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Biomedical subjects

S Khosla

Publications and source records attributed to S Khosla.

At least 109 records · Page 6Linked to original sources
PubMed1996

Non-suppressible parathyroid hormone secretion is related to gland size in uremic secondary hyperparathyroidism.

To determine the relative importance of parathyroid gland enlargement and alterations in calcium sensing (set-point changes) in the pathogenesis of uremic secondary hyperparathyroidism (2 degrees HPT), we investigated the relationship between estimates of parathyroid gland size and calcium-mediated parathyroid hormone (PTH) suppression in 19 normocalcemic 2 degrees HPT patients on chronic maintenance hemodialysis. We compared our results to calcium-mediated PTH suppression in 12 normal volunteers, 12 patients with familial benign hypocalciuric hypercalcemia (FBHH), a disorder of abnormal calcium sensing, and 9 subjects with primary hyperparathyroidism (1 degree HPT), which is characterized by both calcium set-point abnormalities and parathyroid gland enlargement. We found that the 2 degrees HPT group displayed a distinctive pattern of calcium-mediated PTH suppression characterized by a failure to normally suppress PTH at supraphysiologic ionized calcium concentrations, similar to 1 degree HPT, but without the rightward shift of the calcium-PTH suppression curve that characterizes calcium sensing abnormalities in FBHH and 1 degree HPT. In the patients with 2 degrees HPT, hypercalcemic suppression resulted in an ending PTH (as a percent of baseline) that was significantly higher (39.8 +/- 4.47%), and a slope of the calcium-PTH suppression curve that was significantly less negative (-4.8 +/- 0.53), compared to respective values of 19.4 +/- 1.81% (P = 0.0009) and -9.0 +/- 1.02 (P = 0.001) in normals and 19.1 +/- 2.49% (P = 0.001) and -9.6 +/- 1.11 (P = 0.0006) in FBHH. Values of ending PTH and slope in 2 degrees HPT patients, however, were similar to those found in 1 degree HPT (49.8 +/- 6.35%, P = 0.21 and -4.5 +/- 0.74, P = 0.72). The ionized calcium concentration required to attain half maximal PTH suppression (EC50) in 2 degrees HPT (1.20 +/- 0.02 mmol/liter) was not significantly different from normals (1.25 +/- 0.01 mmol/liter, P = 0.12) but was significantly less than in 1 degree HPT (1.52 +/- 0.02 mmol/liter, P < 0.0001) and in FBHH (1.44 +/- 0.02 mmol/liter, P < 0.0001). More importantly, we found a significant linear correlation between the natural logarithm of gland size and ending PTH suppression (r = 0.71, P < 0.001) and slope of the calcium-PTH curve (r = 0.67, P = 0.002) in 2 degrees HPT. Thus, calcium non-suppressible PTH secretion in 2 degrees HPT does not represent a simple set-point error, but rather correlates with the degree of parathyroid gland enlargement.

Calcium↗
PubMed1996

Gender differences in drug therapy.

Patient response to drug therapy is affected by multiple factors, including age, renal function, diet, smoking, congestive heart failure and gender. However, the data on gender differences in pharmacotherapy are limited, predominantly because women are excluded from clinical research due to the potential risks involved during pregnancy and co-existing illnesses in elderly women. Currently some information is available on gender differences in drug therapy. Differences in drug distribution and response due to different body composition as well as the effects of hormonal differences are the few that have been documented. Differences in drug metabolism due to differences in blood concentration of enzymes such as alcohol dehydrogenase has been recently described. Pharmacotherapy may also have to be altered due to differences in disease expression, like increased vasomotor tone in women. Drug efficacy has been found to be affected by gender---an example is antiplatelet therapy for stroke prevention. Finally, the side effects of drugs may differ depending on gender. Those involved in pharmacotherapy should be aware of these differences when prescribing drugs to female patients, since the majority of clinical data regarding pharmaceuticals has been derived primarily from a population of young males.

