Biomedical subjects
Publications and source records attributed to K Tewari.
A case of critical mitral stenosis with severe pulmonary hypertension in a twin pregnancy is presented. On therapeutic evacuation at 15 weeks' gestation the patient became critically unstable, necessitating emergency open heart surgery with mitral valve replacement.
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From December 1982 to December 1986, 52 patients with recurrent ovarian cancer were treated with single-agent HMM. Chemotherapy was given for a period of 1 year unless progression of disease or toxicity was noted. Survival was determined from the time of diagnosis to the date of death or September 30, 1992. The regimen was well tolerated with only one case of severe gastrointestinal toxicity. Nine patients were found to be clinically free of disease following completion of HMM treatment; they had initially responded to cisplatin-based therapy (i.e., potentially cisplatin-sensitive) and subsequently recurred. Four were found to have gross disease at the time of reassessment laparotomy. Three of these 9 patients are alive 81-92 months since diagnosis, having maintained disease-free intervals of up to 6 years. The median survival for the 9 patients without evidence of disease at the end of therapy was 75 months versus 9 months for the nonresponders. No patient who had progressive disease on first-line cisplatin-based combination chemotherapy (i.e., primary cisplatin-resistant) responded to second-line single-agent oral hexamethylmelamine. With a follow-up close to 10 years, our data show that hexamethylmelamine, with reasonable toxicity, can provide an extended, disease-free interval to a selected group of patients.
A case of Paget's disease of the vulva is presented which, over a period of 6 years, was characterized by local recurrences and metastases to the bone marrow. Detailed examination of multiple sections of the primary tumor and of the bone marrow biopsy specimen failed to demonstrate an underlying adenocarcinoma in any of the sites. The routine histologic staining and immunohistochemical staining demonstrated that the metastatic cells strongly correlated with cells from the vulvar lesion. Specifically, immunohistochemical staining of the specimens from the primary and metastatic sites was positive for the gross cystic disease fluid protein-15, which has been associated with extramammary Paget's disease uncomplicated by underlying malignancies. Finally, during several years of close follow-up, no other primary site of Paget's disease declared itself clinically or was found by radiographic studies or analysis of serum tumor markers.
We report the longest disease-free survival achieved in an advanced-stage small cell carcinoma of the ovary. The patient had a stage IIIc tumor diagnosed during pregnancy. She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and optimal tumor debulking. Following her immediate postoperative recovery, she was treated with a multiagent chemotherapy regimen with germ cell activity consisting of vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide. She is alive and without evidence of disease 5(1/2) years after diagnosis. This is the second reported case in pregnancy and the longest disease-free survivor of metastatic small cell ovarian carcinoma in the medical literature.
OBJECTIVE: Management of locally advanced cervical cancer consists primarily of combination external and internal radiation. In order to investigate the impact of intracavitary brachytherapy versus interstitial brachytherapy on local tumor control, survival, and complications, we retrospectively reviewed the concomitant experience of two institutions, each of which practice exclusively one of these radiotherapeutic techniques. METHODS: Between 1979 and 1989, 61 patients with bulky stage II, III, or IVA cervical cancer were treated using a combination of teletherapy and intracavitary brachytherapy at one institution, while 70 similar patients were treated with teletherapy and interstitial brachytherapy at another institution. Patients in both groups were similar with respect to age, FIGO stage, tumor size, surgical stage, and histologic subtype. Patients treated with intracavitary therapy received a mean cumulative dose of 7706 cGy to point A and 5523 cGy to point B using standard Fletcher-Suit techniques. Those who received interstitial irradiation were treated with a mean external dose of 5050 cGy and 2 interstitial implants using a transperineal Syed-Neblett template with a mean tumor dose of 2239 and 1,942 cGy with each application, respectively. Patients treated with chemoradiation were excluded from this review. RESULTS: Although initial rates of local control were not different, prolonged 5-year disease-free survival (50% vs 21%, P = 0.01) and improved 5-year local control (61% vs 32%, P = 0.01) were observed among patients with stage II disease treated with intracavitary irradiation. No statistical differences in survival could be detected among stage III and IVA patients. Women treated with intracavitary irradiation received a larger dose of brachytherapy than those treated with interstitial therapy (4608 vs 3504 radium milligram hours equivalent, P < 0.0001) because a tandem was only used in 17 (24%) interstitial implants. Major complications occurred in 21% of patients in each group. CONCLUSION: When a tandem is infrequently used during interstitial brachytherapy, the toxicity is similar to that of intracavitary techniques. However, more relapses are observed among patients with stage II lesions treated with interstitial irradiation.
