Biomedical subjects
Publications and source records attributed to A Varghese.
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.
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.
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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.
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.
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.
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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.
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.
PURPOSE: This study aimed to quantify the risk of gastrointestinal cancer following Hodgkin's disease treatment according to age at treatment, type of treatment, and anatomic sites. METHODS AND MATERIALS: Cases were identified from the records of 2,441 patients treated for Hodgkin's disease between 1961 and 1994. Follow-up averaged 10.9 years, representing 26,590 person-years of observation. Relative risks (RR) for gastrointestinal cancer incidence and mortality were computed by comparison with expected annualized rates for a general population matched for age, sex, and race. RESULTS: Gastrointestinal cancers developed in 25 patients. The incidence RR was 2.5 [95% confidence interval (CI), 1.5-3.5] and mortality RR was 3.8 (CI, 2.4-4.7). Sites associated with significantly increased risks included the stomach [RR 7.3 (CI, 3.4-13.8)], small intestine [RR 11.6 (CI, 1.9-38.3)], and pancreas [RR 3.5 (CI, 1.1-8.5)]. Risk was significantly elevated after combined modality therapy, RR 3.9 (CI, 2.2-5.6). The risk after radiotherapy alone was 2.0 (CI, 1.0-3.4), not a statistically significant elevation. The RR for gastrointestinal cancer was greatest after treatment at young age and decreased with advancing age. It was significantly elevated within 10 years after treatment [RR 2.0 (CI, 1.1-3.5)] and increased further after 20 years [RR 6.1 (CI, 2.5-12.7)]. Risk assessed by attained age paralleled risk according to age at treatment. Fifteen cases of gastrointestinal cancers arose within the irradiation fields. CONCLUSION: Patients treated for Hodgkin's disease are at modestly increased risk for secondary gastrointestinal cancer, especially after combined modality therapy and treatment at a young age. Risk was highest more than 20 years after treatment, but was significantly elevated within 10 years. Gastrointestinal sites with increased risk included the stomach, pancreas, and small intestine.
OBJECTIVES: To study the long-term results of treatment of patients with stage IA mycosis fungoides and analyze the factors related to disease progression and the effect of initial therapy on survival and freedom from relapse. DESIGN: A single-center, 32(1/2)-year, retrospective cohort analysis. SETTING: Private referral medical center. PATIENTS: One hundred twenty-two patients with clinical stage IA (T1, N0, M0) mycosis fungoides. MAIN OUTCOME MEASURES: Long-term actuarial survival and freedom-from-relapse results as calculated by the technique of Kaplan-Meier. RESULTS: The long-term (30-year) survival of patients with stage IA mycosis fungoides is similar to the expected survival of a race-, age-, and sex-matched control population. The median survival of this group has not been reached at 32(1/2)-years. Eleven patients (9%) who progressed to more advanced disease had a lower complete response rate to initial therapy than did other patients (36% vs 82%) and an older mean age than did other patients with T1 disease (61 vs 48 years, P < .05). Only 3 (2%) of 122 patients died of disease. Among stage IA patients who achieved a complete response, 25% are relapse free at 10 years. Patients who received total skin electron beam therapy (n = 34) had a more favorable freedom-from-relapse outcome than those treated with topical mechlorethamine hydrochloride (nitrogen mustard) (n = 73, P < .05). No significant difference was seen in the long-term survival between the 2 treatment groups. CONCLUSIONS: Patients with clinical stage IA mycosis fungoides treated at Stanford University do not have an altered life expectancy. Fewer than 10% progressed to more advanced stages and few died of disease. Although the response rate to total skin electron beam therapy was superior to that of topical mechlorethamine, the longterm survival results were similar. Topical mechlorethamine is a cost-effective and convenient therapy for patients with limited patch and plaque mycosis fungoides.
