OKT3 in renal allografts: survival and complications.
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Adolescent↗
Biomedical subjects
R Chang
Publications and source records attributed to R Chang.
Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells.
Neurotrophin-3 (NT-3) and its receptor TrkC are known to be important for neuronal survival. More recently, NT-3 has been implicated as playing a role in oligodendrocyte (OL) proliferation and survival in vitro. Examination of NT-3 and TrkC knockout mice revealed a reduction in NT-3-dependent neurons. To date, no study has examined alterations in glial cell populations in these knockout mice. In this report, we demonstrate a decline in OL progenitor cell numbers within the CNS of NT-3 and TrkC knockout mice. We also observed that immature and mature OL-specific markers were attenuated in the NT-3 and TrkC knockout animals. Deficiencies in other CNS glial cells, including astrocytes and ameboid microglia, were also observed. The subventricular zone (SVZ), a highly proliferative region for progenitor glial cells, was reduced in size. Furthermore, a nuclear-specific stain revealed a decline in the numbers of pyknotic nuclei in and around the SVZ of the knockout mice. These data will support an in vivo NT-3-dependent mechanism for the normal development of CNS glial cells.
Animals↗
[Mite-induced interleukin-5 and interleukin-4 expressions in peripheral blood mononuclear cells from asthmatic children with respiratory syncytial virus infection].
OBJECTIVE: To investigate the effects of respiratory syncytial virus(RSV) infection on mite-induced interleukin-5 and interleukin-4 expressions in cultures of PBMC from asthmatic children and their correlation with asthmatic symptoms. METHODS: IL-5 and IL-4 expressions in mite (D. Pteronyssinus)-stimulated PBMC were assessed ex vivo by ELISA and reverse transcription-polymerase chain reaction (RT-PCR) in 16 allergic asthmatic children with RSV infection(A) and 14 patients without RSV infection(B), as well as 10 normal controls(C) (5.1 +/- 2.4 yrs). Meanwhile their correlation with serum ECP or current wheezing was analysed in patients after RSV infection. RESULTS: (1) Stimulation of PBMC with mite antigens induced significantly higher IL-4 (34 +/- 24) ng/L vs (8 +/- 5) ng/L, (P < 0.01) and IL-5 (26 +/- 15) ng/L vs (6 +/- 5) ng/L release in allergic patients(B) as compared with healthy controls(C). The release was in a mite dose-dependent manner. Meanwhile, IL-5 level in group A (A) was the highest (73 +/- 47) ng/L, P < 0.05 compared with (B)). Similar results were obtained with IL-5 mRNA expressions. (2) Serum ECP level was significantly higher in group A (73 +/- 47) micrograms/L than in group C (18 +/- 12) micrograms/L, P < 0.01. There was a significant correlation between IL-5 release and ECP levels (r = 0.49, P < 0.05). (3) Mite-induced IL-5 release in PBMC was significantly increased in the group with wheezing symptom (71 +/- 40) ng/L compared with the asymptomatic group (34 +/- 29) ng/L, (P < 0.05). CONCLUSIONS: Our findings indicated that during RSV infection, mite-induced IL-5 expression in PBMC of asthmatic children was up-regulated, which may enhance activation of eosinophils and precipitate or exacerbate asthma symptoms.
Animals↗
Analysis of binding and membrane destabilization of phospholipid membranes by surfactant apoprotein B.
To further elucidate the nature of the molecular interactions of surfactant apoprotein B (SP-B) with phospholipid (PL) membranes, we studied the binding of SP-B to PL membranes and the lipid-dependency of its subsequent effects on leakage and fusion of membranes. SP-B binding to membranes was studied by labeling the protein with the fluorophore 7-nitro-2,1,3-benzoxadiazol-4-yl (NBD) and measuring the fluorescence of the labeled protein in the presence of varying amounts of dipalmitoylphosphatidylcholine-egg phosphatidylglycerol (DPPC-eggPG; 7-3). Leakage of contents from liposomes made of DPPC and varying molar fraction of egg phosphatidylcholine (eggPC) or eggPG was assessed by measuring the fluorescence of entrapped water-soluble probes ANTS and DPX. Fusion of membranes was assessed by measuring the fluorescence of membrane-bound NBD-phosphatidylethanolamine (NBD-PE) and rhodamine-PE (RHO-PE). We found that SP-B bound to PL membranes with high affinity and appeared to irreversibly cluster at the membrane surface, leading to graded release of the vesicle contents and eventually fusion of the membranes with increasing protein-lipid ratios. All lipid mixtures tested were susceptible to the membrane disruptive effects of SP-B, but DPPC-eggPG membranes displayed a biphasic response to increasing molar fractions of eggPG, whereas increasing fractions of eggPC elicited a monotonic response.