We studied the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP), on the macroscopic and single-channel currents due to the 22-pS Ca2+ channel in smooth muscle cells from guinea pig basilar artery. In nystatin-perforated whole-cell recordings, 50 nM SNP decreased the macroscopic current to 63+/-12% of control values, without changing the voltage dependence of the current. In cell-attached patches with BAY-K8644 in the pipette, SNP caused a comparable decrease in single-channel availability (n . Po) that was dose dependent over the range of 10 nM to 10 microM SNP. SNP had no effect on single-channel properties, including slope conductance, voltage dependence of activation, the number of open states, the time constants of the open states, and the proportion of time spent in each open state. The effect of SNP (50 nM) on single Ca2+ channel openings was reproduced by 8-Br-cGMP (100 microM), which also reduced channel availability without altering channel properties. The protein kinase inhibitor H-8 (1.5 microM), which exhibits relative specificity for cGMP-dependent protein kinase, completely inhibited the decrease in single-channel availability expected with SNP. The dose-dependent decrease in Ca2+ channel availability caused by SNP was not altered by prior application of 8-Br-cAMP or forskolin, both of which cause an increase in Ca2+ channel availability in these cells. Our findings suggest that NO decreases openings of Ca2+ channels in basilar artery smooth muscle cells without altering channel properties, and that it does so by a mechanism likely to involve cGMP-dependent protein kinase.
We report the first case of legionella infection in pregnancy complicated by sepsis and hemodynamic compromise. Legionnaires' disease is rarely found in pregnancy, possibly because subacute infections may often be overlooked and empiric therapy of pneumonia in pregnancy may be curative without definitive etiologic diagnosis.
We studied the effects of endotoxin from Escherichia coli (E. coli) on Ca2+ channel activity in PC12 cells using the cell-attached patch clamp technique. Endotoxin (1-100 ng/ml) decreased channel availability (n x Po) to about one third of control values, an effect that required 3.5 +/- 1 min (mean +/- SD; n = 13) to reach steady state. The biophysical properties of the channel, including slope conductance (22 pS; 40 mM Ba2+), voltage dependence of n x Po, and open times (tau 1 = 0.78 ms, tau 2 = 8.9 ms) for the two open states at 0 mV, were not altered. The effect of endotoxin was blocked by polymyxin-B, indicating involvement of the lipid-A moiety of lipopolysaccharide, and by the tyrosine kinase (tk) inhibitor, tyrphostin. The effect of endotoxin was mimicked by 8-bromo-cGMP (100 microM), and was blocked by the inhibitor of cGMP-dependent protein kinase (PKG), H-8, suggesting involvement of the cGMP/PKG pathway. The effect of endotoxin also was blocked by the nitric oxide (NO) synthase inhibitor, NG-monomethyl-L-arginine monoacetate, suggesting involvement of nitric oxide synthase (NOS). The rapidity of the effect of endotoxin on Ca2+ channel activity suggested that constitutive NOS (cNOS) was involved, in accordance with our finding that endotoxin-induced transcriptional induction of NOS, as measured by nitrite production, required > 6 hr. We conclude that early signaling events by endotoxin in PC12 cells involve tk, cNOS, cGMP/PKG, and Ca2+ channels.
Subcutaneous administration of monosodium glutamate (MSG) to normal adult male mice for 6 days at dose levels of 4 and 8 mg/g body weight caused a significant increase in erythrocyte glucose content accompanied by increased lipid peroxidation. The levels of total glutathione and protein-bound glutathione were significantly increased in the erythrocytes, whereas non-protein glutathione was significantly decreased. The administration of 4 and 8 mg/g body weight of MSG significantly increased the activities of glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione peroxidase (GPX). It was observed that MSG, above 4 mg/g body weight, produced oxidative stress which was counteracted by the body by maintaining the level of glutathione, which was done by increasing the activity of its metabolizing enzymes.
