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Biomedical subjects

S Khosla

Publications and source records attributed to S Khosla.

At least 127 records · Page 7Linked to original sources
PubMed1994

Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25-dihydroxyvitamin D3.

Serum PTH concentrations increase with aging and may play an important causal role in age-related bone loss. To better define possible PTH secretory abnormalities with aging, we studied 10 young (aged 27-34 yr) and 10 elderly (aged 71-77 yr) women using sequential infusions of calcium and EDTA. To assess possible age-related resistance of PTH secretion to modulation by 1,25-dihydroxyvitamin D [1,25-(OH)2D], the infusions were repeated after 1 week of oral 1,25-(OH)2D3 therapy (1 microgram/day). Baseline serum intact PTH concentrations were higher in the elderly compared to the young women (mean +/- SEM, 3.8 +/- 0.5 vs. 2.7 +/- 0.4 pmol/L; P = 0.03). In addition, the elderly women had a significantly higher maximal PTH response to hypocalcemia compared to the young women (16.6 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = 0.03). The elderly women also had a greater nonsuppressible component of PTH secretion (0.8 +/- 0.1 vs. 0.4 +/- 0.1 pmol/L; P < 0.001). The set-point for PTH secretion, however, was identical in the elderly and young women (1.18 +/- 0.01 vs. 1.19 +/- 0.01 mmol/L; P = NS). After 1,25-(OH)2D3 administration, both groups had similar reductions in baseline and maximally stimulated PTH levels, indicating that elderly women have normal responsiveness to 1,25-(OH)2D3 suppression of PTH secretion. In addition, maximally stimulated PTH levels in the 1,25-(OH)2D3-treated elderly women decreased to the pretreatment values of young women (13.3 +/- 1.1 vs. 12.8 +/- 1.0 pmol/L; P = NS). thus, elderly women have greater basal, maximal, and nonsuppressible levels of PTH secretion, without alterations in the set-point. These abnormalities are similar to those found in patients with secondary hyperparathyroidism and parathyroid hyperplasia. Further, the abnormal PTH secretory dynamics in elderly women are reversible by short term 1,25-(OH)2D3 therapy.

Adult↗
PubMed1994

Circulating cytokine levels in osteoporotic and normal women.

Interleukin-1 (IL-1) and IL-6 have been postulated to play roles in the pathogenesis of postmenopausal osteoporosis. To test this hypothesis, we measured circulating levels of IL-6, IL-1 alpha, and IL-1 beta in 40 age-matched normal and 40 osteoporotic women with vertebral fractures and increased bone turnover. Since IL-1 activity is modulated by the IL-1 receptor antagonist (IL-1ra), we also measured circulating IL-1ra levels in these women. Despite having higher rates of bone turnover as assessed by bone biochemical markers, the osteoporotic women had serum levels of IL-6, IL-1 alpha, and IL-1 beta that were similar to the normal women. IL-1ra levels (mean +/- SEM) tended to be lower in the osteoporotic women (143 +/- 21 pg/mL) vs. the normal women (189 +/- 22 pg/mL; P = 0.08). The IL-1 alpha/IL-1ra ratio, an index of IL-1 alpha bioactivity, was higher in the osteoporotic women (6.4 +/- 1.1) than in the normal women (4.4 +/- 0.5; P < 0.05). There were nonsignificant trends for increased IL-1 beta/IL-1ra and (IL-1 alpha + IL-1 beta)/IL-1ra ratios in the osteoporotic vs. normal women. None of the cytokines correlated with markers of bone resorption in either group of women. In summary, although there was a trend for a higher IL-1/IL-1ra ratio in the osteoporotic women, we were unable to demonstrate unequivocal abnormalities of cytokines affecting bone resorption in peripheral serum of women with postmenopausal osteoporosis. However, it is possible that increased production of these cytokines occurs in the local environment of bone or bone marrow and is not detected by analysis of peripheral serum. Thus, further studies will be required to exclude this possibility.

