Biomedical subjects
S Reddy
Publications and source records attributed to S Reddy.
Clinical and neurohormonal effects of nicardipine hydrochloride in patients with severe chronic heart failure receiving angiotensin-converting enzyme inhibitor therapy.
It has been proposed that worsening of heart failure with dihydropyridines, such as nicardipine, is related to the activation of the neuroendocrine system. To test this, we evaluated 20 patients with severe heart failure (mean age, 55 +/- 13 years; New York Heart Association functional class III; left ventricular ejection fraction, 18% +/- 8% on maintenance therapy with captopril, digoxin, and diuretics) who were randomized to nicardipine (60 or 90 mg/d) or placebo during a 4-month double-blind protocol. The following measurements were obtained at baseline, monthly, and at 4 months or last follow-up visit: rest and exercise radionuclide ventriculography, maximal treadmill time, 6-minute walking test distance, serum norepinephrine and aldosterone concentrations, and plasma renin activity. During the follow-up period, worsening of heart failure occurred in 6 patients in the nicardipine group and in 2 patients in the placebo group (p = 0.06). The maximal treadmill time for a 6-minute walking distance and exercise radionuclide ejection fraction at the last follow-up visit did not change in patients who did not deteriorate with heart failure in the placebo or nicardipine groups as compared with baseline values. In this study group of patients with severe heart failure receiving therapy with digoxin, captopril, and diuretics, nicardipine was associated with worsening heart failure without an apparent activation of the neurohormones. However, because of the small number of patients and a significant number of patients who deteriorated during the follow-up period, no definitive conclusions can be made.
Acute volume expansion and salt-loading studies in rats. The role of atrial natriuretic peptide and catecholamines.
Differences have been postulated for the mechanism of natriuresis due to atrial natriuretic peptide (ANP), salt loading with high salt diet (HS) and acute volume expansion (AcVE), in particular between AcVE and ANP based on the observed synergism between the two. Therefore the effects of and the interaction between the three were investigated in rats. ANP and AcVE produced the same natriuresis in HS as in normal salt (NS) rats and, in both, the actions of ANP and AcVe were significantly additive showing similarity in mechanisms. Synergism [(AcVE + ANP) - AcVE] was, however, present only in the NS rats. Proximal tubular sodium transport was the same with AcVE and ANP+AcVE suggesting that synergism is a property of more distal nephron segments. In conscious HS rats, plasma ANP was significantly less but natriuresis was higher than in NS rats. ANP therefore probably has some causative role in the natriuresis of AcVE but none in that of HS loading. Urinary dopamine was significantly increased by HS and further increased by AcVE in both NS and HS rats, the relationship between dopamine and natriuresis being significantly positive (r2 = 0.328) reaching equivalent levels in both NS and HS rats. Systemic benserazide prevented the increase in urinary dopamine but only attenuated the natriuresis of AcVE. We conclude that HS does not potentiate the natriuresis of AcVE or ANP, synergism between AcVE and ANP is not a proximal tubule event and dopamine accounts for significant natriuresis of VE in addition to other natriuretic factors.
Effect of methimazole, with or without L-thyroxine, on remission rates in Graves' disease.
Medical treatment of Graves' disease involves antithyroid drugs with or without the addition of exogenous T4. There have been conflicting reports as to whether the addition of T4 improves remission rates or delays relapse. To evaluate this issue in a North American population, 199 patients were treated with methimazole until they were euthyroid. They were then randomized to either methimazole alone in a dose sufficient to normalize TSH (group 1), or to 30 mg methimazole daily plus sufficient T4 to maintain TSH in the upper normal range (group 2), or to 30 mg methimazole daily plus sufficient T4 to suppress TSH below 0.6 mIU/L (group 3). After 18 months, methimazole was stopped, and T4 was continued in groups 2 and 3. Because not all patients in groups 2 and 3 achieved their target TSH concentration, they were reassigned to group A (TSH > or = 1.0) or group B (TSH < 1.0), based on the mean TSH achieved during methimazole treatment. One hundred forty-nine patients have been followed for at least 6 months after stopping methimazole (mean 27 months). Fifty-eight percent of patients have relapsed. There were no significant differences in relapse rates after stopping methimazole. Among those patients who did relapse, however, there was a significant difference in the months to relapse after stopping methimazole between groups B and 1 (group 1: 3.3 +/- 0.7, group A: 5.6 +/- 0.8, group B: 7.4 +/- 1.7; P = 0.01 for the comparison between groups B and 1). We conclude that the addition of T4 to methimazole does not improve long-term remission rates in Graves' disease.
