Biomedical subjects

R C Lin

Publications and source records attributed to R C Lin.

At least 37 records · Page 2Linked to original sources

PubMed1997

Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome.

Holt-Oram syndrome is characterized by upper limb malformations and cardiac septation defects. Here, we demonstrate that mutations in the human TBX5 gene underlie this disorder. TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family. A nonsense mutation in TBX5 causes Holt-Oram syndrome in affected members of one family; a TBX5 missense mutation was identified in affected members of another. We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome.

Abnormalities, Multiple↗

PubMed1997

Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Abnormalities, Multiple↗

PubMed1997

Neonatal whisker removal reduces the discrimination of tactile stimuli by thalamic ensembles in adult rats.

Simultaneous recordings of up to 48 single neurons per animal were used to characterize the long-term functional effects of sensory plastic modifications in the ventral posterior medial nucleus (VPM) of the thalamus following unilateral removal of facial whiskers in newborn rats. One year after this neonatal whisker deprivation, neurons in the contralateral VPM responded to cutaneous stimulation of the face at much longer minimal latencies (15.2 +/- 8.2 ms, mean +/- SD) than did normal cells (8.8 +/- 5.3 ms) in the same subregion of the VPM. In 69% of these neurons, the initial sensory responses to stimulus offset were followed for up to 700 ms by reverberant trains of bursting discharge, alternating in 100-ms cycles with inhibition. Receptive fields in the deafferented VPM were also atypical in that they extended over the entire face, shoulder, forepaw, hindpaw, and even ipsilateral whiskers. Discriminant analysis (DA) was then used to statistically evaluate how this abnormal receptive field organization might affect the ability of thalamocortical neuronal populations to "discriminate" somatosensory stimulus location. To standardize this analysis, three stimulus targets ("groups") were chosen in all animals such that they triangulated the central region of the "receptive field" of the recorded multineuronal ensemble. In the normal animals these stimulus targets were whiskers or perioral hairs; in the deprived animals the targets typically included hairy skin of the body as well as face. The measured variables consisted of each neuron's spiking response to each stimulus differentiated into three poststimulus response epochs (0-15, 15-30, and 30-45 ms). DA quantified the statistical contribution of each of these variables to its overall discrimination between the three stimulus sites. In the normal animals, the stimulus locations were correctly classified in 88.2 +/- 3.7% of trials on the basis of the spatiotemporal patterns of ensemble activity derived from up to 18 single neurons. In the deprived animals, the stimulus locations were much less consistently discriminated (reduced to 73.5 +/- 12.6%; difference from controls significant at P < 0.01) despite the fact that much more widely spaced stimulus targets were used and even when up to 20 neurons were included in the ensemble. Overall, these results suggest that neonatal damage to peripheral sense organs may produce marked changes in the physiology of individual neurons in the somatosensory thalamus. Moreover, the present demonstration that these changes can profoundly alter sensory discrimination at the level of neural populations in the thalamus provides important evidence that the well-known perceptual effects of chronic peripheral deprivation may be partially attributable to plastic reorganization at subcortical levels.

Animals↗

PubMed1997

Cerebellar nitric oxide synthase is expressed within granule cell patches innervated by specific mossy fiber terminals: a developmental profile.

The nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) staining technique was utilized as a marker of nitric oxide synthase (NOS) to map NOS expression in developing and adult rat cerebellum. NADPH-d-positive cells were first visualized in the cerebellar cortex at postnatal day 5 (PND5) which increased to peak levels by PND30 when they began to exhibit a patch-like organization. In order to determine the relationship of the NADPH-d staining pattern with mossy fiber innervation, mossy fiber projections were traced using cholera toxin B subunit or biocytin injected into the lateral reticular nuclei (LRtN) or pontine nuclei (PtN), respectively. Double staining revealed that the clustered mossy fiber terminals projecting from the ventrorostral LRtN and caudal PtN were well matched with NADPH-d-stained patches. This patch-like localization of NOS matched with specific mossy fiber terminals in adult cerebellum implicates these NOS patches as defining distinct anatomical zones.

Afferent Pathways↗

PubMed1997

Helicobacter pylori infection and risk of peptic ulcer among cirrhotic patients.