Journal Article↗
PubMed1996

Cytokine production in the bone marrow microenvironment: failure to demonstrate estrogen regulation in early postmenopausal women.

Recent studies in rodents and in human in vitro systems suggest that the action of estrogen on bone is modulated by various bone-resorbing cytokines produced by osteoblasts, bone marrow cells, or both, but results among studies have been conflicting. Thus, we studied 20 untreated women (controls) and 20 women who had received estrogen replacement therapy since the time of menopause; both groups were 5 +/- 1 yr (mean +/- SE) postmenopausal. From bone marrow aspirates, we obtained marrow plasma to evaluate the production of cytokines by marrow and trabecular bone cells in vivo and marrow mononuclear cells to assess in vitro the constitutive and lipopolysaccharide-stimulated production of cytokines and also to test the in vitro effects of 17 beta-estradiol (10(-8) mol/L). Interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-1 receptor antagonist, and IL-6-soluble receptor were measured by specific enzyme-linked immunosorbent assay. No statistically significant difference between the two groups in the level of any of these cytokines was detected in the bone marrow plasma or the conditioned medium in vitro. Furthermore, in vitro treatment with 17 beta-estradiol did not affect basal or lipopolysaccharide-stimulated cytokine production. Thus, our data suggest that for normal post-menopausal women, mediation of the effects of estrogen by a single cytokine is unlikely. Either multiple cytokines are involved and small changes in these are difficult to detect in clinical investigative studies, or other mechanisms are operative.

Antigens, CD↗
PubMed1996

Role of calcium intake in modulating age-related increases in parathyroid function and bone resorption.

Serum parathyroid hormone (PTH) and bone resorption increase in elderly women and contribute to age-related bone loss. Whether these abnormalities are caused by calcium deficiency resulting from age-related decreases in absorption and renal conservation is unclear. We studied 28 normal elderly women (mean +/- SD, age 69.3 +/- 2.7 yr) who were maintained for 3 yr on usual calcium intake levels (20.4 +/- 7.2 mmol/day [815 +/- 289 mg/day]; n = 15) (known as the usual calcium group) or high calcium intake levels (60.4 +/- 6.5 mmol/day [2414+/260 mg/day]; n = 13) (known as the high calcium group) and a reference group of 12 normal young adult women (age 30.1 +/- 4.4 yr), whose calcium intake was 23.0 +/- 4.8 mmol/day (918 +/- 193 mg/day) (known as the young group). Serum PTH was measured every 2 h, and urinary excretion of deoxypyridinoline (Dpd), a new marker for bone resorption, was measured in 4 h collections. Parathyroid gland secretory capacity was assessed during induced hypocalcemia. The mean 24 h serum PTH was 40% lower (P < 0.001), and the mean 24 h urinary Dpd was 35% lower (P < 0.005) in the high than in the usual calcium group. Mean parathyroid gland secretory capacity also was 47% lower (P < 0.005) in the high calcium group than in the usual calcium group. However, the usual calcium group had a mean 24 h serum PTH level that was 70% higher (P < 0.001) and a mean 24 h urinary Dpd level that was 30% higher (P < 0.005) than the young group, whereas the high calcium group was indistinguishable from the young group. Thus, failure of elderly women to increase their calcium intake to offset age-related increases in calcium requirement contributes substantially to their development of increased parathyroid activity and increased bone resorption, whereas a high calcium intake can reverse both abnormalities.

Adult↗
PubMed1995

Can nitroglycerin convert effort-induced angina in men into silent myocardial ischemia?

