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Biomedical subjects

A Varghese

Publications and source records attributed to A Varghese.

At least 19 recordsLinked to original sources
PubMed2001

Effects of premature stimulation on HERG K(+) channels.

1. The unusual kinetics of human ether-à-go-go-related gene (HERG) K(+) channels are consistent with a role in the suppression of arrhythmias initiated by premature beats. Action potential clamp protocols were used to investigate the effect of premature stimulation on HERG K(+) channels, transfected in Chinese hamster ovary cells, at 37 degrees C. 2. HERG K(+) channel currents peaked during the terminal repolarization phase of normally paced action potential waveforms. However, the magnitude of the current and the time point at which conductance was maximal depended on the type of action potential waveform used (epicardial, endocardial, Purkinje fibre or atrial). 3. HERG K(+) channel currents recorded during premature action potentials consisted of an early transient outward current followed by a sustained outward current. The magnitude of the transient current component showed a biphasic dependence on the coupling interval between the normally paced and premature action potentials and was maximal at a coupling interval equivalent to 90 % repolarization (APD(90)) for ventricular action potentials. The largest transient current response occurred at shorter coupling intervals for Purkinje fibre (APD(90) - 20 ms) and atrial (APD(90) - 30 ms) action potentials. 4. The magnitude of the sustained current response following premature stimulation was similar to that recorded during the first action potential for ventricular action potential waveforms. However, for Purkinje and atrial action potentials the sustained current response was significantly larger during the premature action potential than during the normally paced action potential. 5. A Markov model that included three closed states, one open and one inactivated state with transitions permitted between the pre-open closed state and the inactivated state, successfully reproduced our results for the effects of premature stimuli, both during square pulse and action potential clamp waveforms. 6. These properties of HERG K(+) channels may help to suppress arrhythmias initiated by early afterdepolarizations and premature beats in the ventricles, Purkinje fibres or atria.

Action Potentials↗
PubMed2001

Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels.

1. We studied the gating kinetics of Kv4.2 channels, the molecular substrate of neuronal somatodendritic A-type currents. For this purpose wild-type and mutant channels were transiently expressed in the human embryonic kidney (HEK) 293 cell line and currents were measured in the whole-cell patch-clamp configuration. 2. Kv4.2 channels inactivated from pre-open closed state(s) with a mean time constant of 959 ms at -50 mV. This closed-state inactivation was not affected by a deletion of the Kv4.2 N-terminus (Delta2-40). 3. Kv4.2 currents at +40 mV inactivated with triple-exponential kinetics. A fast component (tau = 11 ms) accounted for 73 %, an intermediate component (tau = 50 ms) for 23 % and a slow component (tau = 668 ms) for 4 % of the total decay. 4. Both the fast and the intermediate components of inactivation were slowed by a deletion of the Kv4.2 N-terminus (tau = 35 and 111 ms) and accounted for 33 and 56 %, respectively, of the total decay. The slow component was moderately accelerated by the truncation (tau = 346 ms) and accounted for 11 % of the total Kv4.2 current inactivation. 5. Recovery from open-state inactivation and recovery from closed-state inactivation occurred with similar kinetics in a strongly voltage-dependent manner. Neither recovery reaction was affected by the N-terminal truncation. 6. Kv4.2 Delta2-40 channels displayed slowed deactivation kinetics, suggesting that the N-terminal truncation leads to a stabilization of the open state. 7. Simulations with an allosteric model of inactivation, supported by the experimental data, suggested that, in response to membrane depolarization, Kv4.2 channels accumulate in the closed-inactivated state(s), from which they directly recover, bypassing the open state.

Cell Line↗
PubMed2001

Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides.

PURPOSE: To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement. PATIENTS AND METHODS: One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique. RESULTS: The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P =.047 and 1.70 v 0.57 years, P =.011, respectively). At 20 years from diagnosis, the risk for progression to extracutaneous disease by initial extent of skin involvement was 0% for limited patch/plaque, 10% for generalized patch/plaque, 35.5% for tumorous disease, and 41% for erythrodermic involvement. CONCLUSION: This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.

Adult↗
PubMed2001

Prevalence of microalbuminuria in type 2 diabetes mellitus at a diabetes centre in southern India.

OBJECTIVE: The aim of this study was to determine the prevalence and risk factors for microalbuminuria among south Indian type 2 diabetic patients attending a diabetes centre. METHODS: One thousand four hundred and twenty five type 2 diabetic patients attending a diabetes centre in south India were recruited for the study. Urinary albumin concentration was measured by immunoturbodimetric assay. Microalbuminuria was diagnosed if the urinary albumin excretion was >30 mg/g of creatinine. RESULTS: Overall prevalence of microalbuminuria was 36.3% (95% confidence interval 33.8 to 38.9). The prevalence of microalbuminuria increased with the increase in duration of diabetes. Multivariate regression analysis revealed age, diastolic blood pressure, glycated haemoglobin, fasting plasma glucose, and duration of diabetes to be associated with microalbuminuria. CONCLUSION: The overall prevalence of microalbuminuria in this south Indian clinic population and its risk factors are similar to that reported in Europeans.