Animals↗
Mutational abrogation of the PTEN/MMAC1 gene in gastrointestinal polyps in patients with Cowden disease.
BACKGROUND & AIMS: To understand the molecular etiology of Cowden disease-associated gastrointestinal polyps, we analyzed the mutational status of PTEN/MMAC1, a recently identified Cowden disease gene located at 10q23, in gastric hamartomas, colonic adenoma, and juvenile polyps of 3 patients with Cowden disease. METHODS: Messenger RNA expression, gene deletion, and sequence alteration of PTEN/MMAC1 were evaluated by quantitative polymerease chain reaction (PCR), PCR-single-strand conformation polymorphism, and sequencing analysis. RESULTS: Germline missense mutation at codon 289 (AAA to GAA, Lys to Glu) and deletion of the wild-type allele were detected in the polyps of 2 patients with Cowden disease in the same family. Germline allelic deletion and transcriptional silencing of the remaining allele, probably caused by abnormal methylation, were also observed in a gastric hamartoma of 1 patient. CONCLUSIONS: The germline mutation and alteration of the remaining allele observed in this study strongly support that PTEN/MMAC1 functions as a tumor suppressor in Cowden disease. This study is the first to show that the mutational abrogation of PTEN/MMAC1 plays a causal role in the genesis of gastrointestinal polyps in Cowden disease, providing molecular genetic evidence that colonic adenoma, juvenile polyp, and gastric hamartoma could be included in the manifestations of Cowden disease.
Adolescent↗
Cosegregation of single genes associated with fertility restoration and transcript processing of sorghum mitochondrial orf107 and urf209.
Defective nuclear-cytoplasmic interactions leading to aberrant microgametogenesis in sorghum carrying the IS1112C male-sterile cytoplasm occur very late in pollen maturation. Amelioration of this condition, the restoration of pollen viability, involves a novel two-gene gametophytic system, wherein genes designated Rf3 and Rf4 are required for viability of individual gametes. Rf3 is tightly linked to, or represents, a single gene that regulates a transcript processing activity that cleaves transcripts of orf107, a chimeric mitochondrial open reading frame specific to IS1112C. The mitochondrial gene urf209 is also subject to nucleus-specific enhanced transcript processing, 5' to the gene, conferred by a single dominant gene designated Mmt1. Examinations of transcript patterns in F2 and two backcross populations indicated cosegregation of the augmented orf107 and urf209 processing activities in IS1112C. Several sorghum lines that do not restore fertility or confer orf107 transcript processing do exhibit urf209 transcript processing, indicating that the activities are distinguishable. We conclude that the nuclear gene(s) conferring enhanced orf107 and urf209 processing activities are tightly linked in IS1112C. Alternatively, the similarity in apparent regulatory action of the genes may indicate allelic differences wherein the IS1112C Rf3 allele may differ from alleles of maintainer lines by the capability to regulate both orf107 and urf209 processing activities.
Alleles↗
Earlier identification of patients at risk from acetaminophen-induced acute liver failure.
OBJECTIVE: To determine whether the Acute Physiology and Chronic Health Evaluation (APACHE) II system for the measurement of severity of illness is able to provide an accurate risk of hospital death in patients with acetaminophen-induced acute liver failure or identify those patients needing transfer for possible hepatic transplantation. DESIGN: Data for admission (first 24 hrs) APACHE II scores and King's criteria for urgent transplantation were collected prospectively to compare the APACHE II system and the King's criteria for the prediction of death or need for transplantation. SETTING: A nine-bed specialist liver failure unit (LFU). PATIENTS: One hundred two consecutive patients admitted to the LFU with acetaminophen self-poisoning and a prolonged prothrombin time were studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An APACHE II score of > 15 points was associated with a high mortality (13/20 patients, five of whom survived following hepatic transplantation). There was no relation between APACHE II risk and outcome (mean APACHE II risk of death 0.8%, actual hospital mortality 16%). An APACHE II score of > 15 had a similar power of prediction of death as the King's criteria (sensitivity 82% and 65%, respectively; specificity 98% and 99%, respectively), when considering those patients who were transplanted as "deaths." An APACHE II score of > 15 was able to identify four more patients than the King's criteria on the first day of admission to the LFU. CONCLUSIONS: The crude admission APACHE II score correlated well with mortality in patients with acetaminophen-induced acute liver failure. However, the calculated APACHE II risk of death, using the original drug overdose coefficient, was poorly calibrated. Since specialist liver scores are unfamiliar in the general intensive care setting, the use of an APACHE II score might earlier identify more patients at risk of needing a liver transplant, and hence, expedite appropriate transfer to a specialist liver unit.
