Biomedical subjects
Publications and source records attributed to R Ahmed.
T-cell tolerance to self antigens is maintained by events that occur within the thymus and in the periphery. Mechanisms that operate on immature T cells within the thymus are effective in induction of tolerance to viruses, but mechanisms of tolerizing mature T cells are likely to break down. This failure of peripheral mechanisms to induce T-cell tolerance to viruses has implications for autoimmunity and for treatment of chronic viral infections.
Virus-antibody immune complexes form during infection with most RNA and DNA viruses, including those with human immunodeficiency virus (HIV). Yet a subset of individuals so infected apparently does not mount such responses. To understand the principles involved, we studied the formation and deposition of virus-antibody immune complexes in the circulation in a model system utilizing mice persistently infected with lymphocytic choriomeningitis virus (LCMV). Although mice of several genetic haplotypes could be persistently infected with LCMV, mount anti-LCMV antibody responses, and form immune complexes levels varied among murine strains. Earlier, genetic analysis of high and low immune complex formers, their F1 crosses, and appropriately selected recombinant inbred strains located the ability to mount heightened immune responses in genes within the MHC. Further, variations among LCMV strains in the capacity to incite high levels of immune complex formation were found. Persistent infection with LCMV Armstrong (ARM) strain was associated with high levels of complexes in the circulation and marked deposits in the glomeruli of high-responder SWR/J mice. In contrast, persistent infection of SWR/J mice with LCMV Traub strain led to very low levels of circulating complexes and minimal immune complex deposition in tissues. The amount of virus carried during both infections was roughly equivalent indicating that the genetics of both the host and the virus play essential roles in whether or not immune complexes develop. Antibody responses in SWR/J mice persistently infected with LCMV ARM were 5- to 10-fold higher than responses of age- and sex-matched mice infected with LCMV Traub.(ABSTRACT TRUNCATED AT 250 WORDS)
STUDY OBJECTIVE: Incidence of spontaneous cardiac arrhythmias and inducibility of ventricular arrhythmias in the cardiomyopathic hamster, BIO 14.6 strain, were examined. DESIGN: A 3 min electrocardiogram (ECG) was recorded weekly to 50 weeks of age. Programmed ventricular stimulation was then performed with single and double ventricular premature stimuli during both sinus rhythm and ventricular pacing, and with brief bursts of ventricular pacing to induce ventricular arrhythmias. EXPERIMENTAL MATERIAL: 19 male cardiomyopathic and 10 age matched normal hamsters from 16 to 50 weeks were used for recording the 3 min ECG; 11 cardiomyopathic and 10 normal hamsters aged 50 to 55 weeks were used for the induction of ventricular arrhythmias. MEASUREMENTS AND MAIN RESULTS: Spontaneous and sporadic ventricular premature contractions were documented in 8.3% of 218 ECGs from the cardiomyopathic hamsters between the ages of 30 and 46 weeks, whereas no ventricular arrhythmia was recorded in normal hamsters throughout the entire follow up period. Non-sustained ventricular tachycardia (NSVT) was induced in 7/11 cardiomyopathic hamsters by single ventricular premature stimulus. Either NSVT or ventricular fibrillation was induced in all cardiomyopathic hamsters with a significantly prolonged intraventricular conduction delay and refractory period. In contrast, neither NSVT nor ventricular fibrillation was induced in normal hamsters. CONCLUSION: This study provides the first evidence of the high arrhythmogenicity of the ventricles in cardiomyopathic hamsters.
To determine if pacing might prevent syncope in cardioinhibitory 'Malignant Vasovagal Syndrome' (also known as 'Neurally-Mediated Bradycardia/Hypotension'), a study of dual chamber pacing during head-up 60 degrees tilt was undertaken. Paired invasive tilts were performed in 10 patients who had a history of recurrent syncope, normal routine investigations including electrophysiological study and prior tilt-induced vasovagal syncope. Vasovagal reactions of identical severity were produced by prolonged 60 degrees head-up tilt on consecutive days in seven out of 10 patients. On day 2, without pacing, seven patients had tilt-induced vasovagal reactions and six became syncopal during the reaction. On day 3, with temporary DVI pacing with rate hysteresis, seven patients had tilt-induced vasovagal reactions and 1 patient was syncopal. Syncope was aborted in the other five patients. DVI pacing significantly improved cardiac index (CI) (one +/- 0.2 to 1.6 +/- 0.3 L/min/m2, P less than 0.01) and mean arterial blood pressure (MABP) (30 +/- 11 to 48 +/- 12 mmHg, P less than 0.01) during vasovagal reactions on day 3 compared with day 2. The mean period of time that patients could tolerate in the tilted position after the onset of the tilt-induced vasovagal reaction was significantly prolonged by pacing from 0.9 +/- 1.2 to 3.2 +/- 1.6 min (P less than 0.01). Dual chamber pacing may abort syncope in 85% of patients with cardioinhibitory malignant vasovagal syndrome. Pacing may prolong consciousness sufficiently during a vasovagal reaction to allow injury to be avoided.