There is a higher prevalence of peptic ulcer disease in cirrhotic patients than in the general population. Whether Helicobacter pylori is a risk factor for peptic ulcer in cirrhosis remains controversial. The aim of this study was to determine whether there is a significant correlation between H.pylori infection and peptic ulcer in liver cirrhosis. In a cross-sectional study, 49 cirrhotic patients underwent upper gastrointestinal endoscopy and 75 controls (health examinees) without liver disease were also examined by endoscopy. The presence of H. pylori was assessed by culture, histologic findings and rapid urease test of gastric antrum biopsy specimens. Thirty of the 49 (61%) cirrhotic patients had peptic ulcers as compared to 24 of the 75 (32%) controls. The frequency of H. pylori in the antrum in the cirrhotic group was significantly lower than in the control group (39% vs 69%). The presence of H. pylori was more frequent in control patients with gastric (75%) and duodenal ulcers (95%) than nonulcer control patients (59%) whereas the difference between patients with peptic ulcer and nonulcer (40% vs 37%) was not significant in cirrhotic patients. H. pylori was identified in 40% of the cirrhotic patients with duodenal ulcers compared with 95% of controls with duodenal ulcers (p < 0.05). Nevertheless, this difference was not significant among patients with a gastric ulcer between the two groups (40% vs 75%). There was no significant difference in the frequency of H. pylori infection among nonulcer patients between the cirrhotic and control groups (37% vs 59%). In conclusion, we found no evidence to substantiate an etiologic role of H. pylori in the development of a duodenal ulcer in cirrhotic patients.

Adult↗

PubMed1997

Alcohol feeding impedes early atherosclerosis in low-density lipoprotein receptor knockout mice: factors in addition to high-density lipoprotein-apolipoprotein A1 are involved.

The effect of alcohol feeding on the development of atherosclerosis was investigated in low-density lipoprotein receptor gene-knockout (LDLR-/-) mice. Eight-week-old male mice were pair-fed atherogenic liquid diets containing ethanol at different levels (w/v; group A, 5%; group B, 2.5%; and group C, 0%). Tissue sections of the heart were stained with Oil Red O to examine for fatty lesions in proximal aorta. Results showed that the lesion size of group A was 70% smaller than group C after 6 weeks. By contrast, the lesion size of group B was not significantly different from that of group C. Serum high-density lipoprotein-apolipoprotein A1 (apo A1) A1 in LDLR-/- mice was suppressed by feeding the atherogenic diet, but the decrease was negated by alcohol (both groups A and B). The effectiveness of 5% alcohol to protect against atherosclerosis waned with time, but was still noticeable at 12 weeks, even though serum apo A1 remained high. Serum apolipoprotein E was increased by the high fat diet, but not altered by alcohol in the diet. Our data, therefore, show that: (1) alcohol-feeding impedes early atherosclerosis in LDLR-/- mice (this effect of alcohol is dose-dependent); (2) the protective effect of alcohol is not entirely attributable to an elevated serum high-density lipoprotein-apo A1; and (3) severe impairment of lipoprotein metabolism due to a lack of low-density lipoprotein receptors can eventually overwhelm the protective effect of alcohol against atherosclerosis.

Alcohol Drinking↗

PubMed1996

Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils.

Although adenosine receptor-based treatment of cerebral ischemia and other neurodegenerative disorders has been frequently advocated, cardiovascular side effects and an uncertain therapeutic time window of such treatment have constituted major obstacles to clinical implementation. Therefore, we have investigated the neuroprotective effects of the adenosine A1 receptor agonist adenosine amine congener (ADAC) injected after either 5 or 10 min ischemia at 100 micrograms/kg. When the drug was administered at either 6 or 12 h following 5 min forebrain ischemia, all animals were still alive on the 14th day after the occlusion. In both ADAC treated groups neuronal survival was approximately 85% vs. 50% in controls. Administration of a single dose of ADAC at times 15 min to 12 h after 10 min ischemia resulted in a significant improvement of survival in animals injected either at 15 or 30 min, or at 1, 2, or 3 h after the insult. In all 10 min ischemia groups, administration of ADAC resulted in a significant protection of neuronal morphology and preservation of microtubule associated protein 2 (MAP-2). However, postischemic Morris' water maze tests revealed full preservation of spatial memory and learning ability in animals injected at 6 h. On the other hand, the performance of gerbils treated at 12 h postischemia was indistinguishable from that of the controls. Administration of ADAC at 100 micrograms/kg in non-ischemic animals did not result in bradycardia, hypotension, or hypothermia. The data indicate that when ADAC is used postischemically, the most optimal level of protection is obtained when drugs are given at 30 min to 6 h after the insult. Although the mechanisms involved in neuroprotective effects of adenosine A1 receptor agonists require further studies, the present results demonstrate the feasibility of their clinical applications.