Aged↗
PubMed1993

Risk factors not addressed in antihypertensive therapy based solely on blood pressure control.

There has been a considerable revolution in the field of hypertension therapy. We have gone through an era in which patients with severe hypertension and those with accelerated hypertension had a very short life expectancy. Currently blood pressure can be readily controlled with a marked improvement in longevity. We have gone from an era in which stroke was common due to hypertensive cardiovascular disease to an era in which patients are effectively treated and there has been a marked reduction in the incidence of stroke. The challenge is whether we can reduce the very high mortality due to coronary artery disease in patients with hypertension as we have done with stroke. New groups of drugs that may have a more favorable effect on metabolic and hemodynamic risk considerations have been developed over the last decade. These agents may reduce the risk for coronary heart disease to a greater extent than previously employed therapy. While there are no randomized placebo-controlled studies demonstration this, a theoretical basis does exist to give the physician reason to think about prioritizing therapies and tailoring them to the needs of the individual patient.

Animals↗
PubMed1993

The clinical implications of first-pass metabolism: treatment strategies for the 1990s.

The first-pass effect is real. It may pose obstacles to the treatment of disease, and strategies need to be developed to address the problem that first pass can cause. First we have to look at identifying the problem, and this symposium has helped to further emphasize that the problem exists and awareness is increasing. The first-pass effect has been a basic tenant of pharmacology but an area not receiving active research interest and one that is often overlooked in the clinical arena. Avoiding drug interactions is a consideration, and that is a major challenge to the field of clinical pharmacology. Clinicians need to be aware of the problem, aware of the danger areas with drugs, and first pass. Another alternative is to turn to chemical modification of a drug that avoids needing to take first pass into consideration.

Drug Therapy↗
PubMed1993

Muscle strength in osteoporotic versus normal women.

Strong back muscles contribute to good posture and skeletal support. Osteoporosis, being a metabolic bone disease, should not affect muscle strength. In this study we were interested in comparing the back extensor strength (BES) of osteoporotic and normal women. Fifty-five women ages 40-85 years who had a documented diagnosis of osteoporosis and were referred for initiation of proper exercise programs were included in our study after meeting the inclusion criteria. They all had evaluation of their posture, back and upper extremity strength, and physical activity score through our Rehabilitation of Osteoporosis Program--Exercise (ROPE). In addition, to avoid the interference of pain on application of maximal effort, we did not include subjects with acute back pain or those who experienced back pain with maximal effort during the testing trial. BES for osteoporotic women ranged from 16 to 65 lb (mean +/- SD, 36.5 +/- 15.5) for ages 40-59 years, 9 to 55 lb (mean +/- SD, 29.9 +/- 10.6) for ages 60-69 years, 6 to 52 lb (mean +/- SD, 24.3 +/- 10.2) for ages 70-79 years, and 17 to 27 lb (mean +/- SD, 21.2 +/- 4.2) for ages 80 years or older. Comparison of these data with the BES of 25 normal women, with statistical adjustment for age, demonstrated that the osteoporotic women had significantly lower BES than the normal women. A longitudinal study of a larger group of women would be of great interest for clarifying whether the weakness of back extensors precedes and, indeed, contributes to compression fractures of the spine.

Adult↗
PubMed1993

Calcium infusion suggests a "set-point" abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism.