Treatment of acute interstitial nephritis.
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Testicular changes due to graded doses of nicotine in albino mice.
Administration of graded doses of nicotine (0.2 mg, 0.4 mg and 0.6 mg/100 g body weight) for 15 days to the adult mice reduced the weight of testis, number of spermatocytes and spermatids, but increased the number of spermatogonia which may be due to reduced conversion to subsequent stages. There is a high cholesterol content and Sudanophilic lipid accumulation in the treated testis. The weight of accessory sex organs which is dependent on androgens produced by the testis is also reduced. These changes are brought because of the non-availability of pituitary gonadotrophins essential for initiation and completion of spermatogenesis and steroidogenesis in the testis due to the administration of nicotine, which being CNS depressor might have caused inhibition in the neural stimulus essential for release of pituitary gonadotrophins.
MR of parenchymal spinal cord signal change as a sign of active advancement in clinically progressive posttraumatic syringomyelia.
Extensive MR signal change in the craniad spinal cord parenchyma was found to be an ancillary sign of disease advancement in three patients with clinically progressive posttraumatic syringomyelia. This craniad margin of parenchymal spinal cord T2 hyperintensity resolved after cystoperitoneal shunt placement. There was a concomittant reduction or disappearance of the cyst in each instance, a halt in the progression of neurologic deficit, and some reversal of signs and symptoms.
Update on the role of radiotherapy in ovarian cancer.
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Proton MR spectroscopic measurement of neurometabolites in hepatic encephalopathy during oral lactulose therapy.
BACKGROUND AND PURPOSE: MR imaging and MR spectroscopy are increasingly being used to determine response to pharmacologic therapy. Hepatic encephalopathy (HE) is characterized by abnormal cerebral metabolites, yet the response to lactulose and other anti-HE measures is still primarily determined by using arbitrary categorical clinical rating scales, rather than MR spectroscopy. The purpose of this study was to determine whether MR spectroscopy could demonstrate relevant neurometabolic changes associated with lactulose therapy and thereby provide further support for the use of MR spectroscopy in clinical trials. METHODS: Ten control subjects and 23 patients with grades I to III HE were studied by proton MR spectroscopy with imaging parameters of 2000/26 (TR/TE). Metabolic ratios were calculated for myo-inositol (mI)/creatine (Cre), choline (Cho)/Cre, (glutamine + glutamate) (Glx)/Cre, N-acetylaspartate (NAA)/Cre, and (Cho + mI)/Glx. A time series design trial was used in which eight patients with HE were compared before and after lactulose therapy (60 mL by mouth three times per day). RESULTS: Relative to control subjects, HE was characterized by 43%, 64%, and 5% reductions, respectively, in mI/Cre, (Cho + mI)/Glx, and Cho/Cre. In comparison, Glx/Cre was increased by 75% and NAA/Cre was not changed. Therapy with lactulose was associated with increases of 29%, 37%, and 7%, respectively, in mI/Cre, (Cho + mI)/Glx, and Cho/Cre, as well as respective decreases of 15% and 42%, respectively, in Glx/Cre and HE grade. NAA/Cre did not change with lactulose therapy. CONCLUSION: MR spectroscopy detects neurometabolic changes associated with pharmacologic therapy for HE. The metabolic ratios ml/Cre and (Cho + mI)/Glx are the most sensitive measures of lactulose effect. These data support the expanded use of MR spectroscopy as an adjunctive technique in pharmaceutical development and clinical trials for HE.
Vital signs services for secure telemedicine applications.
