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Biomedical subjects

S R Patel

Publications and source records attributed to S R Patel.

At least 91 records · Page 5Linked to original sources
PubMed1994

Regulation of calcitriol receptor and its mRNA in normal and renal failure rats.

Homologous up-regulation of calcitriol receptor (VDR) by calcitriol is believed to be a transcriptional event. In this experiment, we studied the effect of calcitriol on VDR in normal and renal failure rats. The time course of the effect of calcitriol on VDR mRNA showed a biphasic change in VDR mRNA in response to calcitriol. The concentration of intestinal VDR mRNA increased at six hours and reached peak levels approximately 15 hours after calcitriol injection. Thereafter, the mRNA began to decrease and by 48 hours the level had declined to below the control values. The VDR levels also increased, though they lagged behind the VDR mRNA, and nearly plateaued at 24 hours after calcitriol treatment. In renal failure, the concentrations of VDR were lower and the levels of VDR mRNA were higher than the respective values of normal rats, suggesting that VDR synthesis was inhibited at post-transcriptional sites. Chronic administration of calcitriol increased the VDR but lowered the VDR mRNA levels in both normal and renal failure rats. Infusion of uremic ultrafiltrate to normal rats resulted in lower VDR and higher VDR mRNA levels similar to those found in rats with renal failure. The results indicate that uremic toxins are responsible for the low VDR and high VDR mRNA in renal failure.

Animals↗
PubMed1994

Inhibition of nuclear uptake of calcitriol receptor by uremic ultrafiltrate.

The biological action of calcitriol is mediated through a hormone-receptor complex interacting with nuclear chromatin. Interaction of the calcitriol receptor (VDR) with VDR response elements produces bioactive proteins which carry out the physiological actions of calcitriol. Since biological response to calcitriol appears to be diminished in renal failure, we studied the effect of uremic toxins on the interaction of VDR with nuclear chromatin using in vitro nuclear uptake of the 3H-calcitriol labeled VDR by intestinal nuclei. We found that nuclear uptake of the labeled intestinal VDR from renal failure rats was significantly lower than that from the control animals. HPLC fractionated uremic ultrafiltrate directly inhibited nuclear uptake of the labeled VDR when the labeled VDR was incubated with 50% of the ultrafiltrate for various time intervals ranging from 15 minutes to 6 hours. Infusion of uremic ultrafiltrate to normal rats for 20 hours also produced intestinal VDR with a lower binding affinity for intestinal nuclei when compared to the controls infused with normal ultrafiltrate. The latter study suggests that uremic toxins are responsible for the decreased nuclear uptake of VDR of rats with renal failure. Although it is difficult to extrapolate these results directly to the intact cells, our findings suggest that part of the calcitriol resistance in renal failure could be explained by decreased entry of receptor into the nucleus.

Animals↗
PubMed1994

Effect of vitamin D metabolites on calcitriol degradative enzymes in renal failure.

We have demonstrated that in renal failure calcitriol degradation is decreased and that administration of vitamin D metabolites increases the degradation. In this study, we measured intestinal 24- and 26-hydroxylase activities and the effects of chronic infusion (7 days) of vitamin D metabolites on these enzymes' activities in rats with experimental renal failure. The enzymatic activity of intestinal 24-hydroxylase, but not 26-hydroxylase, was significantly lower in renal failure rats compared to control sham operated rats. Replacement of calcitriol (3 ng/day) significantly increased 24-hydroxylase activity by 17% in rats with renal failure (P < 0.01), although the activity remained 15% lower than the controls (P < 0.01). Intestinal 26-hydroxylase activity was not lower in renal failure; however, calcitriol treatment increased the activity beyond that of normal controls. In contrast, administration of 25(OH)D3 (600 ng/day) and 24,25(OH)2D3 (1 microgram/day) reduced the conversion of calcitriol to 1,24,25(OH)3D3 by more than 50% and to 1,25,26(OH)3D3 by more than 38%, respectively. We conclude that calcitriol increased its own degradation in renal failure by increasing the enzymatic activities of both 24- and 26-hydroxylase. However, the mechanisms of increased calcitriol degradation by 25(OH)D3 and 24,25(OH)2D3 in renal failure remain unknown.

24,25-Dihydroxyvitamin D 3↗
PubMed1994

Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.

PURPOSE: To evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression. PATIENTS AND METHODS: PIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321. RESULTS: Treatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P < .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days < 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P < .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P < .02), with the peak effect observed at 750 micrograms/m2/d. CONCLUSION: These results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.

Adult↗
PubMed1994

Presentation and management of bronchogenic cysts in the adult.

