Biomedical subjects

S B Patel

Publications and source records attributed to S B Patel.

At least 19 recordsLinked to original sources

PubMed2002

Oesophageal atresia: a simplified approach to early management.

Management following the repair of oesophageal atresia (OA) with tracheooesophageal fistula (TOF) in the past included the routine use of an intercostal chest drain, a gastrostomy, or a transanastomotic tube (TAT) for enteral nutrition and a routine contrast swallow (CS) before oral feeds. There has been a trend towards simplification of the management, but this is not universal. The aim of this study was to evaluate the safety of a simplified management regime in infants undergoing primary repair of OA in a retrospective case note review of infants undergoing surgery for OA with TOF under the care of one consultant over a 12-year period. Intercostal chest drains, TATs, and CSs were not routinely used. Early enteral feeding was initiated and oral feeding was allowed in babies of adequate birth weight (BW) and gestation. A CS was only performed when there were specific anastomotic concerns. Parameters recorded included demographic details, time to first enteral feed by tube or mouth, time to full oral feeds, and complications. Forty patients were studied; 17 were managed without (group 1) and 23 with (group 2) a TAT. Sex distribution, gestational age, and BW were comparable in the two groups. In group 1, the time to the establishment of full oral feeds was 2-8 days (average 3.9). Four infants developed strictures; 2 were managed with dilatation alone and 2 required surgery. In group 2, the time to the establishment of full enteral feeds was 2-12 days (average 5.9). Four patients developed strictures; 2 underwent an anti-reflux procedure and a 3rd resection of a cartilaginous remnant. There was 1 death in a patient with intractable cardiac failure. The majority of infants with OA and TOF can thus be safely managed without routine chest drainage or CS. A sizeable minority do not require a TAT. Early introduction of oral feeds in the non-TAT group is not associated with an increased complication rate.

Birth Weight↗

PubMed2001

Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.

Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2001

Dietary cholesterol absorption; more than just bile.

Absorption of dietary cholesterol from the intestine is an important part of cholesterol homeostasis and represents the first step that allows dietary cholesterol to exert its metabolic effects. Although the role of bile salts in the initial absorption of dietary cholesterol, by the formation of emulsions, is readily appreciated, the recognition that other molecular mechanisms might govern this process is only recently gaining momentum. Not only does the intestine regulate the amount of dietary cholesterol that enters the body; it is very selective with regard to the sterols that are allowed in. The human intestine is responsible for absorbing a significant amount of cholesterol each day. In addition to approximately 0.5 g d(-1) of dietary cholesterol, many other sterols are also present in almost equal abundance in the normal diet. Approximately 0.4 g of plant sterols, such as sitosterol, brassicasterol and avanesterol, are also present. However, the human body seems to allow only cholesterol to enter and remain in the body, with almost negligible amounts of plant sterols being retained. That specific molecular mechanisms are responsible for this behavior is supported by the identification of the genetic defect(s) in a rare disorder, beta-sitosterolemia (MIM 210250), where this process is disrupted. Such studies are now beginning to throw light on sterol absorption and excretion and elucidate the molecular mechanisms that govern these processes.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2001

Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2001

High-resolution physical and transcript map of human chromosome 2p21 containing the sitosterolaemia locus.

Sitosterolaemia (phytosterolaemia) is an autosomal recessive disorder characterised by the presence of tendon xanthomas in the face of normal or mildly elevated plasma cholesterol levels, premature atherosclerotic disease and has diagnostically elevated plasma and tissue plant sterol concentrations. 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. The defective gene is therefore hypothesised to play a crucial role in regulating dietary cholesterol absorption, and its elucidation may shed light on these molecular processes. We have previously localised the defective gene to human chromosome 2p21, between microsatellite markers D2S1788 and D2S1352, a distance of approximately 15 cM. Recently, the disease locus interval has been narrowed to lie between D2S2294 and D2S2291/D2S2174. We have constructed a high-resolution YAC and BAC contigs by using known STSs and generating novel STSs from the minimal interval. Eight previously identified genes and 60 ESTs were mapped to these contigs. The BAC contig contains 60 BAC clones and 108 STSs and encompasses a physical distance of approximately 2.0 cM between microsatellite markers D2S2294 and D2S2291. These results will not only facilitate cloning of the sitosterolaemia gene, but also other disease genes located in this region, and accelerate sequencing of the corresponding genomic clones.

Arteriosclerosis↗

PubMed2001

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities.

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.

Arteriosclerosis↗

PubMed2001

Genetic basis of sitosterolemia.

The molecular mechanisms regulating the amount of dietary cholesterol retained by the body, as well as the body's ability to exclude other dietary sterols selectively, are poorly understood. An average Western diet will contain approximately 250-500 mg of dietary cholesterol and approximately 200-400 mg of non-cholesterol sterols, of which plant sterols are the major constituents. Approximately 50-60% of dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. There thus exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb and retain not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. Consequently, patients with this disease have very high levels of plant sterols in the plasma, and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosome 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectively, are now known to be mutant in sitosterolemia. The identification of these genes should now lead to a better understanding of the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of this disease that has given credence to the hypothesis that there is a molecular pathway that regulates dietary cholesterol absorption and sterol excretion by the body.