Adult↗
PubMed2001

Ventricular activation during sympathetic imbalance and its computational reconstruction.

We characterized the epicardial activation sequence during a norepinephrine (NE)-induced ventricular arrhythmia in anesthetized pigs and studied factors that modulated it. Subepicardial NE infusion caused the QRS complex to invert within a single beat (n = 35 animals, 101 observations), and the earliest epicardial activation consistently shifted to the randomly located infusion site (n = 14). This preceded right atrial activation, whereas the total ventricular epicardial activation time increased from 20 +/- 4 to 50 +/- 9 ms (P < 0.01). These events were accompanied by a ventricular tachycardia and a drop in left ventricular pressure, which were fully reversed after the infusion was stopped. Epicardial pacing at the infusion site mimicked all electrical and hemodynamic changes induced by NE. The arrhythmia was prevented by propranolol and abolished by cardiac sympathetic or vagal nerve stimulation. Focal automaticity was computationally reconstructed using a two-dimensional sheet of 256 x 256 resistively coupled ventricular cells, where calcium handling was abnormally high in the central region. We conclude that adrenergic stimulation to a small region of the ventricle elicits triggered automaticity and that computational reconstruction implicates calcium overload. Interventions that reduce spatial inhomogeneities of intracellular calcium may prevent this type of arrhythmia.

Animals↗
PubMed1999

Clinical characteristics and long-term outcome of patients with generalized patch and/or plaque (T2) mycosis fungoides.

OBJECTIVES: To study the long-term results of treatment of patients with generalized patch and/or plaque mycosis fungoides and to identify clinical characteristics predictive of survival and response to treatment. DESIGN: A single-center, 35.5-year retrospective cohort analysis. SETTING: Private referral medical center. PATIENTS: One hundred seventy-six patients with generalized patch and/or plaque (T2) mycosis fungoides. MAIN OUTCOME MEASURES: Long-term actuarial survival and freedom-from-relapse results as calculated by the Kaplan-Meier method. RESULTS: The long-term (35.5-year) survival of patients with T2 mycosis fungoides is worse than the expected survival of a race-, age-, and sex-matched control population (P<.001). The median survival of the T2 group is 11.7 years. Patients younger than 58 years (median age) at presentation have a more favorable overall and disease-specific survival than the patients who are 58 years or older (P<.001 vs P<.025). Patient sex or race had no significant effect on overall survival. Patients who presented with palpable clinically significant lymph nodes (stage IIA) had long-term survival results similar to those without lymphadenopathy (stage IB), despite improved freedom-from-relapse outcome for patients with stage IB. Twenty-four percent of patients who progressed to more advanced disease had a lower complete response rate to initial therapy than did other patients (21% vs 65%) (P<.001). Patients who received total skin electron beam therapy had a better complete response rate than patients treated with topical mechlorethamine hydrochloride alone; the relapse-free results were superior in patients with a total dose of 30 Gy or higher and in patients who received topical mechlorethamine as adjuvant therapy following total skin electron beam therapy. Despite differences in freedom-from-relapse results among different treatment groups, long-term overall or disease-specific survivals were not significantly different. CONCLUSIONS: A significant proportion (24%) of patients with generalized patch and/or plaque (T2) mycosis fungoides experience disease progression to a more advanced clinical stage, and nearly 20% eventually die of the disease. Younger patients have a more favorable disease-specific long-term outcome than patients who are older. Presence of lymphadenopathy (stage IIA) at diagnosis does not predict worse long-term survival outcome. Clinical features predictive of disease progression include initial lymphadenopathy (stage IIA) and lack of complete response to initial treatment. Despite superior complete response rate to a 30-Gy or higher dose of total skin electron beam therapy, topical mechlorethamine proves to be a cost-effective initial treatment for patients with T2 disease. The concept of an adjuvant therapy after irradiation is appealing, although it may not lead to improved long-term survival.

Adult↗
PubMed1999

Postoperative irradiation of minor salivary gland malignancies of the head and neck.