Adenosine↗

PubMed1996

A new syntaxin family member implicated in targeting of intracellular transport vesicles.

Despite the central role vesicular trafficking occupies in protein targeting, the molecular coding of the trafficking signals and the mechanism of vesicle docking and fusion are just beginning to be understood. We report here the cloning and initial characterization of a new member of the syntaxin family of vesicular transport receptors. Syntaxin 6 is a 255-amino acid protein with two domains predicted to form coiled-coils, as well as a carboxyl-terminal membrane anchor. Syntaxin 6 is broadly expressed and localizes in the region of the Golgi apparatus. In vitro binding studies established that syntaxin 6 binds to alpha-soluble NSF attachment protein (alpha-SNAP). The sequence homology, topology, localization, and alpha-SNAP binding suggest that syntaxin 6 is involved in intracellular vesicle trafficking.

Biological Transport↗

PubMed1996

Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist.

Agonists of adenosine A1 receptors have been frequently proposed as candidates for clinical development in treatment of cerebral ischemia and stroke. Numerous experimental studies have shown that pre- and postischemic administration of these drugs results in a very significant reduction of postischemic brain damage. However, only a few studies determined the impact of cerebral ischemia and drug treatment on postischemic recovery of spatial memory. The present paper demonstrates that preischemic i.p. administration of adenosine amine congener (ADAC) at 100 micrograms/kg in gerbils results in a significant (P < 0.05) reduction of postischemic mortality and hippocampal, cortical and striatal morbidity. Postischemic Morris' water maze tests show that preischemic treatment with ADAC also leads to a very significant (P < 0.001) reduction of postischemic spatial memory loss. Our results indicate feasibility of further consideration of adenosine A1 receptor agonists as a clinically applicable acute treatment of brain ischemia. Recent development of neuroprotective adenosine A1 receptor agonists that are free of cardiovascular side effects supports such development.

Adenosine↗

PubMed1996

Calbindin-containing non-specific thalamocortical projecting neurons in the rat.

Immunoreactivity for calcium binding proteins was used to demonstrate the neurochemical profiles of non-specific thalamocortical neurons located in the ventromedial nucleus, the centrolateral nucleus, and the nucleus reuniens that project to the somatosensory cortex in the adult rat. Cortical injections of fluorescent tracers combined with immunohistochemistry for calcium binding proteins revealed that retrogradely labeled neurons in these three thalamic nuclei are immunoreactive for calbindin. The present results suggest the presence of a chemically distinct non-specific thalamocortical system which terminates in the neocortex.

Animals↗

PubMed1996

Identification of the 37-kd rat liver protein that forms an acetaldehyde adduct in vivo as delta 4-3-ketosteroid 5 beta-reductase.

Acetaldehyde, the first product of alcohol metabolism, is highly reactive. Several proteins have been shown to be covalently modified by acetaldehyde in vivo. We have previously reported the detection of a cytosolic 37-kd protein-acetaldehyde adduct (-AA) in the liver of alcohol-fed rats. The liver extract from an alcohol-fed rat was subjected to 2-dimensional (2D) sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis (PAGE), transferred to polyvinylidene difluoride (PVDF) membrane, and the 37-kd protein-AA spot was digested with trypsin and sequenced for amino acids. Degenerate oligonucleotides corresponding to a peptide sequence of the protein-AA were used as the probe to screen a lambda gt11 rat liver complementary DNA (cDNA) library. A clone that extended to a potential ATG start codon was identified. The open reading frame was 978 nucleotides long, encoding 326 amino acid residues. The sequence matched that of rat liver delta 4-3-ketosteroid 5 beta-reductase. The cloned cDNA was expressed in Escherichia coli using pGEX-KG as the vector. The expressed protein was found to be of correct molecular weight. It reacted with an antibody that recognized the unmodified liver 37-kd protein by Western blotting. Peptide profiles of tryptic-digested recombinant protein and the purified rat liver 37-kd protein were similar and yielded the same peptide sequence. delta 4-3-ketosteroid 5 beta-reductase catalyzes the reduction of key intermediates during bile acid biosynthesis. Whether modification of the 5 beta-reductase by acetaldehyde affects the enzyme activity and bile acid synthesis remains to be studied.

Acetaldehyde↗

PubMed1996

Uptake and distribution of fluorescein-labeled D2 dopamine receptor antisense oligodeoxynucleotide in mouse brain.