ATP-Binding Cassette Transporters↗

PubMed2001

7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome.

Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Prenatal lethality was not noted, but newborn homozygotes breathed with difficulty, did not suckle, and died soon after birth with immature lungs, enlarged bladders, and, frequently, cleft palates. Despite reduced sterol concentrations in Dhcr7(-/-) mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, protein levels and activities of HMG-CoA reductase were markedly reduced. Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins. These results demonstrate that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally. This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency.

Animals↗

PubMed2001

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.

Adolescent↗

PubMed2000

Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.

The Smith-Lemli-Opitz syndrome (SLOS; also known as the RSH syndrome) is an autosomal recessive genetic disorder, leading to characteristic multi-organ developmental abnormalities, dysmorphic facies, limb malformations and mental retardation. Mutations in the gene for Delta(7)-dehydrocholesterol reductase (Delta(7)-reductase), which catalyzes the last step in cholesterol biosynthesis, cause the disease. We screened 32 patients with SLOS, 28 from the USA and four from Sweden. Twenty-two different nucleotide changes, predicted to be disease-causing mutations, were identified; 20 missense mutations, one nonsense mutation and one splice-site mutation involving the exon 9 acceptor site (IVS8 -1G-->C) were detected. All probands were heterozygous for mutations. Twelve of these mutations have not been reported previously, including missense mutations L148R, F168I, D175H, P179L, P243R, F284L, N287K, F302L, R404S, Y462H, R469P and one nonsense mutation W37X [corrected]. Coupled with previously reported mutations, these findings bring the total of different Delta(7)-reductase mutations to 36. These are distributed throughout the coding sequence of the Delta(7)-reductase gene except exons 3 and 5, with a clustering in exon 9. Three mutations account for 54% of those observed in our cohort, the splice acceptor site mutation IVS8 -1G-->C (22/64 alleles, 34%), T93M (8/64, 12.5%) and V326L (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. We estimate that between 33 and 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol. Thus, factors other than plasma cholesterol are additionally involved in determining severity.

Adolescent↗

PubMed2000

Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-G-->C is found in over sixty percent of US propositi.

The RSH or Smith-Lemli-Opitz syndrome (SLOS) is a relatively common autosomal recessive disorder of cholesterol biosynthesis resulting from a deficiency of the enzyme 7-dehydrocholesterol delta7-reductase (7-DHCR). Mutations in 7-DHCR gene cause SLOS. Among these, a G-->C transversion in the splice acceptor site of exon 9 (IVS8-1G-->C) was suspected to be a frequent mutation, having been detected in about 18% of SLOS patients so far. This mutation results in the elimination of a AlwN1 restriction endonuclease site. We report a simple PCR-RFLP assay to detect the IVS8-1G-->C mutation. Using this method, we identified the IVS8-1G-->C mutation in 21 of 33 SLOS propositi. This mutation was detected in one of 90 normal adult Caucasian Americans; but not among 121 Africans from Sierra Leone, 120 Caucasians from Finland, 95 Chinese or 103 Japanese adults. The results of this study provide further evidence that IVS8-1G-->C transversion is a very common mutation in SLOS patients from the US and that the carrier rate in US caucasians may be high. The simple PCR-RFLP assay developed makes identification of this mutation convenient for diagnosis and for carrier detection.

Adult↗

PubMed2000

Microsomal triglyceride transfer protein expression during mouse development.

Feto-maternal transfer of lipophilic nutrients is an important factor in the normal development of the fetus and may be mediated by lipoproteins as carriers of these nutrients. Two proteins that may be important in this process are apolipoprotein B (apoB, the major structural protein of secreted lipoproteins) and microsomal triglyceride transfer protein (MTP) whose normal activity is required for the secretion of apoB-containing lipoproteins. Although no abnormalities of conception and embryonic lethality are known in humans who inherit genetic deficiencies of either of these proteins, homozygous mice bearing knockouts of either apoB or MTP show early embryonic lethality. To characterize the ontogeny of MTP expression during embryonic mouse development, we have used in situ hybridization to characterize the pattern of expression. By using microwave heating of tissue sections to optimize hybridization, we show that there is robust MTP expression in the yolk sac tissues followed by expression in the primordial liver cell nests as early as day 9 post-coitum (E9.5). Intestinal expression is detected around E12.5 and attains full adult expression patterns by E14.5. No expression in any other tissues was observed, including developing heart, kidney, placenta, and maternal decidua. Thus the pattern of MTP expression is compatible with a role in the transfer of lipophilic nutrients from the yolk sac, prior to hepatic development and to the liver, once the circulatory system has been established.

Animals↗

PubMed2000

Removal of Foscarnet by hemodialysis using dialysate-side values.

Foscarnet is an antiviral agent widely used in the treatment of cytomegalovirus (CMV) infection. We describe a cardiac transplant patient, who while being maintained with hemodialysis because of tobramycin-induced acute renal failure, was given Foscarnet for disseminated CMV infection. Using dialysate-side clearance methodology, we found the dialyzer clearance of Foscarnet to be in the order of 89 ml/min.

Acute Kidney Injury↗

PubMed1999

Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2.

The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.

Acetyl-CoA Carboxylase↗

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↗