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Biomedical subjects

S Rajendra

Publications and source records attributed to S Rajendra.

At least 19 recordsLinked to original sources
PubMed2006

Loss of human leucocyte antigen class I and gain of class II expression are early events in carcinogenesis: clues from a study of Barrett's oesophagus.

BACKGROUND: Human leucocyte antigen (HLA) expression is altered in oesophageal carcinomas compared with normal tissue. It is unclear, however, whether this phenotype precedes malignant transformation or results as a consequence of it. AIM: To investigate HLA class I and II expression in Barrett's oesophagus and normal squamous oesophageal tissue. METHODS: Asian patients with Barrett's oesophagus (n = 64) and a control group (n = 60) with a normal oesophagus but without reflux symptoms were recruited using endoscopic and histopathological criteria. Tissue samples were stained with monoclonal antibodies specific for HLA-ABC, HLA-DR alpha chain or HLA-DP/DQ/DR, and scored semiquantitatively. The results of immunohistochemical staining were correlated with clinical and histopathological characteristics of patients. RESULTS: Marked expression of HLA-ABC was observed in 50% of Barrett's oesophagus sections as compared with 68.3% of controls (p = 0.038). HLA-DR staining was seen in 51.6% of Barrett's oesophagus samples versus 11.7% of controls (p<0.001). Expression of HLA-DP/DQ/DR was evident in 73.4% of oesophageal intestinal metaplasia tissue as opposed to 18.3% of controls (p<0.001). Importantly, a total loss of HLA-ABC and a concomitant gain of HLA-DP/DQ/DR expression were seen in 37.5% of patients with Barrett's oesophagus but in none of the controls (p<0.001). Interestingly, this phenotype was associated positively with dysplasia (adjusted p, p* = 0.031) but negatively with non-steroidal anti-inflammatory drug use (p* = 0.004). CONCLUSIONS: HLA class I expression is down regulated and class II expression is up regulated in Barrett's oesophagus. As these changes predate malignant transformation, altered major histocompatibility complex expression may be a key event in disease progression, possibly in facilitating evasion from immune surveillance.

Adult↗
PubMed2005

Human leucocyte antigen determinants of susceptibility to Barrett's oesophagus in Asians--a preliminary study.

BACKGROUND: Characteristic immune profiles have been demonstrated in gastro-oesophageal reflux disease. However, the genetic basis of gastro-oesophageal reflux disease remains unclear. AIM: To investigate whether certain human leucocyte antigen genes are associated with Barrett's oesophagus. METHODS: Asian patients of Malay, Chinese and Indian descent with Barrett's oesophagus (n = 59) and those without reflux symptoms and a normal oesophagus (n =60) were recruited prospectively using endoscopic and histopathological criteria. Human leucocyte antigen class I and II typing was performed using a polymerase chain reaction sequence-specific primers method. RESULTS: The HLA-B7 allele was present in 17% (10 of 59) of patients with Barrett's oesophagus when compared with 0% (zero of 60) of controls [P = 0.0006, corrected P = 0.0171, OR = 25.67]. Subgroup analysis revealed that the HLA-B7 allele was confined almost exclusively to Indians with Barrett's oesophagus, 43% (nine of 21) vs. 0% (zero of 19) Indian controls (P = 0.0014, corrected P = 0.0406, OR = 29.64). No class II associations, protective human leucocyte antigens or extended haplotypes for disease susceptibility were identified. CONCLUSIONS: Barrett's oesophagus in Asians, particularly Indians, is strongly positively associated with HLA-B7; reinforcing a genetic component to gastro-oesophageal reflux disease. A larger sample size and different ethnic populations should be genotyped to further confirm this association and identify possible additional risk factors in the human leucocyte antigen locus.

Asian People↗
PubMed2003

Ulcerative colitis and motor neurone disease: causal or coincidental?

Neurological involvement associated with inflammatory bowel disease is well established though rarely reported in the literature. The coexistence of motor neurone disease with ulcerative colitis has never been previously documented. The case of a 53-year-old Indian male with distal ulcerative colitis who, two and a half years later, developed dysarthria, dysphagia, a wasted fasciculating tongue and palatal palsy characteristic of bulbar type motor neurone disease is described. Topical and oral steroids together with azathioprine and mesalazine suppositories controlled the bowel symptoms but did not improve the neurological deficit. Subsequently, the antiglutamate agent riluzole improved the mobility of his tongue. The close temporal relationship and relative infrequency of both these conditions in a Malaysian population along with the recognised association between ulcerative colitis and other neurological conditions deserve careful consideration as to whether a common denominator is involved. Documentation of coexistence of both disorders in a single patient is important in case similar associations are reported in future.

Biopsy↗
PubMed2000

Very negative potential for half-inactivation of, and effects of anions on, voltage-dependent sodium currents in acutely isolated rat olfactory receptor neurons.