Bronchogenic cysts are congenital anomalies of the bronchial tree that are often asymptomatic at presentation in adults. Management of asymptomatic bronchogenic cyst in this population remains controversial. Eighteen patients with bronchogenic cysts were treated at our institution since 1975. At initial presentation, 10 patients (56 percent) were asymptomatic and 8 (44 percent) were symptomatic. Cough and pain were the most frequent symptoms. Two patients presented with potentially serious complications, one with respiratory distress from airway compression and the other with infection and airway fistulae. Chest radiographs were abnormal but nondiagnostic in 17 out of 18 (94 percent) patients. Chest computerized tomography (CT) scans were abnormal in eight of eight (100 percent) patients, but they confirmed the benign cystic nature in only five of eight (62.5 percent). Overall, considering the use of all imaging modalities and clinical suspicion, bronchogenic cyst was considered in the preoperative differential diagnosis in only 11 of 18 (61 percent) patients. Fifteen of 18 cysts were resected initially. Three of the asymptomatic patients who were followed up initially ultimately required resection because of the development of symptoms. A trend toward increased postoperative complications was noted in patients who were symptomatic at the time of surgery (27 percent vs 14 percent). In conclusion, adult patients with asymptomatic bronchogenic cyst may develop symptoms over time. Symptoms in adults can sometimes be potentially serious. Since a confident preoperative diagnosis is not always possible and because surgical complications may be more common in the symptomatic patient, we recommend surgical resection of all suspected bronchogenic cysts in operable candidates.

Adolescent↗
PubMed1994

Kinetic response of human marrow myeloid progenitor cells to in vivo treatment of patients with granulocyte colony-stimulating factor is different from the response to treatment with granulocyte-macrophage colony-stimulating factor.

We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) induced sustained increases in cycling of myeloid progenitors in patients with sarcoma. However, decreased proliferation of these cells to a slow- or noncycling state, below pretreatment levels, occurred within 1 to 2 days and maintained for at least 1 week after discontinuation of GM-CSF. To assess possible biological differences in GM-CSF and granulocyte (G)-CSF in such kinetic effects, we evaluated cycling status of marrow progenitors before, during, and after administration of recombinant human G-CSF (5 micrograms/kg/d subcutaneously [s.c.]) to six patients with sarcoma for 8 days. On the last (8th) day of G-CSF treatment, cycling rates of colony-forming units-granulocyte/macrophage (CFU-GM), burst-forming units-erythroid (BFU-E), and multipotent colony-forming units (CFU-GEMM) were enhanced 1.5- to 1.9-fold, to values of 40 +/- 10% to 58 +/- 5%. In sharp contrast to patients receiving GM-CSF, however, progenitor cells from patients off G-CSF treatment for 2 to 4 days were still rapidly proliferating. These differences in proliferative kinetics may be of use for design of clinical trials to efficaciously utilize these growth factors.

Bone Marrow↗
PubMed1993

Combination chemotherapy in adult desmoid tumors.

BACKGROUND: Desmoid tumors are locally aggressive tumors, with no metastatic potential, that generally are amenable to local treatments, such as surgery and radiation therapy. Systemic therapy is considered for selected cases that are not amenable to local treatment. METHODS: The authors reviewed their experience with chemotherapy in desmoid tumors. A patient population was identified through a search of the data base maintained by the Department of Patient Studies. RESULTS: Between January 1971 and December 1991, 180 patients with a histologically confirmed diagnosis of desmoid tumor were seen at the authors' institution. Twelve patients (8 male and 4 female patients; age range, 16-66 years; median age, 29 years) received chemotherapy. Eleven patients received doxorubicin (60-90 mg/m2) plus dacarbazine (750-1000 mg/m2)-based regimens for a median of 5 cycles (2-10 cycles). Six of the nine patients who could be evaluated for response had an objective response (two complete responses and four partial responses), one patient had a minor response, and two patients had stable disease. Two other patients treated in the early 1970s could not be evaluated objectively because of lack of modern imaging; however, they were reported to have "responses" that enabled resection of axillary and pelvic disease. All four patients with Gardner syndrome experienced disease response. One of these four patients had a complete response twice with doxorubicin-based chemotherapy and eventually died with an ejection fraction of 0.22. Five patients are alive with no evidence of disease (NED), four are alive with disease, and two are lost to follow-up after having an NED status at their last visit. CONCLUSION: The authors conclude that desmoid tumors in adults are responsive to chemotherapy, and such treatment should be considered before embarking on radical treatment to avoid obvious functional consequences and delayed complications.

Adolescent↗
PubMed1993

Characterization of the quaternary structure and conformational properties of the human stem cell inhibitor protein LD78 in solution.