APACHE↗
Experimental simian varicella virus infection of St. Kitts vervet monkeys.
Experimental simian varicella virus (SVV) infection of St. Kitts vervet monkeys was evaluated as an animal model to investigate human varicella-zoster virus (VZV) infections. During the incubation period, viremia disseminated infectious virus throughout the body via infected peripheral blood lymphocytes (PBLs). A vesicular skin rash in the inguinal area, and on the abdomen, extremities, and face appeared on day 7-10 postinfection. Necrosis and hemorrhage in lung and liver tissues from acutely infected monkeys were evident upon histologic analysis. Recovery from simian varicella was accompanied by a rise in the serum neutralizing antibody response to the virus. SVV latency was established in trigeminal ganglia of monkeys which resolved the acute infection. This study indicates that experimental SVV infection of St. Kitts vervets is a useful animal model to investigate SVV and VZV pathogenesis and to evaluate potential antiviral agents and vaccines.
Animals↗
Hypocalcemic stimulation and nonselective venous sampling for localizing parathyroid adenomas: work in progress.
PURPOSE: To evaluate whether the release of parathyroid hormone (PTH) from parathyroid tumors during selective parathyroid arteriography can help localize the tumors. MATERIALS AND METHODS: In 20 patients (six men, 14 women; age range, 24-72 years) with parathyroid tumors undergoing parathyroid arteriography after failed surgery, serial measurements of PTH were obtained during selective arteriography with nonionic contrast material. PTH levels were measured in the superior vena cava (SVC) before and at varying times from 20 to 120 seconds after arteriography. RESULTS: A 1.4-fold increase in the PTH level of the postarteriographic SVC samples enabled correct prediction of the site of adenoma in 13 of the 20 patients (65%). Of nine patients with positive arteriograms, eight had positive results of postarteriographic sampling. Of 11 patients with negative arteriograms, five had positive results of postarteriographic sampling. CONCLUSION: Sampling the SVC for PTH gradients after selective parathyroid arteriography correctly indicated the site of the adenoma in 13 of 20 patients (65%).
Adenoma↗
Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal.
OBJECTIVE: Neurophysiological and pathological effects of ethanol may be mediated, to an important extent, via the glutamatergic system. Animal studies indicate the acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Persistent attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in the compensatory up-regulation of NMDA receptors. Whether glutamatergic neurotransmission and oxidative stress are enhanced during ethanol withdrawal in humans is unknown. METHOD: CSF was obtained from 18 matched comparison subjects and from 18 patients with alcohol dependence 1 week and 1 month after cessation of ethanol ingestion. CSF samples were analyzed for excitatory neurotransmitters, gamma-aminobutyric acid (GABA), and markers for oxidative stress. RESULTS: The alcohol-dependent patients' CSF levels of aspartate, glycine, and N-acetylaspartylglutamate were all higher than those of the comparison subjects, and their concentration of GABA was lower. In addition, there were significant correlations between excitatory neurotransmitters and oxidative stress markers, which suggest that the two mechanisms may play an interactive role in neurotoxicity mediated by ethanol withdrawal. CONCLUSIONS: The data suggest that augmentation of excitatory neurotransmission may lead to enhanced oxidative stress, which, in concert with reduced inhibitory neurotransmission, may contribute to the symptoms of ethanol withdrawal and associated neurotoxicity in humans. Whether these abnormalities represent a trait- or state-dependent marker of ethanol dependence remains to be resolved.
Adult↗
Transplantation of CG4 oligodendrocyte progenitor cells in the myelin-deficient rat brain results in myelination of axons and enhanced oligodendroglial markers.