OBJECTIVES: (1) To review the Stanford experience with postoperative radiotherapy for minor salivary gland carcinomas of the head and neck. (2) To identify patterns of failure and prognostic factors for these tumors. MATERIALS AND METHODS: Fifty-four patients with localized tumors were treated with curative intent at Stanford University between 1966 and 1995. The 1992 AJCC staging for squamous cell carcinomas was used to retrospectively stage these patients. Thirteen percent had stage I, 22% stage II, 26% stage III, and 39% stage IV neoplasms. Thirty-two patients (59%) had adenoid cystic carcinoma, 15 (28%) had adenocarcinoma, and seven (13%) had mucoepidermoid carcinoma. Thirty (55%) had positive surgical margins and seven (13%) had cervical lymph node involvement at diagnosis. The median follow-up for alive patients was 7.8 years (range: 25 months-28.9 years). RESULTS: The 5- and 10-year actuarial local control rates were 91 and 88%, respectively. Advanced T-stage (T3-4), involved surgical margins, adenocarcinoma histology, and sinonasal and oropharyngeal primaries were associated with poorer local control. The 5- and 10-year actuarial freedom from distant metastasis were 86 and 81%, respectively. Advanced T-stage (T3-4), lymph node involvement at diagnosis, adenoid cystic and high-grade mucoepidermoid histology were associated with a higher risk of distant metastases. The 10-year cause-specific survival (CSS) and overall survival (OS) were 81 % and 63%, respectively. On multivariate analysis, prognostic factors affecting survival were T-stage (favoring T1-2), and N-stage (favoring NO). When T- and N-stage were combined to form the AJCC stage, the latter became the most significant factor for survival. The 10-year OS was 86% for stage I-II vs. 52% for stage III-IV tumors. Late treatment-related toxicity was low (3/54); most complications were mild and no cranial nerve damage was noted. CONCLUSIONS: Surgical resection and carefully planned post-operative radiation therapy for minor salivary gland tumors is well tolerated and effective with high local control rates. AJCC stage was the most significant predictor for survival and should be used for staging minor salivary gland carcinomas.

Adenocarcinoma↗
PubMed1999

Surgical training for the next millennium.

The Calman reforms in training have meant that surgical training now consists of a 2-year basic training period followed by a 6-year period of higher surgical training. This article addresses the problems faced by the new Calman surgical trainees and proposes some new measures which could be introduced for surgical training in the next millennium.

Education, Medical, Graduate↗
PubMed1998

Alteration of HERG current profile during the cardiac ventricular action potential, following a pore mutation.

HERG is believed to encode the major sub-unit of the cardiac 'rapid' delayed rectifier K channel (I(Kr)). Both I(Kr) and HERG exhibit marked inward rectification at positive membrane potentials due to rapid inactivation and this is thought to influence significantly the contribution of the current to cardiac action potential (AP) repolarisation. We investigated directly the role played by rapid inactivation, by measuring current activated by a ventricular AP waveform, from Chinese Hamster Ovary cells transfected with HERG cDNA with a point-mutation (S631A) in the pore region. Square command pulses elicited HERG-S631A current which increased progressively in magnitude with test potential up to +30/+40 mV (n=6). During test pulses to +40mV, HERG-S631A exhibited little inactivation compared to wildtype HERG. During an action potential command, WT-HERG current developed progressively during the AP plateau and slow repolarisation phase, showing maximal current between -30mV and -40 mV (n=10). In contrast, HERG-S631A current increased earlier during the AP plateau, with a maximal amplitude near +30mV (n=7). Current then declined as the AP proceeded, giving rise to a 'bow'- or 'inverted-U-' shaped current profile. A mathematical model with inactivation removed from the HERG current reproduced the I-V profile of HERG-S631A. These data provide a direct demonstration that rapid inactivation normally plays a critical role in determining both time-course and voltage dependence of HERG/I(Kr) -current during the cardiac ventricular AP.

Action Potentials↗
PubMed1998

Mycosis fungoides in young patients: clinical characteristics and outcome.

BACKGROUND: Mycosis fungoides (MF) can begin as early as the first decade of life. Few studies have reviewed MF in younger patients and none has been large enough to assess prognosis and outcome. OBJECTIVE: We reviewed the clinical characteristics, prognosis, factors related to disease progression, and therapy in patients with MF younger than 35 years of age. METHODS: Fifty-eight patients were entered into this retrospective cohort analysis. RESULTS: Significantly fewer patients with MF who are younger than 35 years presented with erythroderma (T4) and more with limited patch/plaque (T1) disease than older patients. Duration of skin disease before diagnosis of MF did not vary between the two groups. The long-term survival of younger patients with MF is significantly decreased when compared with a race-, age-, and sex-matched control population (p < 0.001). Disease-specific survivals (DSS) of younger and older patients are similar, but young patients show a slight but significantly better overall DSS (p < 0.02). However, DSS comparison of generalized patch/plaque (T2) and tumor stage (T3) patients with MF showed no significant difference between young and old patients (p=0.47, p=0.59). Patient age was not a significant predictor of survival when controlled for T-stage. Sixteen of 58 young patients with MF have died, 13 because of MF (22%), compared with 138 of 500 older patients (28%) who died as a result of MF. All younger patients with MF who progressed had at least T2 disease at presentation. Fifty of 56 young patients with MF and T1-T3 disease were treated initially with total skin electron beam or topical nitrogen mustard. The response to therapy was similar in younger and older patients with MF. CONCLUSION: T1 disease is more common and T4 disease is unusual in young patients with MF compared with an older population of patients with MF. Young patients with T1 disease, all of whom were treated with either topical nitrogen mustard or total skin electron beam therapy, or both therapies, showed no disease progression. Overall, young patients with MF showed slightly better DSS, but this was because of differences in stage distribution.

