Identification of two novel mutations in the CACNA1A gene responsible for episodic ataxia type 2.
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Biomedical subjects
Publications and source records attributed to R Nelson.
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OBJECTIVES: This article reports the characteristics associated with fecal incontinence (FI) in a nursing home population that are also associated with urinary incontinence (UI). METHOD: A cross-sectional survey composed of data from the Wisconsin Center for Health Statistics' Annual Nursing Home Survey in 1992 and 1993. Demographic characteristics, functional status, and disease histories were correlated with UI. RESULTS: Data were available for 18,170 and 17,117 residents respectively, 56% of who were to varying degrees incontinent of urine in each year. Significant positive associations with UI included, in order of adjusted odds ratios: FI, truncal restraints, dementia, female gender, impaired vision, stroke, and constipation. Inverse associations were age, body mass index, tube feedings, and pressure ulcers. Diabetes, heart disease, arthritis, fecal impaction, and race were not associated with UI. CONCLUSIONS: UI frequently coexists with FI in nursing home residents. FI and UI differ in their association with age, body mass, and gender.
The AluQuant Human DNA Quantitation System has been developed for human-specific quantitation of forensic samples. This system uses probes specific to repetitive genetic elements allowing quantitation without target amplification. Target immobilization is unnecessary with employment of solution hybridization. The AluQuant Human DNA Quantitation System uses a series of enzymatic reactions to produce a luminescent signal proportional to the quantity of human DNA present. This report demonstrates a range of quantitation from 0.1-50 ng of human DNA. Signal from non-human DNAs tested was insignificant and addition of non-human DNAs into a human sample did not alter quantitation. Lastly, the system was unaffected by degradation of sample through sonication. The AluQuant Human DNA Quantitation System is a simple and sensitive method for quantitating the concentration of human DNA in forensic samples.
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Fragile X mental retardation is caused by the absence of FMRP, an RNA-binding protein found in a large mRNP complex. Although there is evidence that FMRP exists as a homo-multimer, additional proteins have been identified that associate with FMRP in the mRNP. The autosomal paralogs of FMRP, FXR1P, and FXR2P, associate with FMRP, as do nucleolin and NUFIP1, all RNA binding proteins. Using cell lines that were stably transfected with Flag-Fmr1, we identified an additional protein that coimmunoprecipitates with FMRP. The approximately 50 kDa protein was identified by mass spectrometry as mouse Y box-binding protein 1 (YB1), which is 97% identical to the core mRNP protein p50, an RNA-binding protein. An anti-p50 antiserum recognized the 50 kDa protein, confirming the identification. The association of the FMRP-mRNP with a Y box protein, the latter commonly found in mRNPs, further suggests the involvement of FMRP in translation modulation.
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1. Whole-cell patch recording and puff pipette techniques were used to identify glutamate receptor mechanisms on bipolar cell (BC) dendrites in the zebrafish retinal slice. Recorded neurons were stained with Lucifer Yellow, to correlate glutamate responses with BC morphology. 2. BC axon terminals (ATs) consisted of swellings or varicosities along the axon, as well as at its end. AT stratification patterns identified three regions in the inner plexiform layer (IPL): a thick sublamina a, with three bands of ATs, a narrow terminal-free zone in the mid-IPL, and a thin sublamina b, with two bands of ATs. BCs occurred with ATs restricted to sublamina a(Group a), sublamina b(Group b) or with ATs in both sublaminae (Group a/b). 3. OFF-BCs belonged to Group a or Group a/b. These cells responded to glutamate or kainate with a CNQX-sensitive conductance increase. Reversal potential (Erev) ranged from -0.6 to +18 mV. Bipolar cells stimulated sequentially with both kainate and glutamate revealed a population of glutamate-insensitive, kainate-sensitive cells in addition to cells sensitive to both agonists. 4. ON-BCs responded to glutamate via one of three mechanisms: (a) a conductance decrease with Erev approximately 0 mV, mimicked by L-(+)-2-amino-4-phosphonobutyric acid (APB) or trans-1-amino-1, 3-cyclopentanedicarboxylic acid (trans-ACPD), (b) a glutamate-gated chloride conductance increase (IGlu-like) characterized by Erev >= ECl (where ECl is the chloride equilibrium potential) and partial blockade by extracellular Li+/Na+ substitution or (c) the activation of both APB and chloride mechanisms simultaneously to produce a response with outward currents at all holding potentials. APB-like responses were found only among BCs in Group b, with a single AT ramifying deep within sublamina b; whereas, cells expressing IGlu-like currents had one or more ATs, and occurred within Groups b or a/b. 5. Multistratified cells (Group a/b) were common and occurred with either ON- or OFF-BC physiology. OFF-BCs typically had one or more ATs in sublamina a and only one AT in sublamina b. In contrast, multistratified ON-BCs had one or more ATs in sublamina b and a single AT ramifying deep in sublamina a. Multistratified ON-BCs expressed the IGlu-like mechanism only. 6. Visual processing in the zebrafish retina involves at least 13 BC types. Some of these BCs have ATs in both the ON- and OFF-sublaminae, suggesting a significant role for ON- and OFF-inputs throughout the IPL.