The relief of anginal pain with nitroglycerin may not correspond to the disappearance of ischemia. To evaluate the possible lack of the elimination of ischemia with sublingual nitroglycerin, we studied 25 male patients with stable angina pectoris who underwent exercise stress testing with recording of blood pressure, pulse, and ST-segment displacement. The stress test was repeated 30 minutes after administration of 0.4 mg of sublingual nitroglycerin. All 25 patients had angina and ischemic ST-segment changes in the first stress test. On repeat stress testing, 15 patients had angina and ST-segment changes, 2 patients had angina but no ST-segment changes, and 4 patients had no ST-segment changes and no angina. Four patients, however, had no angina but persistent ischemic ST-segment changes suggesting that angina was converted into silent ischemia. The mean exercise duration was 311 +/- 66 seconds before and 421 +/- 81 seconds after the nitroglycerin test. Peak heart rate and systolic blood pressure before the nitroglycerin stress test were 109 +/- 18 and 155 +/- 23 mm Hg; in the repeat stress test, they increased to 123 +/- 21 and 162 +/- 20 mm Hg, respectively.

Administration, Sublingual↗
PubMed1995

Genetic testing in the diagnosis and management of multiple endocrine neoplasia type II.

PURPOSE: To review significant advances in the early diagnosis and treatment of medullary thyroid carcinoma in patients with the multiple endocrine neoplasia II (MEN II) syndromes, advances made possible by the application of recently discovered genetic information. DATA SOURCES: Recently published English-language literature on linkage analysis and DNA analysis in the MEN II syndromes. STUDY SELECTION: Articles on familial and sporadic forms of medullary thyroid carcinoma; pentagastrin-calcitonin determination; and genetic testing. DATA EXTRACTION: Information from recent studies on 1) the usefulness and limitations of genetic testing, especially DNA and linkage analysis, in the early diagnosis of the familial form of thyroid carcinoma and 2) the correlation between the results of genetic testing and the results of biochemical screening. DATA SYNTHESIS: Medullary thyroid carcinoma accounts for most of the morbidity and mortality among patients with the familial medullary thyroid carcinoma syndromes. Multiple endocrine neoplasia IIa and IIb and familial medullary thyroid carcinoma are inherited conditions with autosomal dominance and incomplete penetrance. Traditionally, diagnosis and screening for these conditions have been done using pentagastrin stimulation tests and plasma calcitonin determinations. Recent genetic mapping, however, has assigned the genes responsible for these tumors to the pericentromeric region of chromosome 10. Available data suggest that mutations in exon 10, 11, or 16 of the RET proto-oncogene are responsible for MEN IIa and IIb and familial non-MEN medullary thyroid carcinoma. Thus, genetic testing can identify affected members of a kindred and will probably lead to early thyroidectomy and possible cure for gene carriers. CONCLUSIONS: Early studies confirm the usefulness of DNA analysis in the diagnosis and treatment of patients with familial forms of medullary thyroid carcinoma. We review changes in the diagnosis and treatment of these patients and offer a strategy for operative intervention based on results of genetic testing.

Algorithms↗
PubMed1995

Familial medullary thyroid cancer and prominent corneal nerves: clinical and genetic analysis.

A unique kindred manifesting medullary thyroid carcinoma and corneal nerve thickening without other aspects of the multiple endocrine neoplasia syndrome (MEN) was analyzed by linkage analysis using four highly polymorphic (CA)n repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, the RET protooncogene was examined for specific mutations by DNA sequence analyses in all affected family members. Screening of 11 family members spanning 4 generations revealed 7 subjects with corneal nerve thickening; of these subjects, 3 had abnormal pentagastrin-stimulated calcitonin studies, and these 3 subjects were each found to have C-cell hyperplasia or medullary thyroid carcinoma at surgery. Linkage analysis showed cosegregation of alleles (as defined by the above markers), with the presence of both corneal nerve thickening and medullary thyroid carcinoma/C-cell hyperplasia (maximum LOD score, 2.69; consistent with, but not proving linkage). DNA sequence analysis showed that none of the affected individuals had mutations in either exon 10 or 11, or in exon 16 of the RET protooncogene, regions where mutations have been described for MEN type 2A (MEN-2A) and MEN-2B families, respectively. Thus, compared to the defined syndromes of MEN-2A and MEN-2B, this kindred appears to represent a true clinical overlap syndrome whose genetic basis may be distinct from these two syndromes.