We used the patch clamp technique to study the effect of acetyl-L-carnitine arginyl amide (ALCAA) and of nerve growth factor (NGF) on availability of L-type Ca2+ channels in rat pheochromocytoma (PC12) cells maintained in defined medium. Channel availability was measured as number of channels in the patch x the probability of opening (n.Po). In patches from control cells, cells exposed to NGF (10 ng/ml) for six days, and cells exposed to ALCAA (1 mM) for six days, n.Po, measured during 200-240 ms pulses to -10 mV (holding potential, -60 mV), was 0.102 +/- 0.089 (5 cells), 0.173 +/- 0.083 (5 cells), and 0.443 +/- 0.261 (7 cells), respectively. The 4.3-fold increase for the ALCAA-treated cells was significantly different from control (P < 0.05), whereas that for the NGF-treated cells was not. For the same conditions, the maximum number of superimposed openings at -10 mV was 1.3 +/- 0.5 (6 cells), 1.6 +/- 0.5 (8 cells), and 3.3 +/- 1.8 (8 cells), with the value for the ALCAA-treated cells being significantly different from control (P < 0.001). Additional analysis showed that the distribution of channel open times, the time constants, and the voltage dependence of activation were not changed by prolonged exposure to ALCAA. Short-term exposure to both ALCAA as well as to the parent compound, acetyl-L-carnitine (ALCAR), did not cause an increase but rather a decrease in n.Po, and this short-term effect of both compounds was blocked by neomycin, an inhibitor of phospholipase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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OBJECTIVE: To determine if blood transfusions during or after radical hysterectomy adversely affect survival in patients with invasive cervical carcinoma. METHODS: Two hundred eighty-three women with stage IA2-IIA cervical cancer were treated with radical hysterectomy and pelvic lymphadenectomy from 1980-1989. Thirteen were lost to follow-up, and five others received adjuvant chemotherapy. Among the remaining 265 patients, 131 were given blood transfusions during surgery or within 30 days, whereas 134 were not. The clinical and pathologic characteristics of these two groups were reviewed and analyzed statistically. RESULTS: Transfused and nontransfused patients did not differ with respect to mean age (45.0 versus 43.4 years, respectively), stage, grade, cell type, depth of invasion, or prevalence of nodal metastasis. Transfused patients more frequently received adjuvant pelvic irradiation than did nontransfused (47 versus 33%, respectively, chi 2 P < .05). After a mean follow-up of 51 months (range 13-125), 19 women (14%) in each group were diagnosed as having recurrent disease, predominantly in the pelvis. Using life-table analysis, the calculated 5-year survival was 86% for transfused and 84% for nontransfused patients, a nonsignificant difference. Disease-free survival was also similar. In the study population, grade, depth of invasion, and nodal status predicted survival. When patients were stratified according to age, cell type, stage, depth of invasion, nodal involvement, and use of adjuvant radiation, blood transfusion still did not adversely influence survival. Using the Cox proportional hazards model, only nodal status was an independent predictor of death. CONCLUSION: Perioperative blood transfusion does not impact overall survival or time to recurrence after radical hysterectomy.
The introduction of the patch clamp technique less than two decades ago revolutionized the study of cellular physiology by providing a high-resolution method of observing the function of individual ionic channels in a variety of normal and pathological cell types. By the use of variations of the basic recording methodology, cellular function and regulation can be studied at a molecular level by observing currents through individual ionic channels. At a cellular level, processes such as signaling, secretion, and synaptic transmission can be examined. In addition, by combining the information from high-resolution electrophysiological recordings obtained by the patch clamp method with modern molecular biological techniques, further insight can be gained into the gene expression and protein structure of ionic channels. Given the ubiquity and importance of ionic channels, it is not surprising that their study has led to a new understanding of the mechanisms of certain disease processes and has given insight into treatments for these diseases. This review gives an historical perspective of the development of the patch clamp technique and an overview of the methodologies currently in use. Examples are shown to illustrate typical uses of the patch clamp technique with emphasis on the variety of recording configurations available and the advantages and drawbacks of each method.