Telemedicine using teleconference provides only a part of the picture. The remote patient's electronic medical record and vital signs may often be essential for proper diagnosis and treatment. While there are commercial solutions for telemonitoring, they do not address issues such as security and interoperability leveraging the growing public communications infrastructure. On the other hand there are performance considerations due to the quality of service over available communications media that can hinder real-time operation. The objective of this research effort is to develop secure tele-monitoring facilities that enable healthcare providers to collaborate over public communication networks; to securely convey their patient's vital signs to a remote specialist; and to enable "near real-time" examination of those vital sign data. It is our belief that such applications can help overcome barriers to quality healthcare in the scattered populations of rural areas enabling telemedicine to be a part of the practice of medicine. The authors, who are developing secure telemedicine applications, describe their approach in developing secure vital signs services.
Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice.
Myotonic dystrophy (DM) is associated with expansion of CTG repeats in the 3'-untranslated region of the myotonin protein kinase (DMPK) gene. The molecular mechanism whereby expansion of the (CUG)n repeats in the 3'-untranslated region of DMPK gene induces DM is unknown. We previously isolated a protein with specific binding to CUG repeat sequences (CUG-BP/hNab50) that possibly plays a role in mRNA processing and/or transport. Here we present evidence that the phosphorylation status and intracellular distribution of the RNA CUG-binding protein, identical to hNab50 protein (CUG-BP/hNab50), are altered in homozygous DM patient and that CUG-BP/hNab50 is a substrate for DMPK both in vivo and in vitro. Data from two biological systems with reduced levels of DMPK, homozygous DM patient and DMPK knockout mice, show that DMPK regulates both phosphorylation and intracellular localization of the CUG-BP/hNab50 protein. Decreased levels of DMPK observed in DM patients and DMPK knockout mice led to the elevation of the hypophosphorylated form of CUG-BP/hNab50. Nuclear concentration of the hypophosphorylated CUG-BP/hNab50 isoform is increased in DMPK knockout mice and in homozygous DM patient. DMPK also interacts with and phosphorylates CUG-BP/hNab50 protein in vitro. DMPK-mediated phosphorylation of CUG-BP/hNab50 results in dramatic reduction of the CUG-BP2, hypophosphorylated isoform, accumulation of which was observed in the nuclei of DMPK knockout mice. These data suggest a feedback mechanism whereby decreased levels of DMPK could alter phosphorylation status of CUG-BP/hNab50, thus facilitating nuclear localization of CUG-BP/hNab50. Our results suggest that DM pathophysiology could be, in part, a result of sequestration of CUG-BP/hNab50 and, in part, of lowered DMPK levels, which, in turn, affect processing and transport of specific subclass of mRNAs.
Mutant molecular motors disrupt neural circuits in Drosophila.
A dominant negative mutation, Glued1, that codes for a component of the dynactin complex, disrupted the axonal anatomy of leg sensory neurons in Drosophila. To examine neuron structure in mutant animals, a P[Gal4] enhancer trap targeted expression of lacZ to the sensory neurons and thereby labeled neurons in the femoral chordotonal organ and their axons within the central nervous system. When these sensory axons were examined in the Glued1 mutant specimens, they were observed to arborize abnormally. This anatomical disruption of the sensory axons was associated with a corresponding disruption in a reflex. Normally, the tibial extensor motor neurons were excited when the femoral-tibial joint was flexed, but this resistance reflex was nearly absent in mutant animals. We used the P[Gal4] insertion strains to target expression of tetanus toxin light chain to these sensory neurons in wild-type animals and showed that this blocked the resistance reflex and produced a phenocopy of the Glued result. We conclude that disruption of the dynein-dynactin complex disrupts sensory axon path finding during metamorphosis, and this in turn disrupts synaptic connectivity.
1,25-Dihydroxyvitamin D3 and its analogues inhibit acute myelogenous leukemia progenitor proliferation by suppressing interleukin-1beta production.
