Biomedical subjects
Publications and source records attributed to V Kumar.
A case of a difficult intubation in a heavy smoker requiring reoperative coronary artery bypass grafting is presented. A technique is described to extubate patients with marginal pulmonary function and a difficult intubation using airway exchange catheters.
Conditions that trigger preadipocyte differentiation in vivo have yet to be elucidated. To investigate the role of endogenous arachidonic acid (AA) metabolites on adipose tissue growth, rat preadipocytes in primary culture were induced to differentiate using medium conditioned by isolated mature adipocytes (ACM). Differentiation was determined by assay of glycerol-3-phosphate dehydrogenase (GPDH). When collected in the presence of indomethacin (10 nmol/L) to inhibit prostaglandin (PG) synthesis by adipocytes, ACM induced greater differentiation (GPDH activity, 405 +/- 68 nmol NADH used/min/mg protein) than when indomethacin was added postcollection to inhibit preadipocyte PG synthesis (205 +/- 24, P < .05) or ACM alone (304 +/- 55). This suggested that PGs released by adipocytes inhibited differentiation, whereas those released by preadipocytes appeared to act in an autocrine manner to stimulate differentiation. However, 24-hour collections of ACM contained 125 pmol/L PGE2 and 900 pmol/L PGI2, concentrations too low to promote differentiation when added exogenously. Nordihydroguaiaretic acid (NDGA; 10 pmol/L), an inhibitor of lipoxygenase (LOX), stimulated the ACM-induced increase in GPDH activity (ACM, 99 +/- 13; ACM + NDGA, 369 +/- 130). In contrast, when differentiation was induced by a hormonal cocktail (MIX), including insulin and corticosterone, NDGA decreased GPDH activity (MIX, 329 +/- 66; MIX + NDGA, 142 +/- 40; P < .03). We concluded that preadipocyte differentiation within adipose tissue may be subject to both positive and negative regulators derived from AA metabolism resulting from both LOX and cyclooxygenase (COX) activity.
Dissection of the internal carotid artery is responsible for approximately 5% of ischemic strokes in adults. The pathophysiology of dissection can be either traumatic or spontaneous. The true incidence of spontaneous dissection is unknown. Once considered very rare, an increased awareness, combined with noninvasive evaluation by ultrasound and magnetic resonance angiography, has demonstrated a more frequent occurrence. Trivial trauma (ie, rather than external blunt or penetrating trauma) such as vomiting has rarely been documented as causing bilateral dissection. It is well recognized by neurologists but often not by other physicians. Prognosis is good, but delay in diagnosis may result in residual neurologic deficits. It should therefore be suspected early, especially in younger patients presenting with transient ischemic attacks or stroke.
BACKGROUND AND STUDY AIMS: There is controversy concerning the need for an antireflux procedure in patients undergoing open or endoscopic cardiomyotomy for achalasia. The addition of an antireflux wrap (partial or total), while preventing reflux, may result in persistence or incomplete relief of dysphagia in patients with total oesophageal aperistalsis. The technique of laparoscopic cardiomyotomy used in Dundee preserves the lateral and posterior attachments of the gastro-oesophageal junction, and was designed to minimize the risk of gastro-oesophageal reflux. PATIENTS AND METHODS: A consecutive series of patients with achalasia (n = 19) were treated by laparoscopic cardiomyotomy using the Dundee technique, which limits the mobilization to the anterior wall of the abdominal and thoracic oesophagus. The patients were followed up prospectively to assess the long-term relief of dysphagia and the postoperative incidence of reflux symptoms, with or without oesophagitis. RESULTS: The follow-up symptoms and assessment of the patients (15-53 months, median 27 months) showed total relief (n = 12) or substantial relief (n = 5) of dysphagia in 89%. On assessment at a median follow-up of 27 months, the number of patients experiencing heartburn after this operation increased from four of 15 to five of 15, and one patient (6.6%) developed endoscopically proved oesophagitis, with a positive oesophageal pH monitoring test. CONCLUSIONS: The routine addition of an antireflux operation is not justified in patients undergoing laparoscopic cardiomyotomy, provided that the lateral and posterior attachment of the oesophagus are kept intact.
A HBx-specific mouse monoclonal antibody was developed and its epitope mapped to a hydrophilic segment 94HKRTLGL100 using the multipin peptide synthesis technique. A sensitive ELISA with a threshold of 5 to 10 ng was developed to identify the HBx-positive hepatitis B cases and measure the levels of HBx in sera. The same patient sera were also analyzed for the presence of anti-HBx using the purified recombinant antigen. HBx was present in 23% of the cases (15/65) whereas only 14% of the cases (9/65) were positive for anti-HBx. The mean value of HBx in acute hepatitis sera was higher (522 ng/ml) than in cirrhosis cases (48 ng/ml). PCR amplification of the S gene showed that all 15 HBx-positive cases were also positive for the viral DNA.