To determine the uptake and distribution of oligodeoxynucleotides in brain, a 20-mer phosphorothioated oligodeoxynucleotide complementary to a portion of the D2 dopamine receptor mRNA was fluorescently labeled with fluorescein isothiocyanate (FITC) and injected into the lateral cerebral ventricles of mice. At various survival times after the injection, the brains were removed, fixed, sectioned, and viewed under a fluorescent microscope. The results showed that the oligodeoxynucleotide was rapidly taken up into the brain. Initially the label was relatively diffusely spread throughout the interstitial spaces of the brain, then became redistributed to the cellular compartments. The signal extended from those forebrain nuclei located immediately in contact with the ventricles, such as the corpus striatum, septum, and hippocampus, to areas further removed from the ventricles, such as the cerebral cortex, nucleus accumbens, and substantia nigra. When the FITC-labeled D2 antisense oligodeoxynucleotide was given once daily for 4 d, the signal intensity seen 24 h after the last injection appeared to be of greater intensity overall compared to that seen after a single injection. At early time-points the oligodeoxynucleotide signals appeared to be punctuated and were found in cell bodies as well as in proximal dendritic processes. However, not all cells were equally labeled, suggesting an uneven uptake and accumulation of the D2 antisense into the various cell types. At later time-points the fluorescent signal appeared granular; at these times the injected material was largely degraded. These studies show that a D2 dopamine receptor antisense oligodeoxynucleotide is rapidly taken up from cerebral ventricles into brain, becomes widely distributed throughout the brain tissue to areas far removed from direct contact with the ventricles, and appears to accumulate to a different extent in the various brain areas and cell types.

Animals↗

PubMed1996

Aferoside A, a steroidal saponin from Costus afer.

A new steroidal saponin, aferoside A, has been isolated from the roots of Costus afer. Its structure was established as 3-O-([beta-D-apiofuranosyl-(1-->2)]-[alpha-L-rhamnopyranosyl-(1--> 4)]-beta-D-glucopyranosyl)-25(R)-spirost-5-en-3 beta-ol by chemical transformations and various spectroscopic methods, mainly 2D NMR techniques (COSY, HMQC and HMBC).

Carbohydrate Conformation↗

PubMed1996

Isoflavonoid compounds extracted from Pueraria lobata suppress alcohol preference in a pharmacogenetic rat model of alcoholism.

The extract from an edible vine, Pueraria lobata, has long been used in China to lessen alcohol intoxication. We have previously shown that daidzin, one of the major components from this plant extract, is efficacious in lowering blood alcohol levels and shortens sleep time induced by alcohol ingestion. This study was conducted to test the antidipsotropic effect of daidzin and two other major isoflavonoids, daidzein and puerarin, from Pueraria lobata administered by the oral route. An alcohol-preferring rat model, the selectively-bred P line of rats, was used for the study. All three isoflavonoid compounds were effective in suppressing voluntary alcohol consumption by the P rats. When given orally to P rats at a dose of 100 mg/kg/day, daidzein, daidzin, and puerarin decreased ethanol intake by 75%, 50%, and 40%, respectively. The decrease in alcohol consumption was accompanied by an increase in water intake, so that the total fluid volume consumed daily remained unchanged. The effects of these isoflavonoid compounds on alcohol and water intake were reversible. Suppression of alcohol consumption was evident after 1 day of administration and became maximal after 2 days. Similarly, alcohol preference returned to baseline levels 2 days after discontinuation of the isoflavonoids. Rats receiving the herbal extracts ate the same amounts of food as control animals, and they gained weight normally during the experiments. When administered orally, none of these compounds affected the activities of liver alcohol dehydrogenase and aldehyde dehydrogenase. Therefore, the reversal of alcohol preference produced by these compounds may be mediated via the CNS. Data demonstrate that isoflavonoid compounds extracted from Pueraria lobata is effective in suppressing the appetite for alcohol when taken orally, raising the possibility that other constituents of edible plants may exert similar and more potent actions.

Alcohol Dehydrogenase↗

PubMed1996

Active tactile exploration influences the functional maturation of the somatosensory system.