Transplantation of oligodendrocyte (Ol) progenitor cells into the central nervous system is a promising approach for the treatment of myelin disorders. This approach requires providing adequate numbers of healthy cells with myelinating potential. We recently showed the successful transplantation of Ol progenitors into the myelin-deficient (md) rat brain. In the present work, CG4 cells, a cell line with properties of Ol progenitors, were labeled with fast blue and grafted into P3-P5 pups born to carrier mothers. Examination of host brains 2 weeks posttransplant indicated that CG4 cells display a much more extensive migration capacity than their wild-type counterparts. These cells synthesized myelin components. In addition, ultrastructural analysis showed myelin formation along axons of md hosts in various brain regions, including corpus callosum, cerebellum, and brainstem. Furthermore, in situ hybridization studies performed on sagittal sections revealed extensive expression of transferrin-mRNA within the md host parenchyma. The high survival and functional features displayed by CG4 cells after transplantation, together with their striking wide distribution within the host parenchyma, as assessed by the presence of myelinated fibers in mutant hosts, emphasizes the importance of using highly motile and proliferative Ol progenitor cells. Strategies to improve the condition and life span of md rat pups are currently under investigation.
Animals↗
Nonsurgical therapy for pulmonary hydatid cyst disease.
Therapeutic and diagnostic aspiration of Echinococcus granulosus liver cysts, but not pulmonary cysts, are increasingly being performed. Documented herein is the utility of percutaneous drainage and of albendazole treatment in a patient with a large recurrent, isolated, pulmonary echinococcal cyst for whom traditional therapy would have resulted in severe morbidity. Therapeutic options and possible complications are discussed.
Adult↗
Identification of essential nucleotides of the FP1 element responsible for enhancement of low density lipoprotein receptor gene transcription.
Low density lipoprotein (LDL) receptor gene is regulated at the transcriptional level by the intracellular level of sterols in animal cells. We have recently identified a 20 bp long region (-145 to -126), designated Footprint 1 (FP1), participating in maximal expression of the human LDL receptor gene in the absence of sterols in HepG2 cells [Mehta, K. D., Chang, R., Underwood, J., Wise, J. and Kumar, A. (1996) J. Biol. Chem ., 271, 33616-33622]. To determine the minimal FP1 sequence and to define the critical nucleotides required for function, a series of single nucleotide substitutions were introduced in the FP1 region. Twenty-three independent mutations were analyzed by transfection into HepG2 cells. These studies localize the regulatory region to 14 bp and demonstrate the requirement for essential guanine nucleotides at positions -135 and -136 for FP1 function. Furthermore, transfection studies suggest that the FP1-dependent increase in reporter gene expression is possibly mediated through interaction with the sterol-regulatory element. UV cross-linking and Southwestern blot analysis identified FP1-binding factors of approximately 50 and 125 kDa, which we have denoted p50 and p125. Mutations of the critical guanine residues (-135/-136) decreased the formation of the specific protein-DNA complex with the FP1 sequence and abolished its binding to the p125. We conclude that direct interaction of the p125 factor with these nucleotides of the FP1 element potentially contributes to FP1-dependent induction of LDL receptor gene expression.
Animals↗
Gait analysis of adult paraplegic rats after spinal cord repair.
This study presents a novel detailed method of analysis of rat gait and uses this method to demonstrate recovery of forward locomotion patterns in adult rats made paraplegic by surgical spinal cord transection and subjected to a novel strategy for spinal cord repair. Six normal rats were compared to five animals in which the cord was transected at T8-T9, and a 5-mm segment of the spinal cord removed, and to seven animals in which, following spinal cord transection and removal of a spinal cord segment, multiple intercostal peripheral nerve bridges were implanted, rerouting pathways from white to gray matter in both directions. The implanted area was filled with fibrin glue containing acidic fibroblast growth factor. Details of the repair strategy have been published (H. Cheng, Y. Cao, and L. Olson, 1996, Science 273: 510-513). Gait analysis was carried out 3 and 4 months after surgery and once in the normal animals. Animals were allowed to walk across a runway with a transparent floor. Each test consisted of five trials, and each trial was videorecorded from underneath. Using frame-by-frame playback, individual footprints were then recorded regarding location and order of limb use, as well as step quality (degree of weight bearing, etc.). These data allowed measuring runway transit time, five different measures of step numbers, all possible temporal patterns of limb use, stride length, and base of support. Transected controls remained paralyzed in the hindlimbs with only occasional reflex hindlimb movements without weight bearing. Animals subjected to the full repair procedure were significantly faster than the controls, used their hindlimbs for 25-30% of the movements, and regained several of the specific limb recruitment patterns used by normal rats. Taken together, the gait analysis data demonstrate remarkable recovery of coordinated gait in the repaired animals, which was significantly better than controls for all relevant parameters, while at the same time clearly inferior to normal rats for most of the examined parameters. We conclude that normal rats use a multitude of interchangeable step sequence patterns, and that our spinal cord repair strategy leads to recovery of some of these patterns following complete spinal cord transection. These data suggest functionally relevant neuronal communication across the lesion.