PTH clearly plays a role in maintaining the hypercalcemia of familial benign hypercalcemia (FBH or familial hypocalciuric hypocalcemia). To better define the abnormalities of parathyroid function in FBH and primary hyperparathyroidism (1 degree HPT), we used a two-site immunochemiluminometric assay for intact PTH to examine PTH suppressibility in normal individuals and patients having FBH or 1 degree HPT. Twelve normal, 11 FBH, and 7 1 degree HPT subjects were given calcium (Ca) iv with frequent sampling for ionized Ca and intact PTH. In normal and FBH subjects, plasma PTH levels decreased essentially identically in response to iv Ca. In the 1 degree HPT group, PTH was not normally suppressible. However, there was a spectrum of responsiveness in 1 degree HPT patients, with a significant correlation between tumor mass and degree of PTH nonsuppressibility (r = 0.87, P = 0.01). Analysis of the relationship between plasma PTH and ionized Ca values in the three groups demonstrated a shift to the right in the FBH curve, with no difference of slope, consistent with the notion of a simple "set-point" error in FBH. In contrast, the curve in 1 degree HPT was not only shifted to the right but also differed from normal in slope (normal, -8.92; 1 degree HPT, -3.92, P = 0.04). Thus, we propose that the parathyroid functional abnormality in FBH represents a simple set-point error, whereas the defect in 1 degree HPT consists of a set-point error combined with varying degrees of Ca nonsuppressible PTH secretion that may be related to tumor mass.

Adult↗
PubMed1993

Mild heart failure: why the switch to ACE inhibitors?

Management of congestive heart failure in the past has focused on sodium and fluid restriction, rest, and digitalis glycosides. Now, significant new evidence justifies early and aggressive ACE inhibitor therapy in patients with asymptomatic or mildly symptomatic LV dysfunction. ACE inhibitors reduce the likelihood of symptomatic heart failure in asymptomatic patients with reduced ejection fraction. Patients with reduced LV function following acute MI who receive ACE inhibitors have a decreased risk of death, a lower probability of developing systematic heart failure, and fewer MI recurrences. Hypotension and azotemia can be avoided by reducing the concomitant dose of diuretics and carefully titrating the ACE inhibitor dosage to target levels.

Aged↗
PubMed1992

Clinical performance of parathyroid hormone immunometric assays.

Three immunometric assays of parathyroid hormone (PTH)--a commercial immunoradiometric assay, an in-house immunoradiometric assay, and an immunochemiluminometric assay--were evaluated in 50 patients with surgically proven primary hyperparathyroidism. Of these patients, 43 had increased values with the commercial assay (sensitivity, 86%), whereas 45 patients had increased concentrations with both the in-house immunoradiometric and the in-house immunochemiluminometric assays (sensitivities, 90%). Because of the results of this comparison study, we confidently chose the immunochemiluminometric assay as our routine assay; this assay was evaluated retrospectively in 361 patients with surgically proven primary hyperparathyroidism. In 45 patients, PTH values were below the upper limit of normal (sensitivity, 88%). The results indicate that the sensitivities of current immunometric assays are approximately 90%. Twenty patients who had hypercalcemia associated with malignant involvement were assessed with the immunochemiluminometric assay. Of these 20 patients, 19 had subnormal PTH values, and 1 had a value within the normal range. In contrast, in the past, PTH values determined with radioimmunoassays have often been in the normal range for such patients. Thus, an immunometric PTH assay is superior to a radioimmunoassay in the differential diagnosis of hypercalcemia associated with malignant disease.

Diagnosis, Differential↗
PubMed1992

In vitro and in vivo detection of somatostatin receptors in pheochromocytomas and paragangliomas.