OBJECTIVE: Inflammatory cytokines, particularly tumor necrosis factor, contribute to myocardial dysfunction after ischemia-reperfusion injury. Aprotinin may improve outcomes in cardiac surgery through suppression of inflammatory mediators. We hypothesized that aprotinin may exert its beneficial effects through suppression of tumor necrosis factor alpha. METHODS: Adult rat hearts were precision cut into slices with a thickness of 200 microm and stored in crystalloid cardioplegic solution alone or with one of the following additions: aprotinin or tumor necrosis factor alpha, aprotinin plus tumor necrosis factor alpha, a monoclonal antibody to tumor necrosis factor alpha, or a polyclonal antibody to the tumor necrosis factor alpha receptor. Myocardial biochemical function was assessed by adenosine triphosphate content and capacity for protein synthesis immediately after slicing (0 hours) and after 2, 4, and 6 hours of storage at 4 degrees C. The content of tumor necrosis factor alpha was measured by an enzyme-linked immunosorbent assay. Six slices were assayed at each time point for each solution. The data were analyzed by analysis of variance and are expressed as the mean +/- standard deviation. RESULTS: When stored in cardioplegic solution containing aprotinin, the heart slices demonstrated (1) an increase in adenosine triphosphate content and protein synthesis (P <.0001), (2) a decrease in intramyocardial generation of tumor necrosis factor alpha (P </=.0311), and (3) a decrease in uptake of tumor necrosis factor alpha into the myocardium (P </=.002) compared with storage in cardioplegic solution alone. The presence of an antibody to tumor necrosis factor alpha or an antibody to the tumor necrosis factor alpha receptor in cardioplegic solution increased intramyocardial adenosine triphosphate content and protein synthesis (P <.0001). CONCLUSIONS: Aprotinin preserves myocardial biochemical function during cold storage. This preservation of biochemical function is mediated through suppression of the release, uptake, and activity of tumor necrosis factor alpha.
Salmon pancreas disease virus (SPDV) has been shown to cause severe economic losses in farmed Atlantic salmon (Salmo salar) and has been reported to occur in Europe, Scandinavia and the United States. This paper describes the biochemical characterization of SPDV in terms of its RNA and protein composition. SPDV was purified by precipitation from infected Chinook salmon embryo (CHSE-214) cell-culture supernatant and sucrose density-gradient centrifugation. Fractions containing virus were identified by an immunodot blot assay using an SPDV-specific MAb. Two major proteins with molecular masses of approximately 55 and 50 kDa, putatively identified as the E1 and E2 alphavirus glycoproteins respectively, were detected when purified virus preparations were analysed by PAGE. Radiolabelling experiments indicated that SPDV infection of CHSE-214 cells did not shut-off host-cell protein synthesis, making attempts to identify virus-specific proteins unsuccessful. However, radioimmunoprecipitation assay (RIPA) experiments showed that two SPDV-specific MAbs reacted with a protein in the 50-55 kDa range. Northern blot hybridization with cloned cDNA probes indicated that infected cells contained RNA species of approximately 11.4 and 4 kb, which correspond to the genomic and subgenomic RNAs specified by SPDV. The results described are consistent with SPDV being characterized as an alphavirus.
Two experiments demonstrate that grouping can be strongly influenced by the presence of figures defined by illusory contours. Rectangular arrays were constructed in which a central column of figures could group either with those on one side, on the basis of perception of figures defined by illusory contours, or with those on the other side, on the basis of physically present inducing elements. In all displays, subjects grouped according to the illusory figures significantly more often than for control displays that contained the same inducing elements, but rearranged so that illusory contours were degraded or eliminated. A second experiment showed that in objectively defined grouping tasks, subjects grouped faster by illusory figures than by inducing elements. These results indicate that grouping can occur after illusory contours have been perceived.
Cryptosporidium parvum leaped to the attention of the United States following the 1993 outbreak in Milwaukee, Wisconsin, which sickened 400,000 people. Other outbreaks in the United States have been associated with drinking and recreational water, consumption of contaminated foods, contact with animals, and childcare attendance. Despite its public health importance, the number of people who become infected each year is not known. In 1997, active surveillance for C. parvum was added to the Foodborne Diseases Active Surveillance Network (FoodNet), a collaborative effort among the Centers for Disease Control and Prevention, selected state health departments, the U.S. Departments of Agriculture and Food and Drug Administration. During the first 2 years of surveillance, 1,023 laboratory-confirmed cases of cryptosporidiosis were detected in FoodNet (Connecticut, Minnesota, Oregon, and selected counties in California, Georgia, Maryland, and New York). The annual rate per 100,000 persons was 2.3. Sixteen percent of case-patients were hospitalized. A seasonal increase in case detection was noted in late summer among persons less than 15 years of age. These data represent the first active multistate ascertainment of laboratory-confirmed cryptosporidiosis cases and provide useful information on the burden of disease in the United States.