The human LD78 protein (sometimes referred to as human macrophage inflammatory protein-1 alpha) has been shown to protect multipotential hemopoietic stem cells from the effects of cytotoxic agents. Administration of the recombinant stem cell inhibitor molecule LD78 as an adjunct to chemotherapy has potential clinical benefit in reducing or preventing the neutropenia associated with this treatment. At physiological ionic strength, the 8-kDa LD78 molecule exists as soluble, heterogeneous, multimeric complexes of mass ranging from 100 to > 250 kDa. The hydrodynamic and structural properties of LD78 have been determined in various buffer solutions using analytical ultracentrifugation, circular dichroism, and fluorescence spectroscopy. The results demonstrate that defined, homogeneous monomer and tetramer forms of LD78 can be prepared which display distinct conformational properties. The combined use of hydrodynamic and spectroscopic analysis provides an insight into the pathway and molecular mechanics of LD78 self-association.

Acetates↗
PubMed1993

SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia.

We have characterised the Ca2+ channel blocking properties of a new non-peptide Ca2+ channel antagonist, SB 201823-A, in cultures of rat sensory neurones. The IC50 for SB 201823-A against total Ca2+ current in sensory neurones was 4.9 microM. SB 201823-A showed little selectivity for sub-types of neuronal Ca2+ channel but was selective for Ca2+ channels over Na+ and K+ channels. Efficacy against other types of cation channel such as agonist gated channels was not assessed. SB 201823-A was neuroprotective in vivo when administered post-ischaemia in one focal and one global model of neuronal ischaemia. In the rat photothrombotic focal lesion model, SB 201823-A administered i.p. 10 min post-ischaemia resulted in a dramatic reduction in lesion volume. In the gerbil bilateral carotid artery occlusion global model, SB 201823-A dosed i.p. 30 min post-occlusion resulted in both histological and functional improvements when compared to vehicle treated animals. These data suggest that such novel neuronal Ca2+ channel antagonists may have potential in ameliorating both the pathological and functional consequences of stroke in man.

Animals↗
PubMed1993

Mechanism of decreased intestinal calcitriol receptor concentration in renal failure.

The biological actions of calcitriol and its receptor synthesis are believed to be mediated through the calcitriol-receptor complex interacting with nuclear chromatin of target cells. Thus inhibition of the receptor interaction with DNA could diminish the biological actions of calcitriol and upregulation of its receptor. We found that uremic ultrafiltrate reduced the receptor interaction with DNA in vitro. DNA-cellulose chromatography showed that the receptor from normal rats and rats infused with normal ultrafiltrate eluted as a single peak at 0.22 M KCl, whereas chronic renal failure rats and rats infused with uremic ultrafiltrate had two receptor peaks, i.e., one of normal activity at 0.22 M KCl and the other of weak activity at 0.12 M KCl. Furthermore, infusion of uremic ultrafiltrate to normal rats reduced the intestinal calcitriol receptor concentration (397 +/- 15.8 vs. 307 +/- 15.4 fmol/mg protein, both n = 4, P < 0.005). Uremic ultrafiltrate also suppressed the calcitriol-induced upregulation of the receptor (816 +/- 34.6 vs. 606 +/- 35.3 fmol/mg protein, P < 0.005). It appears that uremic toxins may reduce the biological action of calcitriol in renal failure by inhibiting receptor synthesis and the interaction of the hormone-receptor complex with nuclear chromatin.

Animals↗
PubMed1993

Case report: colonic obstruction following small bowel barium study.

A case is described in which inspissated barium was retained in the colon for 16 months before causing large bowel obstruction. To our knowledge this is the first case described in which the time interval between barium ingestion and the onset of symptoms was more than a few weeks. Scybalum formation is due to resorption of water from the barium sulphate, which although less common with modern preparations, still appears to be possible in certain high-risk patients. Prolonged retention of barium should be avoided by increased awareness of the problem, encouraging patients to eat and drink normally after the examination, encouraging mobility and administration of lactulose in high risk patients.

Aged↗
PubMed1993

Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience.

We have used ifosfamide to treat patients with sarcomas in four completed single-agent protocols and one pilot study since 1985. All the studies have used either N-acetyl-L-cysteine (NAC) or mesna as a uroprotective agent, except in one arm of one study where hydration alone was employed. Mesna has proven superior to NAC in providing protection against ifosfamide-induced hematuria. Mesna given as a loading dose followed by continuous 24-h infusion has been effective and most practical in this regard. Ifosfamide has demonstrated clinically useful antitumor activity in our hands against most sarcoma subtypes. Our studies suggest a dose-response relationship for ifosfamide. At a total dose of 6 g/m2 per course, the overall response rate was 10%; at 10 g/m2 per course, it rose to 21%. Future clinical trials will determine ifosfamide's role in combination chemotherapy and more clearly define the best schedule or schedules for the uroprotective administration of mesna.

Acetylcysteine↗
PubMed1992

Chemotherapy for hormonally refractory advanced prostate carcinoma. A comparison of combined versus sequential treatment with mitomycin C, doxorubicin, and 5-fluorouracil.