Fifty-one adrenal pheochromocytomas and 14 paragangliomas were evaluated for somatostatin (SRIH) receptor content with in vitro autoradiography on tissue sections from surgically removed tumors, using iodinated 125I[Tyr]3 octreotide as radioligand. Thirty-seven of 51 pheochromocytomas were SRIH receptor positive (73%), as well as 13 of 14 paragangliomas (93%). These SRIH receptors were of high affinity, pharmacologically specific for SRIH and localized on the tumor tissue. Using in vivo imaging techniques with radiolabeled SRIH analogs, paragangliomas could be visualized in five patients, as well as pheochromocytomas in two of three patients. All tumors tested subsequently in vitro (n = 7) were shown to contain SRIH receptors. A majority of pheochromocytomas were also shown to have a high tumoral SRIH content as measured by immunohistochemical techniques. Detection of SRIH messenger RNA in pheochromocytomas by in situ hybridization indicated that the SRIH was produced in the tumors. A weak inverse correlation was observed between SRIH receptor status and tumoral SRIH content, suggesting that SRIH receptors may be down-regulated by high levels of endogenous SRIH in some tumors. There was no correlation between the SRIH receptor status and sex, age, tumor size, benign vs. malignant tumor, or urinary metanephrine excretion. These tumors were also analyzed for allelic losses on various chromosomes and showed significant loss of heterozygosity (LOH) on chromosomes 1p, 3p, 17p, and 22q. All eight tumors with LOH on chromosome 1p were SRIH receptor positive (100%), whereas only 6 of 11 tumors without LOH on 1p (55%) were SRIH receptor positive, suggesting a correlation between LOH on 1p and SRIH receptor positive status. SRIH receptors thus represent a consistent pathobiochemical marker for most of these adrenal and extra-adrenal tumors. In addition, these receptors may be of potential interest for the in vivo localization of these tumors.

Adrenal Gland Neoplasms↗
PubMed1991

Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas.

Loss of heterozygosity (LOH) at specific loci may help localize tumor suppressor genes involved in the formation of various familial and sporadic tumors. In addition, the genetic loci for a number of familial tumor syndromes have been mapped by linkage analysis. To explore the possible role of tumor suppressor genes in endocrine tumors, we tested 41 pheochromocytomas (34 sporadic and 7 familial) and 11 medullary thyroid cancers (MTC) (10 sporadic and 1 familial) for LOH near a variety of potentially important genetic loci: (a) the multiple endocrine neoplasia type 2A (MEN 2A) locus on chromosome 10; (b) the von Hippel-Lindau locus on 3p; and (c) the p53 and neurofibromatosis 1 loci on 17. We also examined chromosomes 1p and 22q because previous studies in a small number of pheochromocytomas and MTCs suggested LOH in these regions. Background rates for LOH were assessed using several "random" probes. Finally, we examined a number of clinical and histologic characteristics of these tumors for possible correlations with specific genetic alterations. LOH in the region of the MEN 2A locus was uncommon (0% for MTCs, 5% for pheochromocytomas). However, we found significant allelic losses in pheochromocytomas on chromosomes 1p (42%), 3p (16%), 17p (24%), and 22q (31%). We also noted a correlation between LOH on 1p and urinary excretion of metanephrine by these patients (P = 0.02). LOH on 1p, 3p, and 17p also appeared to be associated with increased tumor volume. Analysis of the smaller number of MTCs demonstrated allelic losses on chromosomes 1p and 22q. Our results suggest that tumor formation and/or progression in pheochromocytomas and MTCs involves multiple genes, analogous with the model proposed for colon carcinoma.

Adolescent↗
PubMed1990

Parathyroid hormone-related peptide in lactation and in umbilical cord blood.

Parathyroid hormone-related peptide (PTHrP) is expressed in lactating rat mammary glands after suckling, as a result of increases in prolactin rather than suckling per se. In addition, PTHrP produced in the fetal parathyroid glands and placenta may be responsible for stimulation of placental calcium transport. In the current study, we used a radioimmunoassay for human PTHrP to measure levels of the peptide in (1) human breast milk, cow's milk, and two infant formulas; (2) sequential plasma samples in prepartum and postpartum lactating women; (3) women with pathologic hyperprolactinemia; and (4) human umbilical cord blood. In normal subjects, plasma PTHrP levels ranged from less than 2 to 5 pmol/liter. In contrast, human breast milk contained substantially increased levels of immunoreactive PTHrP. Similar elevations were found in cow's milk and in one infant formula. Column chromatography of breast milk demonstrated that PTHrP immunoreactivity included a region of adenylate cyclase stimulating activity, consistent with the presence of biologically active PTHrP. Plasma prepartum PTHrP values did not differ from corresponding postpartum values in lactating women. Women with hyperprolactinemia had a mean plasma PTHrP value in the high-normal range. Umbilical cord blood had considerably suppressed parathyroid hormone values but PTHrP levels that were indistinguishable from those in normal human plasma. Thus, PTHrP is present in high concentrations in breast milk but apparently does not gain access to the maternal circulation in significant amounts. In addition, women with pathologic hyperprolactinemia seem not to have increased levels of circulating PTHrP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Adrenal crisis in the setting of high-dose ketoconazole therapy.

