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Biomedical subjects

S B Patel

Publications and source records attributed to S B Patel.

At least 37 records · Page 2Linked to original sources
PubMed1999

A gene for congenital generalized lipodystrophy maps to human chromosome 9q34.

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.

Acanthosis Nigricans↗
PubMed1999

Saline-induced dilutional acidosis in a maintenance hemodialysis patient.

A patient with end-stage renal disease developed severe hyperchloremic acidosis (venous serum total CO2 level of 10 mmol/L) after treatment with 16 L of isotonic saline. Analysis of this case and published literature indicates that dilutional acidosis may result when very large volumes of isotonic saline are administered intravenously, especially in patients with impaired or absent renal function.

Acidosis↗
PubMed1998

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

Cardiovascular Diseases↗
PubMed1998

An adaptive noise reduction stethoscope for auscultation in high noise environments.

Auscultation of lung sounds in patient transport vehicles such as an ambulance or aircraft is unachievable because of high ambient noise levels. Aircraft noise levels of 90-100 dB SPL are common, while lung sounds have been measured in the 22-30 dB SPL range in free space and 65-70 dB SPL within a stethoscope coupler. Also, the bandwidth of lung sounds and vehicle noise typically has significant overlap, limiting the utility of traditional band-pass filtering. In this study, a passively shielded stethoscope coupler that contains one microphone to measure the (noise-corrupted) lung sound and another to measure the ambient noise was constructed. Lung sound measurements were made on a healthy subject in a simulated USAF C-130 aircraft environment within an acoustic chamber at noise levels ranging from 80 to 100 dB SPL. Adaptive filtering schemes using a least-mean-squares (LMS) and a normalized least-mean-squares (NLMS) approach were employed to extract the lung sounds from the noise-corrupted signal. Approximately 15 dB of noise reduction over the 100-600 Hz frequency range was achieved with the LMS algorithm, with the more complex NLMS algorithm providing faster convergence and up to 5 dB of additional noise reduction. These findings indicate that a combination of active and passive noise reduction can be used to measure lung sounds in high noise environments.

Auscultation↗
PubMed1998

HMG-CoA reductase is not the site of the primary defect in phytosterolemia.

Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevaIonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.

Adolescent↗
PubMed1998

Sitosterolemia: exclusion of genes involved in reduced cholesterol biosynthesis.

Sitosterolemia (phytosterolemia) is a rare autosomal recessively inherited disorder that is characterized by premature coronary artery disease, xanthomas, and increased plasma plant sterols and 5alpha-stanols. Affected individuals show an increased absorption of both cholesterol and sitosterol from the diet, decreased bile clearance of these sterols and their metabolites resulting in markedly expanded whole body cholesterol and sitosterol pools. Biochemical studies have shown that the regulation of the cholesterol biosynthetic pathway may be abnormal in this condition. In particular, the activities and mRNA for the biosynthetic enzymes, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase are low in liver biopsy specimens isolated from affected individuals, suggesting replete intracellular cholesterol pools. However, the membrane expression of hepatocyte low density lipoprotein receptors was increased, suggesting discordant regulation. Segregation analyses in three families for the genes for HMG-CoA reductase, HMG-CoA synthase, and LDL-receptor excluded these as sites of mutation. In view of the previously described discordant regulation of the above genes in sitosterolemia, the two major regulatory genes for this pathway, sterol regulatory element binding proteins (SREBP-1 and -2), were also examined. These genes did not segregate with the disease and were thus excluded. Two other genes involved in cholesterol absorption and chylomicron secretion, namely acyl coenzyme A:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP) were also examined for segregation and similarly excluded. Although the gene defect in sitosterolemia therefore remains to be elucidated, important candidate genes have been excluded.

Adult↗
PubMed1998

Outbreak of viral hepatitis B in a rural community in India linked to inadequately sterilized needles and syringes.

In India, virtually all outbreaks of viral hepatitis are considered to be due to faeco-orally transmitted hepatitis E virus. Recently, a cluster of 15 cases of viral hepatitis B was found in three villages in Gujarat State. The cases were epidemiologically linked to the use of inadequately sterilized needles and syringes by a local unqualified medical practitioner. The outbreak evolved slowly over a period of 3 months and was marked by a high case fatality rate (46.7%), probably because of concurrent infection with hepatitis D virus (HDV) or sexually transmitted infections. But for the many fatalities within 2-3 weeks of the onset of illness, the outbreak would have gone unnoticed. The findings emphasize the importance of inadequately sterilized needles and syringes in the transmission of viral hepatitis B in India, the need to strengthen the routine surveillance system, and to organize an education campaign targeting all health care workers including private practitioners, especially those working in rural areas, as well as the public at large, to take all possible measures to prevent this often fatal infection.

