Biomedical subjects
R Shah
Publications and source records attributed to R Shah.
A paradigm shift in myelodysplastic syndromes.
A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propose that this picture is further complicated by a variety of cytokines, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and interleukin 1beta (IL-1beta) which exert a dual effect on the diseased cells. The immature CD34+ cells are stimulated to proliferate, while their later differentiated daughters are induced to undergo apoptosis accounting for the clinical syndrome of pancytopenia despite hypercellular BMs. Studies directed at measuring the rates of proliferation and apoptosis as well as the levels of TNF-alpha, TGF-beta and IL-1beta confirm this hypothesis and are presented in greater detail. A novel approach towards MDS therapy emerges as a result of this paradigm shift based upon the premise that anti-cytokine therapy would prevent excessive intramedullary apoptosis and result in improved cytopenias as well as cause a slowing down of the diseased precursor cell proliferation resulting in resumption of polyclonal hematopoiesis. Because a number of cytokines function through common lipid second messengers, interruption of this pathway should theoretically cause disruption in the signalling of a cascade of cytokines.
Results of surgical treatment of oesophageal cancer.
Oesophagogastrectomy is the best available treatment for patients with carcinoma of the oesophagus or cardia. A retrospective analysis of our experience with 485 patients who were treated surgically forms the basis of this report. Of the 317 patients who underwent resection (resectability rate of 65%) only 210 were considered to be potentially curative. Overall, the 5-year survival rate for oesophageal cancer was 3%, whilst curative resection had a 5-year survival rate of 22% and varied according to stages. Five-year survival rate was 67.7% for patients with Stage I disease compared with 27.6, 9.4 and 6.4% for Stages IIa, IIb and III disease respectively. There were no 5-year survivors with Stage IV disease or with those patients who underwent an incomplete resection. Curative resection carried a mortality rate of 3.8%, whereas incomplete resection or palliative procedure carried higher mortality rates of 14 and 20.7% respectively. Adequate post-operative analgesia was provided by continuous extrapleural intercostal nerve block. Morbidity, mainly caused by respiratory complications, occurred in 30 patients (6.2%), with three patients requiring ventilatory support. Outcome was influenced mostly by the extent of the disease and the completeness of surgical resection rather than by histological type. We conclude that surgical treatment provides better longevity than any other type of therapy and remains the standard against which combined modality treatment should be compared. Our experience suggests that surgical treatment can be achieved with minimal morbidity and mortality.
CPMP note for guidance: clinical trials on the medicinal products in the treatment of cardiac failure.
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Vascular reactivity in patients with peripheral vascular disease.
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.
Congenital clavicular pseudoarthrosis associated with vascular thoracic outlet syndrome: case presentation and review of the literature.
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.
The pattern of cytokine gene expression induced in rat T cells specific for myelin basic protein depends on the type and quality of antigenic stimulus.
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.
Differential rearing alters spine density on medium-sized spiny neurons in the rat corpus striatum: evidence for association of morphological plasticity with early response gene expression.
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.
1988: Continuous intercostal nerve block for pain relief after thoracotomy. Updated in 1995.
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Traumatic rupture of diaphragm.