Aged↗
PubMed1995

Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption.

PTH has been postulated to play a role in both nocturnal and age-related increases in bone resorption. We tested this hypothesis directly in 10 young (ages 24-35 yr) and 10 elderly (ages 71-78 yr) normal women by measuring the cross-linked N-telopeptide of type I collagen (NTx), a marker for bone collagen breakdown, in 4-h urine collections before and during suppression of PTH secretion by a 24-h iv infusion of calcium. Serum ionized calcium and PTH levels were also measured every 2 h before and during the infusion. In both groups of women, serum PTH levels and urinary NTx excretion followed a circadian pattern before calcium infusion (analysis of variance, P = 0.0001) with peaks in the afternoon and at night for PTH and at night for urinary NTx. During the calcium infusion, the nocturnal urinary NTx excretion peak persisted (P = 0.0001), despite elimination of both PTH peaks. Urinary 24-h NTx excretion (nanomoles per millimoles of creatinine) at baseline was higher in the elderly women (mean +/- SEM, 25.7 +/- 2.1) than in the young women (19.3 +/- 1.7) (P < 0.01), and the decrease during calcium infusion was greater (7.5 +/- 1.9 vs. 4.1 +/- 1.5, P < 0.05). Therefore, the increase in serum PTH levels with age is one of the major factors responsible for the age-related increase in bone resorption. PTH does not mediate the circadian pattern of bone resorption but does play a role in setting the absolute level of bone resorption at which this pattern occurs.

Adult↗
PubMed1995

Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause--a clinical research center study.

To assess the mechanism by which estrogen replacement therapy (ERT) enhances renal calcium conservation in perimenopausal women, we studied 18 normal women in early postmenopause before and after 6 months of ERT (cyclic treatment with transdermal estradiol at 100 micrograms/day and medroxyprogesterone acetate at 10 mg/day for the first 12 days of each cycle). The changes after ERT were: serum ionized calcium and ultrafiltrable calcium, no change; serum intact PTH, 38.2% increase (P < 0.0001); serum 1,25-dihydroxyvitamin D, 23.8% increase (P < 0.0001); urinary calcium excretion, 33.3% decrease (P < 0.001); and deoxypyridinoline (a marker for bone resorption), 19.5% decrease (P < 0.0001). Also, ERT increased tubular reabsorption of calcium (TRCa; 97.6% +/- 0.2% to 98.7% +/- 0.1%; P < 0.0001), and this increase correlated with that in serum PTH (r = 0.49; P < 0.05). After the infusion of human PTH-(1-34), the TRCa maximum was greater after ERT than at baseline (99.4% +/- 0.1% vs. 99.0% +/- 0.1%; P < 0.0001), resulting in decreased calcium excretion (0.9 +/- 0.20 vs. 1.43 +/- 0.20 mumol/dL glomerular filtrate; P < 0.001). Thus, in early postmenopause, the major mechanism of increased renal calcium conservation after ERT is an increase in TRCa due to an increase in serum PTH because of estrogen-induced inhibition of bone resorption. However, ERT also may directly increase the TRCa maximum in response to PTH.

Adult↗
PubMed1995

Mutations in the RET protooncogene in sporadic pheochromocytomas.

Mutations in the RET protooncogene have recently been demonstrated in families with multiple endocrine neoplasia (MEN) types 2A and 2B. We have studied pheochromocytomas from 29 individuals who had no clinical evidence of MEN-2A or -2B to determine the frequency of germline and/or somatic mutations in exons 10, 11, and 16 of the RET protooncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in 1 of the 3 exons. These mutations were not found in the DNA from the peripheral blood from these individuals, indicating that the mutations in the tumors were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET protooncogene, our data suggest that 1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN-2A or -2B; and 2) somatic mutations in exons 10, 11, and 16 in the RET protooncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed1995

Treatment options for osteoporosis.