Animals↗
Regulation of tPA in endothelial cells exposed to cyclic strain: role of CRE, AP-2, and SSRE binding sites.
We have previously reported that exposure of cultured bovine aortic endothelial cells (EC) to 10% average strain resulted in an increase in tissue plasminogen activator (tPA) mRNA, immunoreactive tPA protein, and tPA activity in the medium. The present study was designed to examine the regulation of tPA gene expression in EC by cyclic strain. We performed a functional analysis of the tPA promoter by transfecting bovine aortic EC with a 1.4-kilobase (kb) construct of the human tPA promoter coupled to chloramphenicol acetyltransferase. We found that subjecting the EC to 10% average strain (and not 6% average strain) resulted in a 2.6-fold increase in activity of the 1.4-kb tPA promoter by 4 h. Analysis of deletion mutants of the promoter transfected into EC demonstrated a 60% drop-off in activity between position -145 and -105. Deoxyribonuclease I protection analysis of the segment downstream of position -196 suggested involvement of activator protein-2 (AP-2) and adenosine 3',5'-cyclic monophosphate-responsive element (CRE)-like binding sites, which was confirmed by electrophoretic mobility shift assays. Site-directed mutants of either the AP-2 or CRE-like regions resulted in a 65% decrease in activity compared with the wild type. Double mutations abolished basal transcription and any strain-induced activity. A shear stress responsive element (SSRE) binding site is present at -945, but site-directed mutants did not show any drop in activity compared with wild type by cyclic strain. These studies demonstrate that cyclic strain regulates tPA gene transcription in bovine aortic EC and that this transcriptional activation is dependent on factors that are similar to those activated with phorbol ester.
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The Kinmen Neurological Disorders Survey (KINDS): a study of a Chinese population.
We conducted an epidemiological study of several neurological disorders among the Chinese aged 50 years or older on the islet of Kinmen. All participants were interviewed and examined by neurologists. From the targeted population of 5,061 individuals, 3,915 (77.4%) of them completed the evaluations. Among the 4,087 individuals with whom face-to-face contact was made, the refusal rate was 4.2%. The disorders of interest were dementia, Parkinson's disease, essential tremor, stroke, transient ischemic attacks, and migraine. Among the 3,915 participants, 366 cases were found with 1 or more of the surveyed neurological disorders on the prevalence day, August 1, 1993, yielding a prevalence of 93.5/1,000. The purpose of this study, the general methodology, and some overall findings are presented in this communication in order to provide a common background for detailed findings on each disorder to be reported separately.
Age Factors↗
Tissue plasminogen activator-biologic perspective for surgeons.
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Animals↗
Identification of a novel cis-acting element participating in maximal induction of the human low density lipoprotein receptor gene transcription in response to low cellular cholesterol levels.
In this paper, we present both in vivo and in vitro evidence for the presence of a novel cis-acting regulatory element that is required for maximal induction of the human low density lipoprotein (LDL) receptor gene following depletion of cellular sterols in HepG2 cells. First, in vivo dimethyl sulfate footprinting of the human LDL receptor promoter before and after transcriptional induction in HepG2 cells revealed protection from -145 to -126, 5'-GAGCTTCACGGGTTAAAAAG-3' (referred to as FP1 site). Second, transient transfections of HepG2 cells with promoter luciferase reporter constructs containing the FP1 site resulted in significant enhancement (approximately 375%) of reporter gene expression in response to low levels of sterols compared with parallel plasmid without the FP1 site. In addition, this response was markedly attenuated on nucleotide substitutions within the FP1 site. Third, by electrophoretic mobility shift assays, the FP1 sequence was found to bind protein(s) from HepG2 nuclear extracts in a sequence-specific manner. In vitro binding of the FP1 mutants paralleled the results obtained for their in vivo transcription. On the basis of competition profiles, the FP1-binding factor is different from the known transcription factors binding to the AT-rich CArG and GArC motifs. Furthermore, the FP1-binding protein is not specific to HepG2 cells because nuclear factor(s) with the same specificity was observed in nuclear extracts of non-hepatic HeLa cells. We conclude that transcriptional induction of the LDL receptor gene in response to sterol depletion is mediated, in part, by an highly conserved novel cis-acting element through the binding of specific nuclear protein(s).
Base Sequence↗