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Biomedical subjects

R Williamson

Publications and source records attributed to R Williamson.

At least 91 records · Page 5Linked to original sources
PubMed1998

The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.

Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C, and L182F, which occur in patients in association with GAA expansions. These cases, and a further five reported cases of point mutations causing FRDA, demonstrate that splicing, nonsense, or initiation codon mutations (which cause a complete absence of functional frataxin) are associated with a severe phenotype. Missense mutations, even in highly evolutionally conserved amino acids, may cause a mild or severe phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Friedreich's ataxia presenting as adult-onset spastic paraparesis.

We have studied a man with an atypical form of Friedreich's ataxia (FRDA), who presented at age 26 years with a 2-year history of unsteadiness and clumsiness. The predominant feature of his initial neurological examination was a spastic paraparesis, along with a mild distal weakness and hyperreflexia of the upper limbs. He also displayed limb ataxia. Frataxin GAA repeat sizes were 1,040/690. This unusual FRDA presentation is not dissimilar to that of Acadian spastic ataxia.

Adult↗
PubMed1998

The optimal route of delivery for fetal meningomyelocele.

OBJECTIVE: It has been proposed that cesarean section improves the long-term neurologic outcome of children with meningomyelocele. On the basis of this belief, a trial of labor is not offered in many centers. We hypothesized that there is no difference in immediate or long-term outcome by route of delivery for the fetus with meningomyelocele delivered in a tertiary care center. STUDY DESIGN: All fetuses (n = 60) with meningomyelocele delivered at the University of Iowa Hospitals and Clinics between 1971 and 1995 were analyzed. Thirty-six cases were available for long-term follow-up. Motor, sensory, and anatomic levels were converted to a numeric scale. Variables were compared by one-way analysis of variance, chi2 analysis, and Fisher's exact test with significance at P < .05. RESULTS: There were no significant differences by route of delivery for gestational age of delivery, birth weight, meningomyelocele size, or neonatal mortality (vaginal: 1/22 = 4.5%, cesarean section: 2/17 = 11.8%, P = .82). An antenatal diagnosis was made with similar frequency in the two groups (vaginal: 15/21 = 71.4%, cesarean section: 13/15 = 86.7%). In addition, the length of long-term follow-up was similar (vaginal: 54.7 +/- 11.1 months, cesarean section: 33.7 +/- 8.6 months). There was no difference in long-term neurologic outcome as determined by the change in motor level, the change in sensory level, or when comparing the final motor level with the anatomic level. CONCLUSIONS: This study was unable to detect differences between either immediate or long-term outcome for the infant with isolated meningomyelocele when stratified by route of delivery. A multicenter randomized trial should be required before the acceptance of cesarean section as the optimal route of delivery for the fetus with meningomyelocele.

Adult↗
PubMed1998

Prospective evaluation of prenatal maternal serum screening for trisomy 18.

OBJECTIVE: Our goal was to evaluate the performance of prenatal serum screening for trisomy 18. STUDY DESIGN: All 40,762 samples for maternal serum testing (August 1991 to June 1994) with a trisomy 18-positive screen (n = 175, alpha-fetoprotein < or =0.75 multiples of the median, unconjugated estriol < or =0.60 multiples of the median, human chorionic gonadotropin < or =0.55 multiples of the median) were analyzed. Results of all amniocenteses, ultrasonographic studies, and birth or death certificate information were obtained from the Iowa Expanded Serum Screening Program, the Iowa Department of Public Health, and the Iowa Birth Defects Registry. RESULTS: We obtained the expected screen-positive rate for trisomy 18 (0.43%, 175/40,762). Fourteen samples from outside the state were excluded, which left 161 cases with outcome data obtained through amniocentesis (n = 121), birth certificates (n = 34), telephone contact (n = 2), or a sonogram indicating a nonviable gestation (n = 4). Of 121 screen-positive women undergoing amniocentesis, 119 had a normal karyotype and 2 had an abnormal karyotype: 69,XXY and 47,XY,+18. Of 36 who declined amniocentesis, none had findings consistent with aneuploidy on clinical neonatal examination. Of the 103 patients who had a detailed ultrasonographic study at the University of Iowa, 27 had a subtle fetal abnormality or growth alteration. Both cases with aneuploidy were in this group. An additional 7 cases of trisomy 18 without the typical trisomy 18 maternal serum screening pattern were diagnosed during this period either at amniocentesis performed because of increased Down syndrome risk indicated by serum screening (n = 1), by elevated alpha-fetoprotein level (n = 1), or by advanced maternal age (n = 2) with serum for screening drawn coincidentally, or they were diagnosed postnatally (n = 3). Three of the 7 cases had early second-trimester ultrasonographic examinations, and all showed abnormalities. CONCLUSIONS: The detection rate of trisomy 18 among patients offered amniocentesis was significantly lower (p < 0.05) than the expected rate (10/161 on the basis of published data). Combining serum screening with detailed ultrasonographic evaluations may improve predictive value by more precisely targeting amniocentesis toward those at highest risk.