Patients who develop locally recurrent uterine corpus or uterine cervix cancer after primary surgery are usually treated with radiotherapy. The optimal radiotherapeutic approach, however, has not been defined. We report the use of exploratory laparotomy, omental pedicle grafting, and intraoperative transperineal interstitial brachytherapy in the treatment of 28 such patients (10 with recurrent corpus and 18 with recurrent cervix cancer). In addition, 22 patients also received perioperative whole pelvic teletherapy while 21 also received a second closed interstitial application. Local control was achieved in 20 patients (71%), but only 10 (36%) continue to be alive without disease after a median of 44 months. Eighteen patients have died (17 of disease) a median of 13 months after open implant. Patients treated with a single implant (n = 7), with side wall involvement (n = 5), with tumors greater than 6 cm in size (n = 4), with a history of previous pelvic irradiation (n = 8), or with persistent disease after open interstitial therapy (n = 8), were not salvaged. Ten patients suffered acute morbidity which included deep venous thrombosis (n = 1), wound separation (n = 1), urinary infection (n = 2), wound infection (n = 2), pneumonia (n = 1), and fever (n = 3). Two other patients experienced chronic non-tumor-related comorbidities. These included a vesicovaginal fistula with a rectovaginal fistula in 1 patient and a small bowel obstruction with a ureteral stricture in another. A single individual suffered from both acute and chronic complications (fever, ureterointestinal fistula).(ABSTRACT TRUNCATED AT 250 WORDS)
We studied single Ca2+ channels in smooth muscle cells from the basilar artery of the guinea pig using conventional patch-clamp techniques. With 40 mM or 90 mM Ba2+ as the charge carrier, a 23-pS inward current channel was observed in 46/187 cell-attached patches studied without the dihydropyridine, BAY K8644, in the pipette solution. At 0 mV, this channel exhibited short and long openings with time constants of 1.03 and 3.65 ms, respectively. The probability of channel opening was voltage dependent with half-activation occurring at +9.9 mV. In 14/26 patches tested, addition of 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) to the bath increased the probability of opening at -10 mV by a factor of 2.6, from 0.0272 +/- 0.0429 to 0.0695 +/- 0.0788 (P < 0.01, paired t-test). Mean data from five patches fit to a Boltzmann function indicated that at positive potentials, the probability of opening increased by a factor of 1.7, from 0.352 to 0.600, whereas the voltage dependence, the number of channels, the number of open states, the time constants of the open states, and the proportion of time spent in each open state were unchanged. When BAY K8644 was added to the pipette solution, the 23-pS channel was observed in nearly all patches (62/66), but the voltage dependence of activation was shifted -15.3 mV compared to control. In some patches studied with 90 mM Ba2+, a 9-pS inward current channel also was observed and its activity also was increased significantly by 8-Br-cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
We compared Ca2+ channels in cell-attached patches of smooth muscle cells from cerebral precapillary arterioles and basilar artery of guinea pig. Patches were studied without Ca2+ channel activators in the pipette solution. In both preparations, a 23 pS channel (40 mM Ba2+) sensitive to block by nifedipine was identified. In arteriolar but not in basilar artery patches, channel activity was recorded without apparent inactivation at potentials of -40 to -20 mV. Values for the number of channels in a patch x probability of channel opening (n.Po) at various potentials were fit to a Boltzmann function. For the arteriolar patches (n = 5) and for patches from basilar artery (n = 5), the midpoint potentials for the voltage dependence of n.Po were -9.3 mV and +8.9 mV, and maximum values of n.Po at positive potentials were 1.23 and 0.33. At potentials > or = 0 mV, the average for the maximum number of superimposed openings in basilar artery patches was 1.7 (n = 17) and in arteriolar patches was 6.5 (n = 6). For both preparations, histograms of channel open times at -10 mV required two time constants, 0.48 and 3.95 ms, and the shorter open state accounted for 88% of openings. Our data indicate that Ca2+ channel activity is likely to be more prominent near resting membrane potentials in arteriolar cells than in basilar artery cells.
Zinc levels were estimated from the maternal and cord blood drawn at delivery and in the amniotic fluid drawn before delivery in 9 pregnancies resulting in congenitally abnormal foetuses and 21 pregnancies resulting in normal healthy babies. Zinc levels were significantly lower (P < 0.01) in maternal and cord blood serum in congenitally malformed babies as compared to healthy normal controls. Amniotic fluid zinc levels were significantly higher (P < 0.01) in pregnancies with malformed babies. The use of zinc levels as marker for foetal malformation has been suggested.