We hypothesized that 1,25-dihydroxyvitamin D3 (1,25D3) and its analogues may inhibit acute myelogenous leukemia (AML) proliferation by interrupting IL-1beta-mediated growth-stimulatory signals. The incubation of the IL-1beta- responsive AML cell line OCIM2 with 10 nM 1,25D3 reduced growth 80% in liquid culture, and a 100-1000-fold lower concentration of 20-epi analogues (MC1288 and MC1301) was sufficient to achieve similar growth inhibition. The growth inhibition was associated with a rapid but transient downregulation of IL-1beta and IL-1beta-converting enzyme (ICE) mRNAs in 1,25D3- and 20-epi analogue- treated cells, and the 20-epi analogue was more effective than 1,25D3 in repressing ICE expression. An examination of long-term changes in the levels of mature IL-1beta and its precursor revealed that 24-h incubation of OCIM2 with either 1,25D3 or its 20-epi analogues abolished the production of mature IL-1beta. The effect of 1,25D3 and its analogues on growth of fresh bone marrow cells from seven AML patients was tested by a clonogenic assay. Growth inhibition of 60% was reached in only one of seven 1,25D3-treated samples, but all seven samples were inhibited 60-90% by the 20-epi analogue MC1301. Growth inhibition by 1,25D3 and the analogue was reversible by addition of IL-1beta. These results suggest that 1,25D3 and its 20-epi analogues interrupt IL-1beta autocrine growth regulation by inhibiting IL-1beta production and processing but not the response to IL-1beta.
Carboxymethylethanolamine, a biomarker of phospholipid modification during the maillard reaction in vivo.
Nepsilon-(Carboxymethyl)lysine (CML) is a stable chemical modification of proteins formed from both carbohydrates and lipids during autoxidation reactions. We hypothesized that carboxymethyl lipids such as (carboxymethyl)phosphatidylethanolamine (carboxymethyl-PE) would also be formed in these reactions, and we therefore developed a gas chromatography-mass spectrometry assay for quantification of carboxymethylethanolamine (CME) following hydrolysis of phospholipids. In vitro, CME was formed during glycation of dioleoyl-PE under air and from linoleoylpalmitoyl-PE, but not from dioleoyl-PE, in the absence of glucose. In vivo, CME was detected in lipid extracts of red blood cell membranes, approximately 0.14 mmol of CME/mol of ethanolamine, from control and diabetic subjects, (n = 22, p >> 0.5). Levels of CML in erythrocyte membrane proteins were approximately 0.2 mmol/mol of lysine for both control and diabetic subjects (p >> 0.5). For this group of diabetic subjects there was no indication of increased oxidative modification of either lipid or protein components of red cell membranes. CME was also detected in fasting urine at 2-3 nmol/mg of creatinine in control and diabetic subjects (p = 0.085). CME inhibited detection of advanced glycation end product (AGE)-modified protein in a competitive enzyme-linked immunosorbent assay using an anti-AGE antibody previously shown to recognize CML, suggesting that carboxymethyl-PE may be a component of AGE lipids detected in AGE low density lipoprotein. Measurement of levels of CME in blood, tissues, and urine should be useful for assessing oxidative damage to membrane lipids during aging and in disease.
Simian T cell leukemia virus type I from naturally infected feral monkeys from central and west Africa encodes a 91-amino acid p12 (ORF-I) protein as opposed to a 99-amino acid protein encoded by HTLV type I from humans.
A single protein of 12 kDa, p12 is encoded by the HTLV-I genome from both the singly spliced mRNA pX-ORF-I and doubly spliced mRNA pX-rex-ORF-I. While many full-length sequences of HTLV-1 are known, data on the p12 regions of African STLV-I are unavailable. We have undertaken to sequence the p12 gene in STLV-I from Central and West Africa naturally infected primates, and have compared them to known p12 sequences of HTLV-I. Our data on sequence and in vitro transcription-translation analyses indicate that p12 is a 91-amino acid (aa) protein among STLV-I strains from Central and West Africa, in contrast to the 99-aa protein found among HTLV-I strains around the globe. The p12 sequences of STLV-I exhibit a marked genetic variability at the level of both nucleotide and peptide sequences. Hydropathic and helical wheel analyses reveal that 60% of residues in HTLV-I p12 are hydrophobic, in contrast to 55% in STLV-I from Africa. Although HTLV-I and STLV-I show a similar putative antigenic site, a second potential site was located exclusively in STLV-I from Africa. There are differences in the predicted transmembrane domains in p12 between STLV-I and HTLV-I. Furthermore, the secondary structure data according to the Chou and Fasman algorithm predict an alpha-helical domain at the carboxy terminus in HTLV-I, and this domain may be truncated in STLV-I p12. The amino acid sequence of p12 shows two leucine zipper motifs (LZMs) at the amino terminus and in the middle region, respectively. This is the first report describing the size differences in p12 protein between HTLV-I and STLV-I, which may provide insights into pathogenic mechanisms used by HTLV-I and STLV-I.