Adult↗
PubMed1997

Activation of a cryptic splice-site in intron 24 leads to the formation of apolipoprotein B-27.6.

Apo B expression is confined to the intestine and liver, and its secretion from these tissues is dependent on the expression of a lipid transfer protein, microsomal triglyceride transfer protein (MTP). Previously, we reported a model system for the study of apolipoprotein (apo B) biogenesis using heterologous expression in COS cells (Patel SB, Grundy SM. J. Lipid Res. 1995;36:2090-2103). We now report the characterization of the effects of a T-->C transition in the splice-site at +2 of intron 24 previously reported by Talmud et al. (J. Lipid Res. 1994;35:468-77). Using our heterologous expression system, we show that the mutation led to aberrant processing of intron 24, but normal processing of intron 25. The resultant translation of this mutant mRNA produced a truncated apo B protein of the size of apo B-27.6. Reverse transcription, polymerase chain reaction and sequencing of the amplified products were used to show that a cryptic donor splice-site within intron 24 was utilized, resulting in the generation of a novel hydrophilic 29 amino acid carboxyl-terminal tail. Co-expression of apo B-27.6 with microsomal triglyceride transfer protein (MTP) showed that this protein could bind MTP and resulted in the secretion of a lipoprotein particle with a buoyant density in the range 1.16-1.25 g/ml. These results indicate that this splice-site mutation leads to an activation of a downstream cryptic splice-site within intron 24, causing an insertion of 40 bases of intron 24 sequences into the mature RNA. This leads to a frame-shift of translation resulting in addition of 29 new amino acids at the carboxyl-terminus, before an in-frame stop translation codon is encountered, truncating the apo B at B-27.6.

Alternative Splicing↗
PubMed1997

Obesity in db and ob animals leads to impaired hepatic very low density lipoprotein secretion and differential secretion of apolipoprotein B-48 and B-100.

Dyslipidemia secondary to obesity is commonly observed in both animals and humans. As it has been hypothesized that obesity can result in overproduction of VLDL, leading to the subsequent dyslipidemia, we have examined the triglyceride and apoB secretion rates in vivo in obese C57BI/ KsJ db/db and C57BI/6J ob/ob mice and their lean littermates. In ob/ob animals, obesity resulted in significantly lower, not higher, triglyceride secretion rates in both males (3.94 +/- 0.49 mg/h per g liver vs. 5.45 +/- 0.29 mg/h per g liver in lean littermates, P < 0.001) and females (4.29 +/- 0.81 mg/h per g liver vs. 5.25 +/- 0.59 mg/h/g liver, P < 0.001). For db/db, the obese females did not show a statistically significant triglyceride secretion rate compared to their lean littermates. Only the male db/db animals showed a significantly higher triglyceride secretion rate compared with lean littermates (5.50 +/- 1.1 mg/h per g liver vs. 3.37 +/- 0.36 mg/h/g liver, P < 0.001). Examination of the apolipoprotein B (apoB) secretion rates showed that for ob/ob animals and db/db obese females, apoB48 secretion was significantly decreased compared to that of normal littermates, with a small increase in apoB-100 secretion. Total apoB secreted, however, was not increased. Our data further suggest that the predominant cause of the dyslipidemia under these conditions is a defect in removal of VLDL from the circulation.

Aging↗
PubMed1996

Interactions between microsomal triglyceride transfer protein and apolipoprotein B within the endoplasmic reticulum in a heterologous expression system.

When apolipoprotein B (apoB) is expressed in heterologous cells, it is not secreted but retained and degraded within the endoplasmic reticulum (ER). We have previously characterized carboxyl-terminal truncated forms of apoB expressed in COS cells and have shown that these proteins were readily synthesized but retained within the ER and degraded, if the size of the truncated protein was larger than apoB 29. Below this size, the smaller the size of the apoB truncates, the greater the extent of secretion, although >50% of these smaller proteins were also degraded within the ER. In the present study, we demonstrate that this secretory defect can be overcome by coexpression with microsomal triglyceride transfer protein (MTP); moreover, this complementation is inversely related to the size of apoB. Secretion of apoBs larger than B29 required the coexpression of MTP and, in the presence of MTP, was oleate-responsive. MTP, in the presence or absence of oleate supplementation, had little or no effect on the secretion of the shorter truncates. We discovered, however, that MTP was physically associated with all forms of apoB intracellularly (B13-B41). The association of MTP with apoB 41 was stable to high salt washing, as well as to low pH, suggesting that these interactions may be hydrophobic in nature. In addition to the interaction with MTP, apoB was also found to be associated with calnexin, confirming previous studies, and with proteins bearing the KDEL retention signal. However, studies on overexpression of human calnexin and tunicamycin inhibition of glycosylation showed that interaction with calnexin was not necessary for the formation or secretion of apoB 41-containing lipoproteins; moreover, in the presence of MTP, the association of calnexin with apoB 41 was transient or absent. These data suggest that for apoB to attain a folded state sufficient to escape the quality control of the ER, it needs to obtain neutral lipid (supplied by MTP), as well as its ability to keep it packaged as a rudimentary lipoprotein, dependent on its size being larger than B29.