Adolescent↗
PubMed1998

Modelling of sodium-overload arrhythmias and their suppression.

Models of the electrophysiological properties of cardiac cells are now capable of accounting not only for normal activity, but also for some of the mechanisms of arrhythmia. A good example is the reconstruction of the inotropic and arrhythmogenic effects of sodium pump inhibition leading to the generation of ectopic beats. The models can also be used to investigate the possible mechanisms of suppression of arrhythmias. The authors show how the antiarrhythmic actions of lidocaine may be reproduced. The results account for the large difference between therapeutic levels (approximately 30 microM) in whole tissue and the concentration (approximately 500 microM) required to suppress excitation in isolated cells.

Animals↗
PubMed1998

Improved guinea-pig ventricular cell model incorporating a diadic space, IKr and IKs, and length- and tension-dependent processes.

The guinea-pig ventricular cell model, originally developed by Noble et al in 1991, has been greatly extended to include accumulation and depletion of calcium in a diadic space between the sarcolemma and the sarcoplasmic reticulum where, according to contempory understanding, the majority of calcium-induced calcium release is triggered. The calcium in this space is also assumed to play the major role in calcium-induced inactivation of the calcium current. Delayed potassium current equations have been developed to include the rapid (IKr) and slow (IKs) components of the delayed rectifier current based on the data of of Heath and Terrar, along with data from Sanguinetti and Jurkiewicz. Length- and tension-dependent changes in mechanical and electrophysiological processes have been incorporated as described recently by Kohl et al. Drug receptor interactions have started to be developed, using the sodium channel as the first target. The new model has been tested against experimental data on action potential clamp, and on force-interval and duration-interval relations; it has been found to reliably reproduce experimental observations.

Animals↗
PubMed1997

A conservation principle and its effect on the formulation of Na-Ca exchanger current in cardiac cells.

In this paper we show the presence of a latent conservation principle in the formulation of ionic currents in cardiac cells and examine its effect on a formulation of the sodium-calcium exchange current appearing in the Noble model of the sinoatrial node cell in the mammalian heart [see Noble et al. (1989) or Winslow et al. (1991)]. Our objective is to show that this formulation, if not corrected, will result in a serious instability in this cardiac cell model. In particular, under certain initial conditions, the solutions of the model equations will blow-up in finite time. We also propose a correction to the model equation for the sodium-calcium exchange current, and we show that the modified model agrees favorably with the original model. These phenomena also occur in the other cardiac cell models, such as those modeling the Purkinje fiber, the atrial cell and the ventricular cell. The changes proposed in this paper can be applied directly to these models as well.

Animals↗
PubMed1997

Radiotherapy-associated neutropenia and thrombocytopenia: analysis of risk factors and development of a predictive model.

Risk factors for unscheduled interruptions in radiotherapy courses completed between June 1989 and August 1995, lasting > or = 2 days, and associated with World Health Organization grade III-IV neutropenia or thrombocytopenia were studied retrospectively. A group of controls was randomly selected. Potential risk factors for myelosuppression were analyzed using univariate and multivariate analyses. The most important risk factors for treatment interruption with thrombocytopenia were concurrent chemotherapy (odds ratio [OR], 45.5; P < .001), increasing percentage of marrow irradiated (OR, 4.1 for each 20%; P < .001), and brain metastases (OR, 7.3; P = .01). Other significant (P < .05) factors were leukemia/lymphoma, bone or bone marrow metastases, and prior chemotherapy. The most important risk factors for treatment interruptions with neutropenia were concurrent chemotherapy (OR, 42.1; P < .001) and increasing percentage of marrow irradiated (OR, 3.3 for each 20%; P < .001). Similarly, the most important risk factors for treatment interruptions with both thrombocytopenia and neutropenia were concurrent chemotherapy (OR, 48.6; P < .001) and increasing percentage of marrow irradiated (OR, 3.9 for each 20%; P < .001). Other significant (P < .05) factors in these groups were bone marrow or brain metastases and previous chemotherapy. These data were used to create a model, assigning patients to groups at high, intermediate, or low risk for treatment interruption with thrombocytopenia. High-risk patients may be candidates for clinical trials of a platelet growth factor.

Adult↗