Double-label immunofluorescence study of glutamic acid decarboxylase in the fetal and adult ovine pancreas by light and confocal microscopy: evidence for predominant beta-cell coexpression.
Glutamic acid decarboxylase (GAD) is present in the central nervous system and in several nonneuronal tissues including the pancreatic islets. There are two isoforms with molecular weights of 65 kDa (GAD65) and 67 kDa (GAD67). The cellular specificity of the two molecular forms of GAD and their levels within the mammalian islets may be species-dependent, being coexpressed in both beta and in non-beta cells. We have examined the ovine pancreas, from the adult and fetal stages of late gestation, for the expression of GAD65 within the islet cells by double-label immunofluorescence light and confocal microscopy. In the adult tissue, GAD65 was colocalized in a majority of the beta cells (> 95%), with only a few glucagon and somatostatin cells (< 5%) showing immunolocalization. During the fetal stages GAD65 also showed a similar predominant beta-cell coexpression. The enzyme was also detected in a few fetal glucagon (< 5%) but not somatostatin cells. In the degenerating large fetal islets, GAD65 was also observed in the majority of the residual beta cells. These results demonstrate that in the ovine pancreas GAD65 is expressed during fetal development and is predominantly beta-cell-restricted. This pattern of expression is maintained during adult life. However, the physiological role of pancreatic GAD and/or its biosynthetic product, gamma-aminobutyric acid, in islet function in the sheep and in other ruminants remains unclear.
Hydroxyurea, 5-fluorouracil infusion, and cisplatin adjunct to radiation therapy in cervical carcinoma: a phase I-II trial of the Gynecologic Oncology Group.
BACKGROUND: In a previous study, the Gynecologic Oncology Group (GOG) compared hydroxyurea (HDXR) and the combination of cisplatin (C) and 5-fluorouracil (5-FU) infusion as potentiators of radiation therapy. This study was undertaken to determine whether these two regimens could be combined, concurrent with pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: The GOG entered 75 eligible and evaluable patients on a Phase I-II evaluation of HDXR, C, and 5-FU as adjuncts to radiation therapy for locally advanced carcinoma of the cervix. All patients had histologically verified primary disease and confirmed negative para-aortic lymph nodes. Eligibility was limited to clinical stage IIB through IVA. HDXR was given orally, twice weekly at a dose of 2.5 g/m2; C on Days 1 and 29 at 50 mg/m2; and 5-FU by 96-hr infusion on Days 2-5 and 30-33 at a starting dose of 800 mg/m2. RESULTS: Forty-eight (64%) patients had stage IIB disease, 25 (33%) had stage IIIB, and 2 had stage IVA tumors. Primary tumors 4 cm or less in size were present in 15 patients, between 4 and 6 cm were in 27 patients, and larger than 6-cm were observed in 33 patients. Grade 3/4 acute toxicity was experienced by 41 (54.7%) patients. These acute toxicities caused delays in prescribed radiation therapy of more than 1 week in 14 (18.9%) and low doses of drug in 16 (21.3%), and only 26 (34.7%) patients had the scheduled dose escalation of 5-FU on their second course. Clinical response was excellent with complete and partial response rate of 93.3%. Median time to progression has not been reached. CONCLUSION: Although this dose and schedule could be successfully administered, the delays in therapy should be avoided by a lower starting dose of hydroxyurea. Stomatitis was not a dose-limiting toxicity. These results have formed the basis of a phase III trial comparing this regimen to two other chemoradiation regimens.
Coordinate regulation of the inducible forms of prostaglandin synthase and nitric oxide synthase in fibroblasts and macrophages.
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