The number of women affected by postmenopausal osteoporosis is likely to continue to increase substantially as the population ages. Furthermore, the therapeutic options for such patients are likely to increase. In this brief review, we outline the use of the currently available medications for the management of osteoporosis--namely, estrogen, calcitonin, calcium, and vitamin D. In addition, we discuss the next generation of drugs that are likely to become available in the future--the bisphosphonates and estrogen analogues. As these options become available, the prevention and treatment of osteoporosis will become similar to the management of other common disorders such as hypertension or hyperlipidemia, in which the most appropriate medication may differ for individual patients. Thus, the treatment of osteoporosis is likely to evolve from a decision of whether to initiate estrogen replacement therapy to a more complex decision of the best agent to use for an individual patient.

Female↗
PubMed1995

Ongoing investigations into an implantable electromagnetic hearing aid for moderate to severe sensorineural hearing loss.

Over 20 million Americans have a hearing loss that produces problems in communication. The majority of these hearing-impaired individuals would benefit from conventional hearing aids, yet only about 15% use amplification devices. Many of the reasons for the lack of use of conventional hearing aids can be resolved by an implantable middle ear device directly coupled to the ossicular chain. This article presents the advantages of the implantable middle ear device.

Acoustic Stimulation↗
PubMed1995

Use of distortion product otoacoustic emissions to assess middle ear transducers in rhesus monkeys.

Distortion product otoacoustic emissions (DPOAEs) can provide an objective and noninvasive assessment of the peripheral cochlear function. Auditory brainstem responses measured from implanted rhesus monkeys have shown that middle ear transducers, coupled directly to the incus, are capable of delivering the signals to the central auditory system. The DPOAEs were used as a noninvasive method of assessing the frequency specificity of this mechanical transduction. In two rhesus monkeys implanted with the middle ear transducers, one primary stimulating tone (f1) was presented acoustically, and the other primary tone (f2) was presented by the transducer, which converted the signal into a mechanical motion of the probe tip attached to the body of the incus. The nonlinear characteristics of the cochlea produced the distortion product responses at the expected frequencies (2f1 - f2). This demonstrates the fidelity of the middle ear implant signal transduction in vivo. The DPOAEs also indicate minimal changes in the post-implant middle ear transmission. This study demonstrates that the DPOAEs can be used to assess the function of implanted middle ear transducers objectively and noninvasively.

Animals↗
PubMed1994

Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women.

Interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), and interleukin 6 (IL-6) are cytokines with potent bone-resorbing effects; some of these biologic effects are opposed by interleukin-1 receptor antagonist (IL-1ra). In vitro and animal model studies suggest that these cytokines are paracrine mediators of the increased bone resorption associated with estrogen deficiency, and increases in their production also could contribute to age-related bone loss. Therefore, we measured serum concentrations of these cytokines in 80 normal women who were 24-87 years old. IL-6 concentration correlated highly with age (p < 0.001) and increased three-fold during life. However, multiple-regression analysis showed no significant correlation between serum IL-6 levels and menopausal status, serum estradiol concentration, or markers for bone turnover (serum bone alkaline phosphatase, osteocalcin, carboxyl-terminal telopeptide of type I collagen, or 24 h urinary free pyridinoline excretion). Serum IL-1 alpha, IL-1 beta, or IL-1ra level did not change with age and, by multiple-regression analysis, did not correlate with markers of bone turnover, except IL-1ra weakly with ICTP. We found no relationship between bone-resorbing cytokines and ovarian function. Although the large age-related increase in serum IL-6 concentration could contribute to age-related bone loss, the lack of correlation with markers for bone turnover argues against this. However, based on the strong evidence in experimental animals that these cytokines are involved in estrogen action on bone, further studies in humans are warranted.