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alpha-Blockers and calcium antagonists are commonly used in the treatment of hypertension, but few data are available concerning first dose or steady state (SS) hemodynamic and pharmacokinetic effects of these drugs when they are used in combination therapy. To examine these interactions, we measured supine and standing blood pressure (BP), heart rate (HR), and cardiac index (CI) for 6 h in 24 hypertensive patients after 2 weeks of placebo, again after the first dose or 3 weeks of therapy (SS) with either 120 mg verapamil (V) twice a day, or 1 mg terazosin (T) titrated weekly to 5 mg daily, and finally when T was added to V (group VT) or V added to T (group TV), acutely and at SS. Changes in supine hemodynamics when T was added to V or when V was added to T were similar and included a further reduction in BP, a transient increase in HR, and little or no change in CI. Both groups experienced significant decreases in standing blood pressure, especially 0.5 to 2 h following initiation of combination therapy despite significant increases in standing HR and CI. Standing BP tended to be lower in group TV after the first dose, but minimum standing systolic BP was not significantly different between groups (group TV 97 mm Hg at 1 h; group VT 109 mm Hg at 1.5 h, P > .05). Four patients in group TV and two in group VT experienced symptomatic orthostatic hypotension with the first dose of double-agent treatment. Pharmacokinetic interactions, including an increase in the bioavailability of T when V was added, did not correlate with the degree of orthostasis. After 3 weeks of combined therapy, the orthostatic change in BP had attenuated and symptoms had improved in all patients. We conclude that T and V represent an effective combination for the treatment of essential hypertension, but that orthostasis may result when initiating combination therapy. The orthostasis seen in some patients appears to be due to the combined vasodilatory effects rather than negative ionotropic or chronotropic effects.
BACKGROUND AND DESIGN: There are no large studies evaluating patients with erythrodermic mycosis fungoides and Sézary syndrome to determine the important prognostic factors that may influence survival. This is important since new treatment modalities have been proposed as superior to existing primary therapies. We performed a retrospective cohort study of 106 patients with erythrodermic mycosis fungoides and Sézary syndrome, followed up in the Stanford (Calif) Mycosis Fungoides Clinic, to define the important prognostic factors in this group. RESULTS: Patients younger than 65 years have a more favorable survival profile than those 65 years or older (P < .005). Longer duration of symptoms before diagnosis ( > or = 10 years) tends to be associated with more favorable prognosis (p = .055). Lymph node stage is significantly correlated with survival; patients with overall stage III disease have more favorable prognosis than those with stage IV disease (P < .001). Patients with circulating Sézary cells in their blood have a significantly worse prognosis than those without (P < .005). Patient sex or race had no significant effect on overall survival outcome. Three distinct prognostic groups were identified, "favorable," "intermediate," and "unfavorable," according to the number of unfavorable prognostic factors (P < .005). The median survival in each group is 10.2, 3.7, and 1.5 years, respectively. CONCLUSIONS: In patients with erythrodermic mycosis fungoides and Sézary syndrome, the important prognostic factors are patient age at presentation, the overall stage, and peripheral blood involvement. Survival varies widely, depending on these variables. These prognostic factors should be evaluated when analyzing survival and/or treatment efficacy data of these patients.
A model of the electrical activity in mammalian cardiac Purkinje fiber is examined to study the effects of subcellular oscillations on the transmembrane potential. Inhibition of the sodium/potassium pump causes oscillations in the internal calcium concentration and these oscillations are shown to interfere with the normal pacemaking mechanism of the Purkinje fiber. Bifurcation diagrams were constructed using numerical continuation methods. These results predict a dramatic change in the structure of periodic orbits of the cell electrical activity with pump inhibition and elevated levels of internal sodium concentration.
A biophysically detailed two-dimensional network model of the cardiac atrium has been implemented on the Thinking Machines massively parallel CM-5 supercomputer. The model is used to study the effects of spatially localized inhibition of the Na-K pump. Na overloading produced by pump inhibition can induce spontaneous, propagating ectopic beats within the network. At a cell-to-cell coupling value yielding a realistic plane wave conduction velocity of 0.6 m s-1, pump inhibition in roughly 1000 cells can induce propagating ectopic beats in a 512 x 512 lattice of cells.
PURPOSE: The psychosocial outcomes of testicular cancer and Hodgkin's disease were compared to test our hypotheses that more specific dysfunction and less hiding of symptoms would be found in the former group, as cancer visibly affects a sexual organ. Since those with Hodgkin's disease could more easily deny the disease, poorer psychosocial adjustment was predicted. PATIENTS AND METHODS: The sample consists of 85 men with Hodgkin's disease and 88 men with testicular cancer (seminomatous, n = 39; or nonseminomatous, n = 49). They were interviewed once, at least 1 year following the end of treatment. Measures of sociodemographic characteristics, physical functioning, psychologic distress, and social outcomes were collected. Treatment data were collected from medical records. RESULTS: Men with testicular cancer report more focused symptoms: less sexual enjoyment and poor health habits. Men with Hodgkin's disease report more generalized symptoms: fatigue, energy loss, and work impairment. Multivariate analysis indicates that most of these differences are site-related; independent effects of treatment on outcomes were found for more generalized symptoms. Contrary to expectations, both groups reported similar levels of infertility and erectile dysfunction. CONCLUSION: The response to testicular cancer is site-specific, while the response to Hodgkin's disease is related to both site and treatment (stage-related).