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Auditory neuropathy (AN) is a hearing disorder that presents with a grossly abnormal or absent neural response as measured by evoked potentials in the presence of normal outer hair cell function evidenced by present otoacoustic emissions or cochlear microphonics. Rehabilitation for patients with AN is challenging due to abnormal temporal encoding at the auditory nerve leading to severely impaired speech perception. Although patients with AN may demonstrate improvement in thresholds with amplification, temporal encoding dysfunction, and consequently speech perception degradation, is not alleviated by amplification. Another issue is the heterogeneity of the AN population in terms of audiologic and neurologic findings, in addition to uncertain etiology and pathophysiology. For children with prelingual onset of AN, development of auditory and oral communication skills is particularly compromised. All children with hearing loss in the severe-to-profound range who do not benefit from conventional amplification can be considered candidates for a cochlear implant (CI). This paper presents a case study of a child with AN who received a CI. Whereas no synchronous neural response auditory brainstem response could be elicited to acoustic stimuli, an electrically evoked auditory nerve action potential was evident following implantation, suggesting restoration to some degree of neural synchrony. Significant improvement in speech perception was found post-CI. Recommendation to implant all patients with AN would be premature, but these findings suggest that electrical stimulation in some cases of auditory neuropathy can be a viable option.
The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.
Of the gene-rich regions of the human genome, Xq28 is the most densely mapped. Mutations of genes in this band are responsible for 10 syndromal forms of mental retardation and 5 nonsyndromal forms. Clinical and molecular studies reported here add an additional syndromic form of X-linked mental retardation (XLMR) to this region. The condition comprises short stature, small hands and feet, seizures, cleft palate, and glaucoma. One affected male died at age 19 years in status epilepticus, but others have survived to old age. Carrier females do not have somatic anomalies or mental impairment. The gene is localized to the terminal 8 Mb of Xq28 with markers distal to DXS8011 showing linkage to the disorder with a lod score of 2.11 at zero recombination.
Hepatitis C virus (HCV) has been associated with various lymphoproliferative disorders, and a high prevalence (9%-32%) of chronic HCV infection has been demonstrated among patients with lymphoma. Dual coinfection by HIV and HCV has been demonstrated in approximately 40% of certain populations of HIV-infected individuals. Because of this high prevalence of coinfection by HIV and HCV, the known relations between HCV and lymphoproliferative disorders, and the association of HIV and B cell lymphoma, the potential association between chronic HCV and the development of AIDS-related lymphoma was examined. The prevalence of HCV infection in HIV-infected patients with lymphoma was compared with that in patients with AIDS, diagnosed on the basis of an illness other than lymphoma. Risk factors for HCV infection, overall, were also evaluated. Evidence of HCV infection was ascertained by assessing anti-HCV antibodies, and HCV RNA in serum. The study consisted of 99 homosexual/bisexual men with AIDS-related lymphoma, and 43 other AIDS patients. HCV infection was detected in 11 of 99 (11.1 %) men with lymphoma, and in 5 of 43 (11.6%) other AIDS patients. Further, in patients with AIDS-related lymphoma, no relation was found between HCV infection and lymphoma histology or site. History of use of injected illicit drugs was associated with a significantly elevated risk of HCV infection in the combined group of lymphoma and other AIDS patients. The current study demonstrates no relation between dual infection by HIV and HCV and subsequent increased risk of lymphoma.
The purpose of this study was to evaluate the safety and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in hepatic MRI of patients with suspected liver pathology. A Phase III, multicenter, randomized, double-blind, parallel group study was performed in adults with suspected liver pathology. All patients underwent contrast-enhanced computed tomography within 3 weeks prior to magnetic resonance scanning. Ninety-nine patients received OptiMARK, and 94 patients received Magnevist at a dose of 0.1 mmol/kg. Precontrast T1- and T2-weighted spin-echo imaging and T1-weighted gradient-echo imaging were performed, followed by T1-weighted gradient-echo imaging at 15-20 seconds, 1 minute, and 5 minutes after intravenous contrast injection. Three primary efficacy endpoints (confidence in lesion diagnosis, level of conspicuity, and lesion border delineation) were evaluated on the precontrast image set and compared with the pre plus postcontrast image set. Vital signs, physical examination, electrocardiograms (ECGs), and laboratory parameters (chemistry, hematology, and urinalysis) were measured at various time points. Adverse events were recorded. The study design and statistical analyses were chosen to demonstrate presumed equivalence of OptiMARK and Magnevist. There were no statistically significant differences in efficacy between OptiMARK and Magnevist as assessed by either blinded readers or the on-site principal investigators. No serious or unexpected adverse events were noted. Of the 193 patients receiving contrast media, 82 experienced a total of 154 adverse events. Thirty-three (21.4%) of these 154 adverse events were felt by the on-site investigators to be probably related to either study agent: 15 events in 9 patients in the OptiMARK group, and 18 events in 13 patients in the Magnevist group. Headache was the most common adverse event, occurring in 10.1% of the OptiMARK patients and 12.8% of the Magnevist patients. No clinically relevant trends were observed in any laboratory parameter or ECG findings in either treatment group. The results demonstrate the safety, efficacy, and equivalence of OptiMARK and Magnevist at a dose of 0.1 mmol/kg in hepatic magnetic resonance imaging of patients with suspected liver pathology.