Mouse NK cells may use both cytokine, e.g. IFN-gamma, tumor necrosis factor (TNF)-alpha and IL-12, and cytotoxic, e.g. perforin and Fas-FasL, pathways to reject incompatible bone marrow cell (BMC) grafts. To begin a dissection of these two major pathways, mice bearing deletional mutations of IFN-gamma, TNF-RI/II or perforin, or mice treated with mAb to IL-12, IFN-gamma or NK1.1 were irradiated and challenged with class I-deficient BMC grafts, a system in which only NK cells are the effector cells. Proliferation of the donor-derived cells was judged in terms of splenic incorporation of [125I]iododeoxyuridine 5 or 7 days after cell transfer. All of these mice maintained in a specific pathogen-free (s.p.f.) environment were able to reject the BMC, except those treated with anti-NK1.1 mAb. However, perforin deficient mice maintained in a conventional breeding facility failed to reject class I (Tap-1)-deficient marrow cells. Transfer of mice from the pathogen-free to the conventional facility resulted in a slow and incomplete loss of the ability to reject marrow cells. Thus, the breeding colony environment can elicit otherwise undetectable defects in the rejection ability of perforin-deficient NK cells. This report will hopefully alert those investigators who have only studied immune gene knockout mice in s.p.f. facilities and found no significant abnormalities.
Reactive perforating collagenosis is characterised by trans-epidermal elimination of collagen and is hypothesized to be both autosomally dominant and recessive. We report a family in which two brothers and a sister had lesions of reactive perforating collagenosis.
During many autoimmune conditions, a T-cell response initially focused to a self-antigen evolves towards the recruitment of T cells to multiple antigenic determinants. Here we discuss whether such determinant spreading involves T cells activated in the peripheral lymphoid organs, or alternatively, whether the diversification occurs after infiltration of the initiating T cells into the target organ, for example, into the central nervous system during experimental autoimmune encephalomyelitis, a prototype for multiple sclerosis. The expression of myelin antigens in the thymus and spleen may not only contribute to the induction of tolerance but also to determinant spreading. In this case, the outcome of in vivo diversification may ultimately be determined by the balance between type 1 and type 2 responses to antigenic determinants derived from myelin components. Thus, spreading T cells could modulate disease progression positively or negatively, depending upon the nature of the accompanying cytokine secretion profile.
In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence-activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)-2/15 receptor beta (CD122) chain and common gamma (gamma c) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with gamma c. Recently developed IL-15 and IL-15 receptor alpha knockout mice have pinpointed IL-15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK-cell development as well as minor roles for stem cell factor and IL-7 in expanding NK-cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.
VEGF-C is a recently discovered secreted polypeptide related to the angiogenic mitogen VEGF. We have isolated the quail VEGF-C cDNA and shown that its protein product is secreted from transfected cells and interacts with the avian VEGFR3 and VEGFR2. In situ hybridization shows that quail VEGF-C mRNA is strongly expressed in regions destined to be rich in lymphatic vessels, particularly the mesenteries, mesocardium and myotome, in the region surrounding the jugular veins, and in the kidney. These expression sites are similar to those observed in the mouse embryo (E. Kukk, A. Lymboussaki, S. Taira, A. Kaipainen, M. Jeltsch, V. Joukov and K. Alitalo, 1996, Development 122, 3829-3837). We have observed VEGFR3-positive endothelial cells in proximity to most of the VEGF-C-expressing sites, suggesting functional relationships between this receptor-ligand couple. The comparison of the VEGF and VEGFR2 knockout phenotypes had suggested the existence of another ligand for VEGFR2. We therefore investigated the effect of VEGF-C on VEGFR2-positive cells isolated from the posterior mesoderm of gastrulating embryos. We have recently shown that VEGF binding triggers endothelial differentiation of these cells, whereas hemopoietic differentiation appears to be mediated by binding of a so far unidentified VEGFR2 ligand. We show here that VEGF-C also triggers endothelial differentiation of these cells, presumably via VEGFR2. These results indicate that VEGF and VEGF-C can act in a redundant manner via VEGFR2. In conclusion, VEGF-C appears to act during two different developmental phases, one early in posterior mesodermal VEGFR2-positive endothelial cell precursors which are negative for VEGFR3 and one later in regions rich in lymphatic vessels at a time when endothelial cells express both VEGFR2 and VEGFR3.
The number of coronary stents may be over half a million world-wide. The neurologist and radiologist are frequently confronted with cardiac patients who have had a recent carotid or coronary stent implanted and present with an acute and unrelated stroke for which an MRI is recommended. We have reviewed and classified all the major stents currently available world-wide and discussed their interaction with MRI through their ferro-magneticity. All current stents are MRI safe and MRI can be done anytime.
