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Biomedical subjects

S Cherian

Publications and source records attributed to S Cherian.

At least 19 recordsLinked to original sources
PubMed2006

Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia.

AIM: To assess the prevalence of eosinophilic oesophagitis in a tertiary paediatric gastroenterology clinic population. METHODS: A retrospective audit of Western Australian children investigated for oesophageal disease by paediatric gastroenterologists in the years 1995, 1999 and 2004. Macroscopic appearance of the oesophagus at endoscopy, original histological findings and diagnosis were recorded for each child. Biopsy specimens were blindly re-evaluated, with re-coded histological diagnoses compared with original reports. Age, sex and socioeconomic status were identified for each child. RESULTS: The prevalence of eosinophilic oesophagitis in Western Australia increased over the decade 1995-2004, rising from 0.05 to 0.89 per 10 000 children, with a concomitant increase in the severity of oesophagitis as determined by inflammatory cell numbers and associated features of inflammation. Children diagnosed with eosinophilic oesophagitis had a median age of 78.9 months (6.58 years), with no associated predisposition by sex or socioeconomic status trend. Almost one third of cases were macroscopically normal at endoscopy. All children with an original diagnosis of eosinophilic oesophagitis had > or =40 eosinophils per high-power field. CONCLUSION: Over the decade 1995-2004, a true increase was seen in the prevalence of eosinophilic oesophagitis, not accounted for by diagnostic shift. Histological samples should be taken at endoscopy to confirm or exclude the diagnosis of eosinophilic oesophagitis.

Biopsy↗
PubMed2004

Transforming growth factor-betas in a rat model of neonatal posthaemorrhagic hydrocephalus.

Posthaemorrhagic ventricular dilatation (PHVD) is a common complication of intraventricular haemorrhage in premature infants. The aim of this study was to investigate the role of transforming growth factor-betas (TGF-betas), a family of polypeptides with potent desmoplastic properties, in the aetiology of PHVD in a newly developed neonatal rat model of this disorder. Pups were injected with citrated rat blood or artificial cerebrospinal fluid (ACSF) into alternate lateral ventricles on postnatal days 7 and 8. The brains were perfusion-fixed 14 days later and immunohistochemistry was performed for TGF-beta1, -beta2 and -beta3, p44/42 mitogen-activated protein (MAP) kinases, and the extracellular matrix proteins laminin, vitronectin and fibronectin. Ventricular dilatation occurred in 58.3% of animals injected with blood and 36.7% of those injected with ACSF. Periventricular immunoreactivity for TGF-beta1 and -beta2 increased in injected animals irrespective of the presence or absence of ventricular dilatation, although the levels of both isoforms tended to be higher in animals with hydrocephalus. TGF-beta3 immunoreactivity was elevated in hydrocephalic rats only. The immunolabelling for phosphorylated p44/42 MAP kinases rose in a pattern similar to that for TGF-beta1 and -beta2. Expression of TGF-betas was accompanied by deposition of the extracellular matrix proteins fibronectin, laminin and vitronectin. The changes caused by injection of ACSF were the same as those caused by injection of blood. Our results raise the possibility that expression of TGF-betas, together with extracellular matrix protein deposition, may be involved in the development and/or maintenance of hydrocephalus after ventricular distension due to haemorrhage in the neonate.

Animals↗
PubMed2004

Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment.

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor beta is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.

Cerebral Hemorrhage↗
PubMed2002

Prediction of extubation failure in preterm infants.