Amino Acid Sequence↗
PubMed1995

Can chronic maternal drug therapy alter the nursing infant's hepatic drug metabolizing enzyme pattern?

This study was carried out to investigate whether minute quantities of maternal drugs ingested over an extended period of time by a breast-feeding infant can alter the activity pattern of the infant's hepatic drug metabolizing enzyme (HDME). The HDME activity patterns of 12 breast-fed infants whose mothers were not on drug therapy were compared with those of 11 infants whose mothers had been taking 30 micrograms levo-norgesterel daily for 90 to 195 days (oral contraceptives group) and of 10 infants whose mothers had been taking ethambutol and isoniazid daily since pregnancy (tuberculosis group). As 6 beta hydroxycortisol in urine is considered to be a good and acceptable reflector of HDME activity, it was estimated from the infants' urine using enzyme-linked immunosorbent assay (ELISA) technique. A comparison of the patterns between 90 days of age and 195 days of age of the infants in the control group and the two study groups indicated an increase from 36.6 ng/mL to 58.4 ng/mL at 195 days in the control group. An initial decrease from 36.6 ng/mL to 26.2 ng/mL was noted with commencement of maternal levo-norgesterel therapy, followed by a slow and steady rise to 47.8 ng/mL at 195 days of age, with a shift in the peak from 120 to 135 days of infants age in the oral contraceptive group. A suppressed pattern with decreased levels of 6 beta hydroxycortisol ranging from 19.3 ng/mL to 26.5 ng/mL at 195 days was found in the tuberculosis group. The data were analyzed by two-way analysis of variance (ANOVA) coupled with Duncan's Multiple range test. Both treatment group showed significant differences from the control group at the 0.050 level. The HDME plays an important role in determining the final outcome of any drug in humans, as it controls the metabolism of drugs. Hence, alterations in its activity caused by the transfer of maternal drugs over a prolonged period of time could pose a serious problem to nurslings when they require drugs for their own benefit.

Adult↗
PubMed1995

Low-dose progestogen contraception and the nursing mother.

Breast feeding, though an important and efficient contraceptive method, suffers from one major limitation: the contraceptive protection it offers the nursing mother ends abruptly without giving any physical indication of the return of fertility. Barrier methods and progesterone-only hormonal contraceptives, either in the oral, implant or injectable form, appear to be the primary contraceptive alternative for the nursing mother today. They neither adversely affect lactation, nor does the minute quantity of progesterone (NET or LNG) transferred to the infant affect its growth and physical well-being. Puerperal insertion of IUD carries an inherent risk of pelvic inflammatory disease, high expulsion rates and menorrhagia, once menses resume. Combination contraceptives affect both the quality and quantity of breastmilk; hence they are not recommended. Sterilization is a permanent method and therefore useful only when the family has been completed.

Adult↗
PubMed1995

Is time-interval between mini-pill ingestion and breastfeeding essential?

A study was conducted on four alternate days over an eight-day period in a group of 12 healthy, 20-35 year old exclusively breast feeding women who were interested in weaning their infants. On each study day the women ingested 150 micrograms levonorgestrel. Maternal blood and milk samples were collected at 2, 4, 6, and 8 hr intervals after LNG ingestion on the 1st, 3rd, 5th, and 8th day. A time-dependent decrease in maternal serum and increase in breast milk levels of LNG were observed. Maintaining a time interval between mini-pill intake and breastfeeding results in higher levels of LNG in breast milk, thereby exposing the infant to a bolus of LNG in a "single-delayed" feed.

Administration, Oral↗
PubMed1995

Heterologous expression of apolipoprotein B carboxyl-terminal truncates: a model for the study of lipoprotein biogenesis.