We describe a patient with type I diabetes mellitus and hypothyroidism who developed frank adrenocortical insufficiency while receiving a high-dose ketoconazole therapy for keratitis caused by Acanthamoeba species. While impaired cortisol responses to corticotropin and mildly symptomatic hypoadrenalism have been described previously with ketoconazole therapy, to our knowledge, this case represents the first documented article of an actual adrenal crisis associated with this drug. Two reasons are postulated for the development of this complication in our patient: high-dose ketoconazole therapy given in divided doses during the day, and a possibly impaired central response to stress because of hypothyroidism. Our article points to the need to monitor patients treated with high-dose ketoconazole for adrenal insufficiency, particularly if associated illnesses are present that may impair an adequate stress response.

Acanthamoeba↗
PubMed1988

Nucleotide sequence of cloned cDNAs encoding chicken preproparathyroid hormone.

In order to characterize an avian parathyroid hormone gene, a lambda gt10 cDNA library constructed from chicken parathyroid gland mRNA was screened with a human preproparathyroid hormone (preproPTH) cDNA probe. Nucleotide sequence analysis of three independent clones confirmed that they encoded chicken preproPTH. This analysis, complemented by primer extension and Northern blot analysis of mRNA, demonstrated a 5'-untranslated region for chicken preproPTH of 127 nucleotides, a coding region of 357 nucleotides, and a 3'-untranslated region of approximately 2500 nucleotides. The coding sequence predicts a mature chicken PTH of 88 amino acids in contrast to the 84 amino acids of the mammalian hormones. Comparison of the avian and the mammalian hormones shows striking homology in the region of amino acids 1-32. The middle and carboxyl-terminal portions of chicken PTH, however, differ considerably from the mammalian hormones and include deletions of sequences conserved in mammalian PTH and insertions of novel peptide sequences. Comparison of the avian and mammalian structures suggests potential alterations of the mammalian sequences that may lead to altered bioactivity and/or hormone metabolism.

Amino Acid Sequence↗
PubMed1988

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin.

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.

Animals↗
PubMed1986

Morphology and distribution of cystic cavities in the normal murine thymus.

The normal murine thymus was examined by light- and electron microscopy to determine the distribution and morphology of extracellular cystic cavities. Most cavities were confined to the cranial half of each gland, situated at the junction between cortex and medulla. They varied in size and shape, and gave rise to narrow channels that coursed to the capsular surface of the gland. Large cavities could be divided into three zones. A short cranial zone exhibited gland-like features, consisting of cells lining a clear lumen. A central zone was lined by a diverse population of cells. Some possessed secretory granules, while others exhibited an apical ciliated border. Lining cells inter-digitated with each other and were joined laterally by intercellular junctions. The lumen of the central zone contained lymphocytes and macrophages in an amorphous extracellular matrix. The caudal zone of each cavity had an attenuated and incomplete cellular lining, communicating directly with the surrounding thymic parenchyma. Thymic cavities may represent the initial part of the efferent lymphatic system of the gland, beginning in the tissue spaces at the corticomedullary junction. Selected cells could then enter and interact with the luminal contents in the central zone of the cavity. Ciliated cells may then propel lymphocytes and secretions into the narrow channels radiating from the uppermost part of the chamber, leaving a cell-free lumen in this region. These cavities may function in sequestering lymphocytes, macrophages and thymic secretions before their exit from the gland.

Animals↗