OBJECTIVE: To identify whether the results of assessment of respiratory muscle strength or respiratory load were better predictors of extubation failure in preterm infants than readily available clinical data. PATIENTS: Thirty six infants, median gestational age 31 (range 25-36) weeks and postnatal age 3 (1-14) days; 13 were < 30 weeks of gestational age. METHODS: Respiratory muscle strength was assessed by measurement of maximum inspiratory pressure generated during airway occlusion, and inspiratory load was assessed by measurement of compliance of the respiratory system. RESULTS: Overall, seven infants failed extubation-that is, they required reintubation within 48 hours. These infants were older (p < 0.01), had a lower gestational age (p < 0.01), and generated lower maximum inspiratory pressure (p < 0.05) than the rest of the cohort. Similar results were found in the infants < 30 weeks of gestational age. Overall and in those < 30 weeks of gestational age, gestational age and postnatal age had the largest areas under the receiver operator characteristic curves. CONCLUSION: In very premature infants, low gestational age and older postnatal age are better predictors of extubation failure than assessment of respiratory muscle strength or respiratory load.

Age Factors↗
PubMed2001

Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.

Paraganglioma (PGL) is a rare disorder characterized by tumors of the head and neck region. Between 10% and 50% of cases of PGL are familial, and the disease is autosomal dominant and subject to age-dependent penetrance and imprinting. The paraganglioma gene (PGL1) has been mapped to 11q22.3-q23, and recently germline mutations in the SDHD gene have been identified. The SDHD region contains another gene, DPP2/TIMM8B, the homolog of which causes dystonia and deafness seen in Mohr-Tranebjaerg syndrome. Using four PGL pedigrees, two of which exhibit coinheritance of PGL and sensorineural hearing loss or tinnitus, analysis of 14 microsatellite markers provided support for linkage to the PGL1 locus. Sequence analysis identified novel mutations in exon 1 and exon 3 of the SDHD gene, including a novel two base pair deletion in exon 3 creating a premature stop codon at position 67; a novel three base pair deletion in exon 3 resulting in the loss of Tyr-93; a missense mutation in exon 3 resulting in the substitution of Leu-81 for Pro-81; and a novel G-to-C substitution in exon 1 resulting in the substitution of Met-1 for Ile-1. No base changes were detected in the DPP2/TIMM8B gene. There was no apparent loss of heterozygosity at the site of the SDHD mutations. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. This has not previously been shown for this disorder. The inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting.

Adolescent↗
PubMed2001

Comparison of airway pressure and airflow triggering systems using a single type of neonatal ventilator.

UNLABELLED: The performances of two triggering systems using a single neonatal ventilator type (SLE) were compared. Eight infants, gestational age 27-30 wk, were each recorded during two 1-h periods of patient-triggered ventilation (PTVs), one with airway pressure and one with airflow triggering. The airflow trigger had a shorter trigger delay (p < 0.02), higher sensitivity (p < 0.02) and lower asynchrony rate (p < 0.02). CONCLUSION: In immature infants with mild respiratory distress syndrome using the SLE ventilator with inflation times of 0.3 to 0.36 sec, airflow triggering is more appropriate than airway pressure triggering.

Humans↗
PubMed2000

An outbreak of multi-resistant Shigella sonnei in a long-stay geriatric nursing centre.

An outbreak of Shigella sonnei infection in a long-stay nursing centre was detected during routine surveillance of notifications in July 1999. Subsequent investigations identified 13 cases of multi-resistant S. sonnei infection affecting nine staff, three community members associated with the centre and one resident of the centre. Each isolate of S. sonnei was genetically indistinguishable. The outbreak investigation identified contact with residents with vomiting and diarrhoea as a significant risk factor for infection amongst staff providing nursing care. This association, and the duration of the outbreak over several months, suggests that transmission was most likely person-to-person. This outbreak demonstrates the importance of infection control policies and hygiene measures in long-stay nursing facilities.

Aged↗
PubMed1999

Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.

Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in the identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4 nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.

Alkyl and Aryl Transferases↗
PubMed1999

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

Alkyl and Aryl Transferases↗
PubMed1999

Clinical and angiographic features in patients under 35 years with a first Q wave acute myocardial infarction.