Expression of proteins in cells that lack specific chaperones, or subunits required for correct assembly results in the degradation of these proteins early on after synthesis, probably in the endoplasmic reticulum (ER) or an ER-related compartment. We have explored heterologous expression as a model to study the complex process involved in the biogenesis of apolipoprotein B (apoB)-containing lipoproteins. As an initial step, a series of carboxyl-terminal truncated apoB in COS cells were expressed to characterize this system. ApoB proteins ranging from apoB-13 to apoB-41 were expressed. Truncates larger than apoB-29 were completely retained and degraded within the cells; hence these cells have a 'secretory defect' for the larger truncates. Degradation of these apoB proteins is likely to be in the endoplasmic reticulum or ER-related compartment, as shown by sensitivity to endo beta-N-acetylglucosaminidase, by lack of an effect on the degradation kinetics by brefeldin A treatment, and by ImmunoGold EM. Degradation in COS cells was not affected by a variety of protease inhibitors, including N-acetyl-leucyl-leucyl-norleucinal (ALLN). Addition of oleate to the culture medium did not alter their metabolic fate. In comparison to the larger truncates, apoB proteins less than apoB-29 were partially secreted; the majority of these, too, were also retained and degraded intracellularly in a similar compartment. Secreted apoB-17 protein was shown to have been processed correctly in the Golgi and was secreted as a minimally lipidated protein. This model, based on the expression of apoB truncates larger than B-29 in COS cells, may therefore allow for the identification and study of the requirements of specific factors that may be required for both apoB secretion and lipoprotein biogenesis by in vivo complementation of this 'secretory' defect.

Amino Acid Sequence↗
PubMed1994

Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids.

BACKGROUND: Muscle fatty acid binding protein (M-FABP) is one of a family of cytosolic lipid-binding proteins involved in fatty acid processing. In order to investigate the precise interactions between M-FABP and its ligands and to understand the structural basis of differential binding affinity, we have compared the structures of M-FABP in complex with three C18 fatty acids. RESULTS: We describe the crystal structures of M-FABP in complex with n-octadecanoate (stearate), trans-delta 9-octadecenoate (elaidate) and cis-delta 9-octadecenoate (oleate). These structures were refined using least-squares positional and anisotropic temperature factor refinement to final R-factors of 11.4%, 12.1% and 13.2% respectively for all the data between 8.0 A and 1.4 A resolution. CONCLUSIONS: Stearate, elaidate and oleate each adopt highly similar U-shaped conformations when they bind to M-FABP within a large interior binding cavity, which also contains 13 ordered water molecules. The atomic structure of the protein is virtually identical, regardless of the nature of the bound ligand. The fatty acid is thought to enter the interior cavity of the protein via a portal in its surface while interior solvent is released through a secondary opening. The ligand affinity can be correlated with the conformational energy and the solubility of the bound ligand.

Carrier Proteins↗
PubMed1994

At what 'infant-age' can levonorgestrel contraceptives be recommended to nursing mothers?

OBJECTIVE: Levonorgestrel (LNG), a low-dose progestin, does not affect lactation but like all drugs taken by breastfeeding mothers, it can be transferred to the infant via breast milk. How infants of various ages cope with this unwanted maternal drug would help in deciding when to recommend this method of contraception to breastfeeding mothers. METHODS: The study was conducted in 30 exclusively breastfeeding mothers and their 4-, 12- and 24-week-old infants. The mothers daily received 30 micrograms LNG over a five-week period, thus exposing their infants to maternal LNG for that period. RESULTS: Four-week-old infants could neither absorb nor metabolize LNG efficiently. Twelve-week-old infants could metabolize LNG more efficiently than absorb. Twenty-four-week-old infants could do both efficiently. CONCLUSION: It is safe to introduce LNG to breastfeeding mothers at 12 weeks postpartum.

Adult↗
PubMed1994

A sensitive ELISA for 6 beta-hydroxycortisol in urine using enzyme penicillinase (beta-lactamase).

A sensitive and specific, enzyme labelled immunosorbent assay (ELISA) for 6 beta-hydroxycortisol in diluted urine using penicillinase was developed. 6 beta-Hydroxycortisol-21-hemisuccinate was conjugated with enzyme penicillinase. Antibody immobilized on a polyvinylchloride ELISA plate (Dynatech) was used for separation of bound from free ligand. The sensitivity of the assay was between 2.0-3.0 pg per well and recovery of 6 beta-hydroxycortisol from urine ranged between 85.0-108.0%. The assay is simple, rapid and precise.

Enzyme-Linked Immunosorbent Assay↗