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Alzheimer's disease is a chronically progressive neurodegenerative disorder. Examinations of brains of Alzheimer's disease patients have shown various neuropathologic and neurochemical deficits, especially decreases in acetylcholine, norepinephrine, serotonin, and some neuropeptides. During the long course of the illness, almost every patient experiences psychiatric symptoms and exhibits behavioral disturbance, most of which can be treated effectively with antidepressant, antipsychotic, and mood-stabilizing drugs. This article is divided into several sections to discuss specific symptoms and relevant medications used to treat each of these symptoms: cholinergic drugs, anti-inflammatory agents, antiamyloidigenic strategy and antioxidant therapy, estrogen, management of psychosis and agitation, and management of depression.
Twenty three clinical isolates M. tuberculosis and the reference strain, M. tuberculosis H37Rv were tested for their susceptibility to trifluoperazine (TFP) by the standard broth dilution method and the bioluminescence assay. The results showed that in 15 of the 23 isolates, the minimal inhibitory concentration (MIC) was identical in both the methods and in the remaining 8 isolates the difference in the MIC values between the methods, was less than two fold and was not significant. The findings suggest that the measurement of adenosine triphosphate (ATP) by bioluminescence assay can be employed as an alternative method for the rapid screening of clinical isolates for their susceptibility to anti-mycobacterial agents.
We have assessed whether melatonin can induce c-fos expression at various circadian phases, and whether melatonin can inhibit photically induced c-fos expression in the suprachiasmatic nucleus (SCN) in both rats and Syrian hamsters. Subcutaneous administration of melatonin at a dose of 100 microg/kg neither induced expression of Fos, the protein product of the c-fos proto-oncogene, nor inhibited the expression of Fos-like immunoreactivity (Fos-lir) induced by a light pulse in the SCN of rats and hamsters. In situ hybridization studies also demonstrated the absence of induction by acute melatonin treatments of c-fos mRNA in the SCN. Taken together, these results demonstrate that melatonin effects on SCN cells involve signal transduction pathways that do not include regulation of c-fos gene expression.
Autoimmune diseases are often characterized by spontaneous remission followed by relapses. Although the mechanism(s) controlling pathogenic self-reactive T cells are not fully understood, recent data in experimental autoimmune encephalomyelitis (EAE), a prototype for CD4 T cell-mediated autoimmune diseases, indicate that spontaneous recovery is mediated by regulatory T cells (Treg) specific for peptides derived from the beta-chain of the TCR. Here we have tested whether recombinant single-chain TCRs (scTCRs) containing Vbeta domains can be used as vaccines for efficient priming of Treg. A single injection of mice with these recombinant proteins leads to efficient in vivo priming of Treg and almost complete protection from Ag-induced EAE. Significantly, administration of scTCRs during ongoing disease at a 10-fold lower dose than that required for prophylactic treatment also reverses established EAE. However, if a higher dose of scTCR is administered during ongoing disease, paralytic symptoms become exacerbated and the majority of treated animals die from severe and chronic EAE. Furthermore, we demonstrate that regulatory determinants are processed and presented from scTCRs resulting in the recruitment of both CD4 and CD8 regulatory T cells which are required for efficient regulation induced by scTCR. Reversal of established disease following an optimum dose of recombinant TCRs suggests that proteins expressing appropriate Vbeta domains could be used for the treatment of a variety of T cell-mediated pathologic conditions.
We have developed a stroma-free culture system in which mouse marrow or thymus cells, known to be enriched for lymphoid progenitors, can be driven to generate natural killer (NK) cells. Culture of lineage marker (Lin)-, c-kit+, Sca2+, interleukin (IL)-2/15Rbeta (CD122)- marrow cells in IL-6, IL-7, stem cell factor (SCF), and flt3 ligand (flt3-L) for 5-6 d followed by IL-15 alone for an additional 4-5 d expanded the starting population 30-40-fold and gave rise to a virtually pure population of NK1.1+, CD3- cells. Preculture in IL-6, IL-7, SCF, and flt3-L was necessary for inducing IL-15 responsiveness in the progenitors because the cells failed to significantly expand when cultured in IL-15 alone from the outset. Although culture of the sorted progenitors in IL-6, IL-7, SCF, and flt3-L for the entire 9-11-d culture period caused significant expansion, no lytic NK1.1+ cells were generated if IL-15 was not added, demonstrating a critical role for IL-15 in NK differentiation. Thus, two distinct populations of NK progenitors, IL-15 unresponsive and IL-15 responsive, have been defined. Similar results were obtained with Lin-, CD44+, CD25-, c-kit+ lymphoid progenitors obtained from adult thymus. The NK cells generated by this protocol lysed the NK-sensitive target YAC-1 and expressed markers of mature NK cells with the notable absence of Ly-49 major histocompatibility complex (MHC) receptors. However, despite the apparent lack of these inhibitory MHC receptors, the NK cells generated could distinguish MHC class I+ from class I- syngeneic targets, suggesting the existence of novel class I receptors.
The recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant 'mature' VEGF-C made in yeast bound VEGFR-3 (K[D] = 135 pM) and VEGFR-2 (K[D] = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure-function relationships in the PDGF/VEGF family.