Previous measurements with CsF pipette solutions using whole-cell patch-clamp techniques in dissociated rat olfactory receptor neurons (ORNs) indicated that the sodium currents had very negative inactivation characteristics with the implication that the cell resting potential must also normally have a very negative value. This study supports the conclusions that such an effect was real and not dependent on either the nature of the pipette anions or the recording situation previously used. For all pipette solutions, sodium currents showed a threshold activation approximately -80 mV and half-maximal activation voltages approximately -55 with half-inactivation potential < or =-100 mV, without being significantly affected by the replacement of F(-) by other pipette anions (H(2)PO(-)(4) and acetate(-)) or the addition of nucleotides and glutathione (which did cause a very slight positive shift). F(-), followed by H(2)PO(-)(4) and to a much lesser extent by acetate(-), was the most favorable pipette anion for obtaining good seals and whole-cell sodium currents in these extremely small ORNs. These results implied that resting potentials, for viable responsive cells, should be more negative than about -90 mV, as supported by the observation that action potentials could only be evoked from holding potentials more negative than -90 mV.

Acetates↗
PubMed1997

Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.

Fast synaptic neurotransmission is mediated by transmitter-activated conformational changes in ligand-gated ion channel receptors, culminating in opening of the integral ion channel pore. Human hereditary hyperekplexia, or startle disease, is caused by mutations in both the intracellular or extracellular loops flanking the pore-lining M2 domain of the glycine receptor alpha1 subunit. These flanking domains are designated the M1-M2 loop and the M2-M3 loop respectively. We show that four startle disease mutations and six additional alanine substitution mutations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore conclude that the M1-M2 and M2-M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges governing allosteric control of the M2 domain. As the members of the ligand-gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.

Allosteric Regulation↗
PubMed1997

The glycine receptor.

The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. The GlyR comprises a pentameric complex that forms a chloride-selective transmembrane channel, which is predominantly expressed in the spinal cord and brain stem. We review the pharmacological and physiological properties of the GlyR and relate this information to more recent insights that have been obtained through the cloning and recombinant expression of the GlyR subunits. We also discuss insights into our understanding of GlyR structure and function that have been obtained by the genetic characterisation of various heritable disorders of glycinergic neurotransmission.

Amino Acid Sequence↗
PubMed1995

The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding element.

A loop structure, formed by the putative disulfide bridging of Cys198 and Cys209, is a principal element of the ligand binding site in the glycine receptor (GlyR). Disruption of the loop's tertiary structure by Ser mutations of these Cys residues either prevented receptor assembly on the cell surface, or created receptors unable to be activated by agonists or to bind the competitive antagonist, strychnine. Mutation of residues Lys200, Tyr202 and Thr204 within this loop reduced agonist binding and channel activation sensitivities by up to 55-, 520- and 190-fold, respectively, without altering maximal current sizes, and mutations of Lys200 and Tyr202 abolished strychnine binding to the receptor. Removal of the hydroxyl moiety from Tyr202 by mutation to Phe profoundly reduced agonist sensitivity, whilst removal of the benzene ring abolished strychnine binding, thus demonstrating that Tyr202 is crucial for both agonist and antagonist binding to the GlyR. Tyr202 also influences receptor assembly on the cell surface, with only large chain substitutions (Phe, Leu and Arg, but not Thr, Ser and Ala) forming functional receptors. Our data demonstrate the presence of a second ligand binding site in the GlyR, consistent with the three-loop model of ligand binding to the ligand-gated ion channel superfamily.

Amino Acid Sequence↗
PubMed1995

Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator.

Contrary to its effects on the gamma-aminobutyric acid type A receptor, picrotoxin antagonism of the alpha 1 subunit of the human glycine receptor is shown to be competitive, not use-dependent, and nonselective between the picrotoxin components, picrotin, and picrotoxinin. Competitive antagonism and non-use dependence are consistent with picrotoxin binding to a site in the extracellular domain. The mutations Arg-->Leu or Arg-->Gln at residue 271 of the glycine receptor alpha 1 subunit, which are both associated with human startle disease, have previously been demonstrated to disrupt the transduction process between agonist binding and channel activation. We show here that these mutations also transform picrotoxin from an allosterically acting competitive antagonist to an allosteric potentiator at low (0.01-3 microM) concentrations and to a noncompetitive antagonist at higher (> or = 3 microM) concentrations. This demonstrates that arginine 271 is involved in the transduction process between picrotoxin binding and its mechanism of action. Thus, the allosteric transduction pathways of both agonists and antagonists converge at a common residue prior to the activation gate of the channel, suggesting that this residue may act as an integration point for information from various extracellular ligand binding sites.

Allosteric Regulation↗
PubMed1995

Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.

Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.

Arginine↗
PubMed1995

Molecular mechanisms of inherited startle syndromes.

Inherited neurological disorders involving an exaggerated startle response to unexpected sensory stimuli have been identified in mice, cows, dogs, horses and humans. Recent studies of the molecular pathology of a number of these startle syndromes have revealed that they are caused by defects in the inhibitory glycinergic pathways that mediate reciprocal and recurrent inhibition in the spinal cord. These defects arise from various mutations of the receptor for glycine, which either impair its sensitivity to agonists or reduce its expression in vivo. The emergent models of the molecular mechanisms that underlie startle disorders illustrate how diverse mutations can converge physiologically to produce a common phenotype.

Amino Acid Sequence↗