Viral variants of different phenotypes are present in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates are similar to the parental virus and cause acute infections in adult mice, whereas the lymphoid isolates cause chronic infections associated with suppressed T-cell responses. In this study, we provide a molecular basis for this organ-specific selection and identify a single amino acid change in the viral glycoprotein that correlates with the tissue specific selection and the persistent and immunosuppressive phenotype of the variants. This phenylalanine (F)-to-leucine (L) change at position 260 of the viral glycoprotein was seen in the vast majority (43 of 47) of the lymphoid isolates, and variants with L at this residue were selected in spleens of persistently infected mice. In striking contrast, isolates with the parental sequence (F at residue 260) predominated (48 of 59 isolates) in the CNS of the same carrier mice. Complete nucleotide sequence analysis of the major structural genes of several independently derived (from different mice) spleen isolates showed that these variants were greater than 99.8% identical to the parental virus. In fact, the only common change among these spleen isolates was the F----L mutation at residue 260 of the glycoprotein. These results show that an RNA virus can exhibit minimal genetic drift during chronic infection in its natural host, and yet a single or few mutations can result in the organ-specific selection of variants that are markedly different from the parental virus.
Accurate measurement of physical parameters is essential for the practice of modern medicine and ophthalmology in particular. A measuring device is presented that combines a single lens reflex (SLR) camera body incorporating two aligned in-camera grids with a calibrated macrozoom attachment. The device has multiple applications wherever accurate measurements are required. The ability to measure and record physical parameters in both health and disease is essential to modern medical practice. This is particularly so in ophthalmology. Despite the relative accessibility of external structures, the clinician's measuring equipment often takes the form of a clear plastic ruler with the ever present possibility of inaccuracy from parallax and perspective. Indeed, even in the hands of expert observers, the results from the commercially produced Hertel exophthalmometer are prone to significant variation. Various photographic methods of measurement have been described using a fixed focal length lens system, and recently evaluated. These, however, require processing of the photographs before measurements can be taken. We present a simple, relatively inexpensive multi-purpose device which can measure physical parameters directly and record photographic evidence of these measurements. In essence, the device consists of a single lens reflex (SLR) camera fitted with two carefully aligned grids, linked to a calibrated macrozoom lens.
This study has identified a single amino acid change in the viral glycoprotein that profoundly affects the ability of lymphocytic choriomeningitis virus (LCMV) to persist in its natural host. Adult immunocompetent mice infected with a variant of the Armstrong strain, spleen isolate clone 13 (svA/svA), harbor virus for several months and exhibit suppressed T cell responses. In contrast, adult mice infected with a reassortant virus (svA/wtA) that contains the L segment of the spleen variant and the S segment of the parental wt Armstrong, make potent LCMV-specific CTL responses and clear the infection within 2-4 wk. These two viruses, spleen variant clone 13 and the reassortant svA/wtA, are identical in their noncoding regions and show no amino acid changes in any of their viral genes except for one substitution in the glycoprotein. The reassortant virus svA/wtA has a phenylalanine at amino acid residue 260 of the glycoprotein, whereas the spleen variant clone 13 has a leucine at this position. This study constitutes one of the first reports defining the genetic basis of viral persistence at the whole animal level, and identifying a single mutation that markedly increases the ability of a virus to persist in its natural host.
Nonobese diabetic (NOD) mice are the experimental prototype of type 1 insulin-dependent diabetes mellitus (IDDM). These mice develop a characteristic autoimmune lesion in the pancreatic islets of Langerhans, where infiltrating lymphocytes destroy beta cells, resulting in hypoinsulinemia, hyperglycemia, ketoacidosis, and death. This IDDM, which closely resembles that in humans, is prevented by infecting NOD mice with particular strains of lymphocytic choriomeningitis virus (LCMV), including Armstrong 53b, Traub, WE, and Pasteur. In contrast, the LCMV Armstrong 53b variant, Clone 13, fails to abort IDDM. Hence, although Clone 13 establishes a persistent infection that endures throughout the life spans of NOD mice, their hyperglycemia, hypoinsulinemia, and lymphocytic infiltration into the islets of Langerhans still occur. Genetic reassortant viruses generated between the IDDM therapeutic strain of LCMV Pasteur and the nontherapeutic variant, LCMV Clone 13, were used to treat NOD mice. By using such reassortants and both parental strains of virus to infect NOD mice, the prevention of IDDM was mapped to the S RNA segment of LCMV Pasteur.