Adult↗
PubMed1994

Transforming growth factor-beta 1 induces growth inhibition of a human medullary thyroid carcinoma cell line despite an increase in steady state c-myc messenger ribonucleic acid levels.

Medullary thyroid cancer (MTC) is an endocrine tumor of the thyroid C-cells which provides an important experimental model for studies of tumor differentiation and progression. We investigated the effects of transforming growth factor-beta 1 (TGF beta 1) on the growth and functional characteristics of a human medullary thyroid carcinoma cell line (TT). Because the c-myc protooncogene may play an important role in the growth inhibition induced by TGF beta 1, we also assessed steady state c-myc messenger RNA (mRNA) levels in these cells. A 6-day exposure of TT cells to TGF beta 1 resulted in a dose-dependent inhibition of cell proliferation. In addition, TGF beta 1 exposure led to a 3-fold increase in nonadherent floating TT cells in the culture supernatants. The floating cells exhibited ultrastructural features of dying or apoptotic cells, including chromatin condensation, cytoplasmic and nuclear vesicularization, and DNA degradation with evidence of internucleosomal DNA "laddering." Despite inhibition of cell proliferation, steady state c-myc mRNA levels were 3.6 +/- 0.6-fold higher in cells exposed to TGF beta 1 compared to those in control cells (P < 0.001). Exposure of cells to a 15-base antisense c-myc oligonucleotide (10 microM) resulted in an attenuation of the TGF beta 1-induced growth inhibition and induction of cell death. TGF beta 1 also resulted in an approximately 3-fold decrease in steady state calcitonin and calcitonin gene-related peptide mRNA levels. Finally, using a sensitive bioassay for TGF beta, TT cells were shown to produce and activate significant amounts of TGF beta, particularly under conditions of serum deprivation. Our data thus indicate that TGF beta 1 has multiple effects on TT cell growth and function. It induces growth inhibition in the presence of an increase in steady state mRNA levels of the c-myc protooncogene, which is usually associated with cell proliferation. In addition, TGF beta 1 accelerates apoptosis in TT cells.

Base Sequence↗
PubMed1994

Identification of multiple endocrine neoplasia, type 2 gene carriers using linkage analysis and analysis of the RET proto-oncogene.

Ten kindreds (95 individuals) with multiple endocrine neoplasia, type 2 (MEN 2) were analyzed by linkage analysis using four highly polymorphic (CA)n-repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, we examined the RET proto-oncogene for specific mutations by DNA sequence analyses in these 10 plus 14 members of 3 additional kindred. Nine families had MEN 2A, two had MEN 2B, and two had medullary thyroid cancer alone (FMTC). Using these four markers, all 10 kindreds were informative, with 10 individuals predicted to be presymptomatic MEN 2 gene carriers and 23 individuals predicted not to be carriers. DNA sequence analysis of exons 10 and 11 of the RET proto-oncogene revealed a mutation in all nine MEN 2A kindreds. A missense mutation was found in each case, leading to a loss of a cysteine residue (codon 618 of exon 10 or codon 634 of exon 11). In the MEN 2A families, the linkage analysis and RET mutation analysis gave concordant results for prediction of gene carriers in 100% of the individuals tested. No mutations were found in the two kindreds with FMTC or the two MEN 2B kindreds. Two individuals from two different MEN 2A kindreds were identified who had abnormal calcitonin stimulation tests but were not MEN 2A gene carriers by both linkage analysis and RET mutation analysis. These individuals presumably represented the sporadic occurrence of abnormal calcitonin stimulation tests in the general population. These studies provide further support for a role of the RET proto-oncogene in the pathogenesis of MEN 2A. Additionally, in the absence of identifiable RET proto-oncogene mutations, linkage analysis using (CA)n-repeat markers is a highly accurate alternative for the identification of MEN 2 or FMTC gene carriers.

Drosophila Proteins↗