One hundred forty-two patients with progressive, hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were randomized to receive either combination chemotherapy with 5-fluorouracil (5-FU), doxorubicin, and mitomycin C (FAM) or sequential chemotherapy with the same agents, i.e., mitomycin C, followed by doxorubicin on disease progression, followed by 5-FU. Objective tumor regressions were observed in 10 of 70 (14%) patients receiving the FAM treatment arm and 10 of 72 (14%) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone, 3 (12.5%) achieved objective tumor regression. There were no responses among five patients who received tertiary therapy with 5-FU alone. The median survival time for all patients treated with the combination arm was 8.7 months, compared with 7.1 months for patients who received the FAM arm (P = 0.025). However, this modest survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients. The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer.

Acid Phosphatase↗
PubMed1992

Cisplatin-based chemotherapy in primary central nervous system germ cell tumors.

We report a retrospective review of our experience with cisplatin-based chemotherapy in eight patients (ages 9-44 years) with histologically confirmed primary central nervous system germ cell tumors. Five patients received chemotherapy as the primary treatment, radiation therapy being administered either at completion of chemotherapy or between chemotherapy courses. Three patients received cisplatin-based chemotherapy for recurrent disease after prior radiation therapy and/or surgery. Four of five patients treated with chemotherapy at diagnosis are in complete remission at 11-14 months from diagnosis. The remaining patient twice achieved complete remission prior to dying of progressive disease 16 months after diagnosis. Two of three patients treated with chemotherapy for recurrent disease are in complete remission at 20 and 26 months; the remaining patient deteriorated after the first cycle of chemotherapy and expired six months thereafter. Overall, of seven patients evaluable for response, five achieved complete remission with chemotherapy alone, and two with chemotherapy and radiation therapy. Our results confirm previous reports of high complete remission rates utilizing cisplatin-based chemotherapy in conjunction with radiation therapy. Prospective evaluation of cisplatin-based chemotherapy followed by radiation therapy is warranted.

Adolescent↗
PubMed1992

Identification of albumin in breast tumor cytosol as a factor involved in the stimulation of estradiol 17 beta-hydroxysteroid dehydrogenase (reductive) activity.

Estradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) is the enzyme responsible for the interconversion of estrone (E1), and the more biologically potent steroid, estradiol (E2), and has a crucial role in regulating breast tissue concentrations of E2. It has previously been shown that breast tumor cytosol is able to preferentially stimulate the reductive conversion of E1 to E2 in cultured MCF-7 breast cancer cells. In this study the stimulatory factor(s) from breast tumor cytosol have been partially purified by gel filtration and affinity chromatography. Human serum albumin (HSA) has been identified as a component of this bioactive fraction. Subsequent testing of commercially purified HSA preparations has revealed the ability of some preparations to be highly stimulatory. The albumin present in breast tumor cytosol may therefore be a contributing factor to the observed stimulation of reductive E2DH activity in cultured MCF-7 cells. Such a mechanism may account in part for the higher concentrations of E2 which are observed in breast tumors in vivo.

Breast Neoplasms↗
PubMed1992

Mechanism of decreased calcitriol degradation in renal failure.

Metabolic clearance rate (MCR) of calcitriol is decreased in renal failure, and uremic toxins play a major role in the suppression of calcitriol degradation. In this experiment, we studied the effect of uremic toxins on renal 24- and 26-hydroxylase (HX) activities. Normal rats were infused for 20 h with 30 ml of normal or uremic plasma ultrafiltrates. At the end of infusion, renal enzymes activities were measured by the generations of 1,24,25- and 1,25,26-trihydroxyvitamin D3 10 min after the addition of 25 nM or 1 microM calcitriol. Renal 24-HX activity decreased approximately 50%, whereas 26-HX activity did not decrease in rats infused with uremic plasma ultrafiltrate. The induction of 24-HX activity by 100 ng calcitriol also decreased in rats infused with uremic ultrafiltrate. To examine whether uremic ultrafiltrate could directly inhibit the degradation enzymes, 24- and 26-HX activities were measured in kidney homogenates preincubated for 3 h with either normal or uremic ultrafiltrate. Uremic ultrafiltrate did not directly suppress 24- and 26-HX activities. Furthermore, the disappearance rate of calcitriol was similar for 90 min in kidney homogenates after they were preincubated for 3 h with uremic and normal ultrafiltrates. Because 24-HX synthesis is induced by the calcitriol-receptor complex binding to nuclear chromatin and activating genes coding for the enzyme, we studied the effect of uremic toxins on the binding affinity of calcitriol-receptor complex for DNA-cellulose. Uremic ultrafiltrate significantly reduced the binding affinity of the hormone receptor complex for DNA when the receptor was preincubated with the ultrafiltrate for 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