1. The hypothesis that active exploration of objects is required for the functional maturation of neuronal circuits subserving tactile perception was tested by subjecting 8- to 11-day old rats to a complete unilateral section of the facial nerve. This procedure selectively abolished whisker protraction movements without affecting the sensory innervation of the facial vibrissae, the tactile organs used by rats to discriminate object texture and shape. 2. Six to 14 mo after the facial nerve section, simultaneous recordings of neuronal ensembles located in the ventral posterior medial nucleus (VPM) of the thalamus revealed a marked reduction in receptive field (RF) size (in terms of number of whiskers), and the formation of abnormal RF surrounds, spanning the face and contiguous body regions. In addition, the directional organization of VPM RFs, represented by caudal to rostral shifts in RF centers over 30 ms following whisker stimulation, was greatly reduced in these animals. 3. These results suggest that neonatal active tactile exploration is required to establish normal spatiotemporal patterning of neuronal RFs within the somatosensory system, and consequently, to develop normal tactile perception.

Animals↗

PubMed1996

Self-expandable metallic stents in the management of malignant biliary obstruction.

To overcome problems with conventional plastic endoprostheses, a study was conducted to determine the clinical efficacy of self-expandable metallic stents in the palliative treatment of malignant biliary obstruction. From May 1994 to March 1995, 19 self-expandable metallic stents were implanted in 13 consecutive patients with malignant obstructive jaundice due to cholangiocarcinoma (four patients), ampullary carcinoma (six), pancreatic carcinoma (one), and hepatic hilar lymph node metastasis (two). All patients underwent percutaneous transhepatic biliary drainage followed by stent insertion, except for two patients where the T-tube tract was used as access and another with previous placement of a polyethylene internal-external drainage catheter for more than 6 months. When both lobes of the biliary system were to be drained, stents were placed either side by side through punctured, separate hepatic ducts or, using a T configuration, through a single transhepatic tract. Percutaneous transhepatic stent placement was technically successful in all patients. After a mean follow-up of 5.9 months (range, 1-10 mo), 10 of 13 patients were still alive while three had died of nonprocedure-related causes. In 10 patients, total serum bilirubin levels decreased significantly (from 136.8 +/- 157 mumol/L to 34.2 +/- 22.2 mumol/L), while it increased in three patients. Two patients had stent occlusions at 2 and 3 months after stent placement, which required intervention. The overall patency period ranged from 1 to 9 months (mean, 5.1 mo). Our results confirm that the use of metallic stents is effective in the palliative treatment of malignant jaundice.

Adolescent↗

PubMed1995

Reactive astrocytes express substance-P immunoreactivity in the adult forebrain after injury.

Transformation of normal resting astrocytes to reactive astrocytes after injury is a well-known phenomenon. Using immunofluorescent labelling methods, astrocytes in the ischemically and retrogradely/anterogradely damaged adult forebrain nuclei were shown to express substance-P immunoreactivity. In contrast, astrocytes were not immunostained for substance-P in the normal brain or undamaged areas. Since substance-P has been shown to regulate inflammatory, wound-healing and immune responses in the peripheral tissues, it is likely that this aberrant expression of substance-P immunoreactivity in reactive astrocytes may relate to similar functions in the central nervous system as in the peripheral tissues after injury.

Animals↗

PubMed1995

Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist.

Despite significant progress in understanding of the potential of adenosine A1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A2 receptors in the regulation of cerebral blood flow, we have investigated the effect of both acute and chronic administration of the selective adenosine receptor agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N- ethylcarboxoamidoadenosine (APEC) and antagonist 8-(3-chlorostyryl)caffeine (CSC) on the outcome of 10 min ischemia in gerbils. Acute treatment with APEC improved recovery of postischemic blood flow and survival without affecting neuronal preservation in the hippocampus. Acute treatment with CSC had no effect on the cerebral blood flow but resulted in a very significant protection of hippocampal neurons. Significant improvement of survival was present during the initial 10 days postischemia. Due to subsequent deaths of animals treated acutely with CSC, the end-point mortality (14 days postischemia) in this group did not differ statistically from that seen in the controls. It is, however, possible that the late mortality in the acute CSC group was caused by the systemic effects of brain ischemia that are not subject to the treatment with this drug. Chronic treatment with APEC resulted in a statistically significant improvement in all studied measures. Although chronic treatment with CSC improved postischemic blood flow, its effect on neuronal preservation was minimal and statistically insignificant. Mortality remained unaffected. The results indicate that the acute treatment with adenosine A2A receptor antagonists may have a limited value in treatment of global ischemia. However, since administered CSC has no effect on the reestablishment of postischemic blood flow, treatment of stroke with adenosine A2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.

Adenosine↗