This study demonstrates cell-specific selection of viral variants during persistent lymphocytic choriomeningitis virus infection in its natural host. We have analyzed viral isolates obtained from CD4+ T cells and macrophages of congenitally infected carrier mice and found that three types of variants are present in individual carrier mice: (i) macrophage-tropic, (ii) lymphotropic, and (iii) amphotropic. The majority of the isolates were amphotropic and exhibited enhanced growth in both lymphocytes and macrophages. However, some of the lymphocyte-derived isolates grew well in lymphocytes but poorly in macrophages, and a macrophage-derived isolate replicated well in macrophages but not in lymphocytes. In striking contrast, the original wild-type (wt) Armstrong strain of lymphocytic choriomeningitis virus that was used to initiate the chronic infection and from which the variants are derived grew poorly in both lymphocytes and macrophages. These three types of variants also differed from the parental virus in their ability to establish a chronic infection in immunocompetent hosts. Adult mice infected with the wt Armstrong strain cleared the infection within 2 weeks, whereas adult mice infected with the variants harbored virus for several months. These results suggest that the ability of the variants to persist in adult mice is due to enhanced replication in macrophages and/or lymphocytes. This conclusion is further strengthened by the finding that the variants and the parental wt virus grew equally well in mouse fibroblasts and that the observed growth differences were specific for cells of the immune system.
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This study documents that virus-specific CTL can persist indefinitely in vivo. This was accomplished by transferring Thy-1.1 T cells into Thy-1.2 recipient mice to specifically identify the donor T cell population and to characterize its antigenic specificity and function by using a virus-specific CTL assay. Thy-1.1+ T cells from mice previously immunized with lymphocytic choriomeningitis virus (LCMV) were transferred into Thy-1.2 mice persistently infected with LCMV. The transferred LCMV-specific CTL (Thy-1.1+ CD8+) eliminate virus from the chronically infected carriers and persist in the recipient mice in small numbers, comprising only a minor fraction of the total T cells. Upon re-exposure to virus, these long-lived "resting" CD8+ T cells proliferate in vivo to become the predominant cell population. These donor CD8+ T cells can be recovered up to a year post-transfer and still retain antigenic specificity and biological function. They kill LCMV infected H-2-matched cells in vitro and can eliminate virus upon transfer into a second infected host. In addition, these long-lived CD8+ T cells appear not to be dependent on help from CD4+ T cells, since depletion of CD4+ T cells has minimal or no effect on their biological properties (proliferation, CTL response, viral clearance). These donor CTL also exhibit an immunodominance over the host-derived LCMV-specific CTL response. When both host and donor T cells are present, the donor CTL response is dominant over the potential CTL response of the cured carrier host. Taken together, these results suggest that virus-specific CTL can persist for the life span of the host as memory cells.
The effect of hypercalcemia on T wave morphology, polarity, and amplitude was studied in 14 patients with a primary diagnosis of malignant lymphoma (8 patients), adult T-cell leukemia (5 patients), and Hodgkin's disease (1 patient). Hypercalcemia was severe to extreme in 11 (14.9-22.8 mg/dl), moderate in 1 (13.4 mg/dl), and mild in 2 (11.8 and 12.2 mg/dl) patients. Ten of the 11 patients (91%) with severe hypercalcemia showed inverted, biphasic, and notched T waves, mainly in the chest leads. Notched T waves were observed in all 10 of these patients in anterior to lateral, mid to lateral, or lateral chest leads. Biphasic and/or inverted T waves in anterior or anterior to midchest leads were present in 4 of these 10 patients who had extreme hypercalcemia (greater than 16 mg/dl). Changes in T wave morphology were not observed in moderate or mild hypercalcemia. T wave amplitude showed significant inverse correlation with serum calcium (T mV vs Ca, r = -0.60, p less than 0.001; T/R ratio vs Ca, r = -0.68, p less than 0.001; n = 35). Decrease in T wave amplitude was marked in severe hypercalcemia (p less than 0.0001) and moderate hypercalcemia, but there was no change in mild hypercalcemia. Changes in T wave morphology, polarity, and amplitude either appeared with development of hypercalcemia or disappeared with normalization of serum calcium level. It was concluded that in addition to shortening the QT interval, severe to extreme hypercalcemia can cause development of inverted, biphasic, or notched T wave with a marked decrease in amplitude of T waves.