Traumatic diaphragmatic rupture remains a diagnostic challenge, and associated injuries determine the outcome in those diagnosed early, whereas that of latent cases is dependent on the consequence of the diaphragmatic rupture: namely, the diaphragmatic hernia. To analyze the clinical and radiologic features and the therapeutic implications, we reviewed 980 patients reported in the English-language literature. This injury affects predominantly males (male:female = 4:1) in the third decade of life, and is often caused by blunt trauma (75%). There were 1,000 injuries, of which 685 (68.5%) were left-sided, 242 (24.2%) right-sided, 15 (1.5%) bilateral, and 9 (0.9%) pericardial ruptures; 49 cases were unclassified. Chest (43.9%) and splenic (37.6%) trauma were the most common associated injuries. The diagnosis was made preoperatively in 43.5% of cases, whereas in 41.3% it was made at exploration or at autopsy and on the remaining 14.6% of the cases the diagnosis was delayed. The mortality was 17% in those in whom acute diagnosis was made, and the majority of the morbidity in the group that underwent operation was due to pulmonary complications. Uniform diagnosis depends on a high index of suspicion, careful scrutiny of the chest roentgenogram in patients with thoracoabdominal or polytrauma, and meticulous inspection of the diaphragm when operating for concurrent injuries. Repeated evaluation for days after injury is necessary to discern injury in patients not requiring laparotomy. Acute diaphragmatic injuries are best approached through the abdomen, as more than 89% of patients with this injury have an associated intraabdominal injury. Patients with diaphragmatic rupture presenting in the latent phase have adhesion between the herniated abdominal and intrathoracic organs, and thus the rupture is best approached via a thoracotomy.
Pharmacodynamics of daily subcutaneous recombinant human interleukin-3 in normal volunteers.
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).
Pharmacokinetic evaluation of percutaneous hepatic venous isolation for administration of regional chemotherapy.
Hepatic artery infusion (HAI) chemotherapy has been used to treat patients with unresectable liver tumours. We report a preclinical study of the pharmacokinetics of HAI combined with hepatic venous drug extraction (HVDE) for regional administration of doxorubicin. HVDE was aided by a double balloon catheter inserted via femoral vein cutdown into the inferior vena cava to collect all hepatic vein blood. Pigs received doxorubicin 0.5-9.0 mg kg-1 over 90 min via HAI or systemic infusion (SYSI). HVDE was performed for 240 min. SYSI pigs underwent hepatic venous isolation without drug filtration. Doxorubicin levels were assayed using high-pressure liquid chromatography (HPLC). HAI/HVDE reduced systemic exposure to doxorubicin with equivalent hepatic exposure at all doses. Pharmacokinetic enhancement ranged from 7.0 to 22.3 for peak concentration, 8.8-23.2 for the area under the curve and 2.9-4.2 for tissue concentration. HAI/HVDE also prevented the mortality which was observed with SYSI administration of high-dose (5.0 and 9.0 mg kg-1) doxorubicin. We conclude that HAI/HVDE reduces systemic exposure to doxorubicin as compared with SYSI of equivalent doses. Pharmacokinetic enhancement indices suggest that HAI/HVDE may allow equivalent hepatic drug exposure with reduced systemic exposure. This method may be applicable to other drugs and to other anatomic settings in which enhanced regional drug delivery is desirable.
An evaluation of hepatic extraction and clearance of doxorubicin.
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.
Severe asthenozoospermia: a structural and functional study.
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.
Comparison of M and T type antigen testing to field inversion gel electrophoresis in the differentiation of strains of group A streptococcus.
Recent clusters of patients with acute rheumatic fever and invasive group A Streptococcus (GAS) have stimulated renewed interest in the epidemiology of streptococcal infections. We compared conventional serotyping for M and T antigens and serum opacity factor with field inversion gel electrophoresis (FIGE) for distinguishing among GAS. Fifteen pairs of throat isolates obtained from children positive for GAS before and after therapy were evaluated by conventional serotyping and by FIGE after SmaI digestion. Ten of the 15 pairs were identical by serotyping. FIGE correctly identified the 10 concordant and 5 discordant pairs. Individual clones were identified within each M type tested, including analysis performed on additional isolates of M1 and M3 obtained from the Centers for Disease Control and Prevention. This preliminary experience suggests that FIGE can successfully determine whether serial isolates from a given patient represent persistence of one strain or acquisition of a new strain of GAS and that this method might provide an alternative typing system for GAS.
Self-expanding tracheobronchial stents in the management of major airway problems.
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.
Gastric outlet obstruction of intrathoracic stomach.
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.
Rhabdomyosarcoma of the oesophagus. A case report.
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.