Sixty patients less than 35 years with a first Q wave acute myocardial infarction were prospectively studied to evaluate their features, risk factors and evidence of any viral infection. Typical chest pain was present in 98.3% with Q waves and ST segment elevation in all. None had hypotension or cardiogenic shock. Smoking was the most common risk factor (81.7%). Mean total cholesterol was 5.74 (+/-1.42) mmol/l. History of a viral illness was present in 28.3%, severe emotional stress in 21.7% and exhausting physical activity in 18.3%. Mean left ventricular diastolic and end systolic volumes were increased (90.11+/-22.5 ml/m2) and (46.62+/-20.46 ml/m2), respectively. The ejection fraction was depressed (49.71+/-1.6%). Triple vessel disease was seen only in 6.8 and 26.7% had insignificant or no coronary artery disease. Left anterior descending artery was most frequently involved (66%). None had left main involvement. Coronary ectasia was present in 11.7%, intracoronary thrombus in 28.3% and 40% had collaterals. Patients with no significant disease had no diabetes, a smaller number had a raised total cholesterol or smoked and had a lower ejection fraction. Patients from the Indian subcontinent who had fewer conventional risk factors, had more severe disease than those from the Arab world suggesting that other etiological factors need investigation.

Adult↗
PubMed1999

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs.

Alkyl and Aryl Transferases↗
PubMed1999

Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements.

Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.

3T3 Cells↗
PubMed1998

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

3T3 Cells↗
PubMed1998

Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome.

The transcription factor HNF3 and linker histones H1 and H5 possess winged-helix DNA-binding domains, yet HNF3 and other fork head-related proteins activate genes during development whereas linker histones compact DNA in chromatin and repress gene expression. We compared how the two classes of factors interact with chromatin templates and found that HNF3 binds DNA at the side of nucleosome cores, similarly to what has been reported for linker histone. A nucleosome structural binding site for HNF3 is occupied at the albumin transcriptional enhancer in active and potentially active chromatin, but not in inactive chromatin in vivo. While wild-type HNF3 protein does not compact DNA extending from the nucleosome, as does linker histone, site-directed mutants of HNF3 can compact nucleosomal DNA if they contain basic amino acids at positions previously shown to be essential for nucleosomal DNA compaction by linker histones. The results illustrate how transcription factors can possess special nucleosome-binding activities that are not predicted from studies of factor interactions with free DNA.

Amino Acid Sequence↗
PubMed1998

Simulated microgravity conditions enhance differentiation of cultured PC12 cells towards the neuroendocrine phenotype.

We are studying microenvironmental cues which contribute to neuroendocrine organ assembly and tissue-specific differentiation. As our in vitro model, we cultured rat adrenal medullary PC12 pheochromocytoma cells in a novel cell culture system, the NASA rotating wall vessel (RWV) bioreactors. This "simulated microgravity" environment in RWV bioreactors, characterized by randomizing gravitational vectors and minimizing shear stress, has been shown to favor macroscopic tissue assembly and to induce tissue-specific differentiation. We hypothesized that the unique culture conditions in the RWV bioreactors might enhance the in vitro formation of neuroendocrine organoids. To test our hypothesis, we evaluated the expression of several markers of neuroendocrine differentiation in cultures of PC12 cells maintained for up to 20 d in the slow turning lateral vessel (STLV) type RWV. PC12 cell differentiation was assessed by morphological, immunological, biochemical and molecular techniques. PC12 cells, cultured under "simulated microgravity" conditions, formed macroscopic, tissue-like organoids several millimeters in diameter. Concomitantly, the expression of phenylethanolamine-N-methyl transferase (PNMT), but not of other catecholamine synthesizing enzymes, was enhanced. Increased PNMT expression, as verified on both the gene and protein level, was accompanied by an increase in the specific activity of the enzyme. Furthermore, after 20 d in culture in the STLV, we observed altered patterns of protein tyrosine phosphorylation and prolonged activation of c-fos, a member of the AP-1 nuclear transcription factor complex. We conclude that culture conditions in the RWV appear to selectively activate signal transduction pathways leading to enhanced neuroendocrine differentiation of PC12 cells.

Animals↗