Adult↗
PubMed1998

Lobeline and structurally simplified analogs exhibit differential agonist activity and sensitivity to antagonist blockade when compared to nicotine.

In the present study, lobeline and two structurally simplified analogs were evaluated for activity in muscarinic and nicotinic binding assays, a functional assay for nicotinic receptor activation (86Rb+ efflux from striatal synaptosomes) and an acetylcholinesterase (AChE) assay. Lobeline displaced [3H]cytisine binding to rat cortical membranes with a mean inhibition constant (KI) value of 16.0 nM, while the lobeline analogs CRM-I-13-1 and CRM-I-32-1 exhibited values of 15.0 and 5.4 microM, respectively. [3H]methylscopolamine was displaced by lobeline with a mean KI value of 37.0 microM while CRM-I-13-1 and CRM-I-32-1 exhibited values of 55.0 and 16.0 microM, respectively. While nicotine stimulated 86Rb+ efflux from striatal synaptosomes in a mecamylamine reversible manner at each concentration tested, lobeline slightly increased 86Rb+ efflux at lower concentrations and reduced efflux at higher concentrations. Further, none of the lobeline effects were reversed with mecamylamine. Although less potent, the two lobeline analogs exhibited a similar pattern of activity. These data may suggest that lobeline and structurally similar compounds bind with different subtype selectivity than nicotine, or exert their agonists effects through non-nicotinic mechanisms. All of the compounds tested were at least several hundred times less potent than physostigmine as AChE inhibitors. While some differences were apparent between the lobeline analog which contained the 2-keto-ethyl portion of lobeline and the analog which contained the phenyl 2-hydroxy-ethyl moiety, each compound was much less active than lobeline in most parameters assessed.

Acetylcholinesterase↗
PubMed1998

Review article: one-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori.

BACKGROUND: One-week triple therapies have been endorsed as the treatment regimens of choice for eradication of Helicobacter pylori infection. Those that include clarithromycin appear to be the most effective. AIM: To review reports of triple therapies that include clarithromycin. METHODS: Reports were identified from the literature to May 1998. The variation between study designs prevents a formal meta-analysis. A measure of the relative efficacies of regimens has, however, been gained by comparison and by pooling of intention-to-treat eradication rates. RESULTS: One hundred and ninety-two studies were identified which included 264 treatment arms of a 1-week triple therapy composed of clarithromycin with amoxycillin or a nitroimidazole (metronidazole or tinidazole), and either ranitidine bismuth citrate or a proton pump inhibitor (omeprazole, lansoprazole or pantoprazole). From reports of these studies, an intention-to-treat H. pylori eradication rate could be determined from 210 treatment arms of 151 studies. CONCLUSIONS: There is little to choose between the efficacies of 1-week clarithromycin-based triple therapy eradication regimens. However, those comprising clarithromycin, a nitroimidazole and either ranitidine bismuth citrate or a high dose of omeprazole are, in general, the most effective. Against antibiotic-resistant strains of H. pylori, regimens including ranitidine bismuth citrate may be more effective than those including a proton pump inhibitor.

Anti-Bacterial Agents↗
PubMed1998

New options in Helicobacter pylori eradication: efficacy, resistance and synergy.