Tc-99m labelled 2,6-diethylphenylcarbamoylmethyliminodiacetic acid (EHIDA) is a non-toxic radiopharmaceutical that was found to undergo rapid biliary excretion in a normal human, with accumulation of radioactivity in the gall bladder and intestine. Images in normal subjects and nonjaundiced patients showed rapid concentration of tracer by the liver and the passage of the same into the intestine within 15 to 40 minutes, with or without visualization of the gall bladder. In the jaundiced patient, the tracer blood clearance was delayed and urinary excretion was increased. Tc-99m EHIDA has been extensively investigated in 1634 patients to evaluate its performance in the diagnosis of hepatobiliary disorders.
Chronic hypokalemia (2.9 +/- 0.2 mEq/L) was induced in 10 dogs by a low potassium diet and furosemide administration. Five control dogs with normokalemia (5.0 +/- 0.3 mEq/L) were fed an ordinary diet. Three of the 10 hypokalemic dogs had electrically induced, nonsustained ventricular tachycardia (NSVT) and ventricular fibrillation (VF); none of the 5 control dogs had these ventricular arrhythmias. After ligation of the left anterior descending coronary artery (LAD), 4 of the 10 hypokalemic dogs developed spontaneous VF and 6 had electrically induced NSVT and VF, whereas 2 of the 5 control dogs had only NSVT. The effective refractory period (ERP) of the ventricles of the hypokalemic dogs was slightly longer than that of the control dogs. After LAD ligation, only the ERP of the anterior wall of the left ventricle was prolonged significantly in either group (p less than 0.01). The ventricular fibrillation threshold (VFT) of hypokalemic dogs was significantly lower than the control dogs (p less than 0.05), and was reduced markedly (p less than 0.05) after LAD ligation. A positive correlation between VFT and serum potassium level was observed. Thus, chronic hypokalemia increases ventricular vulnerability. This effect depends upon the severity of hypokalemia and is markedly augmented by acute myocardial ischemia. These findings indicate that, in clinical settings, preexisting hypokalemia and its severity may play important roles in the occurrence of lethal ventricular arrhythmias during the acute phase of myocardial infarction.
HLA typing for A, B, and C locus antigens was performed on 70 patients with ocular cicatricial pemphigoid (OCP) and on 1849 controls. Additionally, typing for DR and DQ antigens and for the complement proteins (C2, factor B, C4A, and C4B) was performed on 63 patients and on the same control population. A significantly higher incidence of the following antigens was found in the OCP patients when compared to the control population: DR4 (43% in patients compared to 18% in controls, p = 0.0001); DR5 (41% compared to 16%, p = 0.0001); DQw3 (57% compared to 31%, p = 0.0010); A2 (60% compared to 28%, p = 0.0001); B8 (24% compared to 13%, p = 0.0086); B35 (19% compared to 9%, p = 0.0097); and B49 (7% compared to 2%, p = 0.0052). The complement types SC01, SC30, SC32, SC41, and SC42 were also significantly increased in patients compared to controls. No significant differences were found based on ethnic background, involvement of multiple mucous membranes, history of glaucoma, or deposition of specific immunoreactants in conjunctival biopsy samples. These findings may provide further insights into the pathogenesis of OCP and may help to localize a susceptibility gene for this autoimmune disease.
The triterapenoids present in the leaves of Achras sapota L belongs mainly to alpha/beta-Amyrin and Lupenol series. A long straight chain hydrocarbon, tritriacontane was also found to be present in the n-Hexane extract of the leaves.
In a randomised controlled prospective trial, different antibiotic regimens were evaluated as prophylaxis in wound infection following elective surgical procedures. Four hundred and four consecutive cases were divided in four groups. Two groups were allotted two different conventional postoperative antibiotic regimens while the fourth group received short term perioperative antibiotic; group one served as control. A higher frequency of postoperative wound infection was observed in the controls. Results showed reduction in gross infection in only group III where short term perioperative antibiotic was used. Combination of penicillin and streptomycin were not found effective, and low infection rate was observed with Cephamendole used perioperatively.
This study demonstrates organ specific selection of viral variants during chronic lymphocytic choriomeningitis virus (LCMV) infection in its natural host. Isolates with different biological properties were present in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the wt Armstrong strain of LCMV. Viral isolates from the CNS were similar to the wt Armstrong strain and induced potent virus-specific cytotoxic T lymphocyte (CTL) responses in adult mice and the infection was cleared within 2 wk. In contrast, LCMV isolates derived from the lymphoid tissues caused a chronic infection in adult mice associated with suppressed CTL responses. Revertants with wt Armstrong phenotype were present in the CNS of mice infected with a spleen isolate showing unequivocally the importance of host tissues in the selection of viral variants. These results provide a possible mechanism by which viral variants emerge in nature and suggest that tissue- and cell-specific selection is an important aspect of virus evolution.