 10 to be abnormal, which indicates the need for functional analysis. Because of the multiple defects seen in these samples, there is a need for a battery of sperm function tests. This study indicates that mitochondrial defects are one of the causes that may account for the loss of sperm motility in the patient population.
The management of patients with critical major airways obstruction has been made possible by the recent introduction of expandable metal stents as the sole treatment or as an adjunct to other treatment modalities, to alleviate the distressing symptoms from tracheobronchial obstructions Gianturco self-expanding stents were used successfully in the management of 27 patients. The indications were: stenosis from postoperative strictures and recurrent tumours (n = 6), extrinsic compression from metastatic disease (n = 9), inoperable primary tumours of central airways (n = 9), airway collapse from relapsing polychondritis (n = 1), excessive mediastinal shift following right pneumonectomy (n = 1) and endobronchial non-Hodgkin's lymphoma (n = 1). Twenty three patients had immediate relief of stridor and the remaining two patients were successfully weaned from ventilatory support. There were two postoperative deaths. The stents were inserted under general anaesthesia through a rigid bronchoscope under direct vision. The ease of insertion under radiological control, self-expanding nature of the stents and the lack of major complications on follow-up of up to 47 months are particular advantages. The self-expanding tracheobronchial stents are a useful addition to our armamentarium in maintenance of the airways in patients with major airway stenosis and collapse.
Two rare cases of organic outlet obstruction of intrathoracic stomach following Ivor Lewis oesophagectomy are presented. Aetiology and the management of the same is discussed.
A rare case of rhabdomyosarcoma of the oesophagus is presented. The clinical, radiologic, and histopathologic features are reviewed. A review of the literature revealed only thirteen cases of this type.
The E. coli RuvC protein resolves Holliday junctions during genetic recombination and postreplication repair. Using recombination intermediates made by RecA protein, we have identified specific "hotspots" for RuvC resolution. Characterization of these sites reveals a common tetranucleotide sequence, with the consensus 5'-A/TTT decreases G/C-3'. The correct orientation of the resolution site is required for cleavage. These observations suggest that the strand bias of this sequence will affect the outcome of recombinational crosses by directing resolution to either "patch" or "splice" recombinant products. Mutation of the consensus site in synthetic Holliday junctions abolishes or significantly reduces the efficiency of cleavage, although binding is unaffected, demonstrating that junction recognition and incision are biochemically separable events. We propose that efficient RuvC resolution requires the translocation of Holliday junctions to specific cleavage sites, thus providing a biochemical basis for the similar genetic defects observed in ruvA, ruvB, and ruvC mutants.
The Escherichia coli RuvC protein is an endonuclease that resolves Holliday junctions. In vitro, the protein shows efficient structure-specific binding of Holliday junctions, yet the rate of junction resolution is remarkably low. We have mapped the sites of cleavage on a synthetic junction through which a crossover can branch migrate through 26 bp and find that > or = 90% of the junctions were cleaved at one site. This observation of sequence-specific cleavage suggests that inefficient resolution may be due to DNA binding events which occur away from the cleavage site and are therefore non-productive. Holliday junction resolution by RuvC protein can be stimulated by a number of factors including: (i) the presence of Mn2+ (rather than Mg2+) as the divalent metal cofactor, (ii) alkaline pH (< or = 10), and (iii) elevated temperature. These observations may indicate that other proteins are required for efficient RuvC-mediated resolution.
Reports of the expression of very similar TCR structures by disparate rodent encephalitogenic T cells reactive with regions of MBP have aroused much interest for both theoretical and practical reasons. To ascertain the extent to which structural requirements of epitope recognition constrain TCR expression by MBP-reactive T cells, we set out to estimate the size of the overall repertoire of TCR beta-chain V beta-D beta-J beta (VDJ) assemblies in T cells of Lewis rats specific for MBP(68-88) as well as those specific for MBP(87-99). We previously reported that such T cells can express a diversity of V beta genes as revealed by PCR analysis. In this study, we have used direct sequencing of PCR products amplified from encephalitogenic T-cell clones and pauciclonal T-cell lines to demonstrate that VDJ structures of the rat T cells specific for either residues 68 to 88 or 87 to 99 of MBP are highly heterogeneous. Our results showed that (1) no pattern is evident in the utilization of germline J gene segments by individual T-cell clones; from a total of over 100 successfully sequenced clones displaying in-frame rearrangements, all the J beta segments have been demonstrated. (2) Even among the T-cell clones which share the V beta expression, J beta is variable. (3) Due to joining variations between the V beta, D beta, and J beta gene segments, no two of the T-cell clones examined share entire VDJ structures. Our study is the first report of nucleotide and amino acid sequences of TCR beta-chains from rat encephalitogenic T cells expressing V beta genes other than V beta 8.2. It demonstrates that the TCR repertoire of the MBP-reactive as well as encephalitogenic T cells is heterogeneous, even though a certain T-cell subset frequently dominated by the mechanism needs to be clarified.
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A postal survey of all trainee anaesthetists in the North West Region of England was conducted to investigate areas important in determining the trainee's quality of life. The questionnaire enquired about life on-call, hospital facilities available to doctors and trainees' morale. The results suggest that changes are urgently required to improve trainees' lifestyles and therefore help raise morale within the profession.
Glomerular mesangial cells are considered to be modified smooth muscle cells and seem to play a role in the maintenance of glomerular hemodynamics. The present study was carried out to determine the effect of opioids on adhesiveness, spreading and migration of mesangial cells. Morphine enhanced spreading of mesangial cells at early time periods (5 mini, control 8 +/- 2% vs. morphine 15 +/- 1%, p < 0.05; 15 min, control 21 +/- 5% vs. morphine 38 +/- 2%, p < 0.05) as well as at later time periods when compared to control cells (at 2 h, control 23 +/- 1% vs. morphine 49 +/- 1%, p < 0.001; at 3 h, control 28 +/- 3% vs. morphine 63 +/- 2%, p < 0.05). beta-Endorphin also enhanced (p < 0.001) spreading of mesangial cells (at 2 h, control 23 +/- 1% vs. beta-endorphin 48 +/- 3%; at 3 h, control 28 +/- 3% vs. beta-endorphin 65 +/- 1%). Morphine decreased adhesion of mesangial cells to the plastic substrate at 24 h as well at 48 h when compared to the control cells. Naloxone attenuated the effect of morphine on adhesion to the substrate. Morphine enhanced (p < 0.05) migration (percentage of denuded area covered by mesangial cells when compared to control cells (control 26.07 +/- 1.08% vs. morphine 37.5 +/- 2.94%; n = 9). Since the morphine-induced decreased adhesiveness could be attenuated by naloxone, this effect of morphine on mesangial cells appears to be mediated by opioid receptors.
Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P < .01 by chi 2 test), and it increased markedly with progression to failure (P = .05). Creatine kinase-B mRNA also rose markedly with heart failure (P < .01). Levels of mRNA encoding beta-myosin heavy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase did not significantly change from baseline, despite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or systolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2 +/- 1.9 mm Hg) compared with those hearts in which it did not change (+4.0 +/- 4.9, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)