The eradication of Helicobacter pylori has become the focus of much attention since the first attempts at developing effective therapies some 10 years ago. This review focuses on ranitidine bismuth citrate (RBC), the first new drug to be introduced for use in the eradication of H. pylori. RBC when combined with clarithromycin gives consistently high eradication rates (above 80% intention-to-treat assessment in double-blind, international studies) as a simple dual therapy for 14 days or when combined with two antibiotics as a triple therapy for 7 days. RBC enhances the in vitro killing of H. pylori by antibiotics, such as clarithromycin, metronidazole or tetracycline, in a synergistic manner. This effect is seen even when the H. pylori strains are 'resistant' to the antibiotics. Such a synergistic effect probably explains the increased efficacy of RBC-clarithromycin dual therapies compared with clarithromycin dosed with acid-suppressive agents such as H2-receptor antagonists or proton-pump inhibitors.

Anti-Bacterial Agents↗
PubMed1998

Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32 in southern African Bantu-speaking families.

Several recent reports have provided evidence suggesting linkage of markers on chromosome 13q14.1-q32 to schizophrenia in families from England, Wales, Japan and the USA, but not in Chinese families. We tested for linkage between markers in this region and schizophrenia in a sample of 16 families multiply affected with schizophrenia drawn from the Bantu-speaking black population of South Africa. Twelve markers spanning 76 cM of chromosome 13q were examined in these analyses, including 10 markers covering the most positive region in the studies of the English, Welsh and Chinese families, and two additional markers yielding the largest positive LOD scores in the American study. The map of markers used was D13S126-14.6cM-D13S119-12.2cM-D13S144-10.+ ++2cM-D13S160-7.9cM-D13S121-6.3cM -D13S71-1.6cM-D13S122- 4.9cM-D13S128-8.9cM-D13S770-1.4cM-D13S7 79-2.2cM-D13S64-7.4cM-D13S173. Parametric two-point analysis yields strongly negative LOD scores across the region D13S71-D13S64 under all models, and D13S71-D13S173 under a recessive model, when analysing either the whole sample or affected individuals only. ALOD maxima are 0.0 when allowing for heterogeneity for all markers in this subset. Under recessive modelling, the ALOD maximum is 0.717, theta = 0.0, alpha = 0.45, for D13S126 when analysing all samples. Affected-only analysis of this marker yields a maximum LOD score of 0.645, theta = 0.1, and an ALOD maximum of 0.697, theta = 0.0, alpha = 0.55. Non-parametric multipoint analysis of these markers provides no support for excess sharing of alleles identical by descent, although D13S119 and D13S770 show some evidence for excess sharing of alleles identical by state.

Black People↗
PubMed1998

Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice.

PURPOSE: Studies in invertebrates and cultured mammalian neurons suggested that valproate (VPA) mediates its main antiepileptic effect by slowing the recovery from inactivation of voltage-dependent sodium channels. This predicts an effect on the refractory period of the action potential and, consequently, on the bursting behavior of neurons. METHODS: We investigated this prediction using intracellular and extracellular recording techniques in hippocampal slices prepared from adult rats. The refractory period (RFP) and the ratio of the slopes (SR) of a pair of action potentials were used as indices of the recovery from inactivation of sodium channels. They were measured by injecting a series of paired depolarizing current pulses into CA1 pyramidal neurons. RESULTS: No significant changes were observed in the RFP or SR measured during a 1-h recording period when VPA was bath-applied (1 mM), or when it was present in the recording electrode (10-50 mM). Lowering the temperature from 34.5 degrees C to 26.4 degrees C resulted in an increase of the RFP by 100% and a decrease of the SR by 40%. However, VPA did not affect any of the measured action potential parameters at this lower temperature. VPA was also without effect on the presynaptic fiber volley of axons recorded extracellularly in the stratum radiatum. The antidromic population spike was unaffected by VPA (2 mM), whereas phenytoin (50 microM) clearly affected this spike in the same slices. The absence of effect of VPA on each of the measured parameters could not be attributed to poor penetration through the slice because bath-applied VPA reduced the frequency of extracellularly recorded spontaneous interictal bursts, induced by bicuculline and elevated K+, within 10 min. CONCLUSIONS: These findings suggest that at least in the hippocampal slice the drug's principal antiepileptic effect cannot be explained by its action on voltage-dependent sodium channels.

Action Potentials↗
PubMed1998

Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene.

Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene. Occasionally, a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats. We have examined the sperm DNA of a premutation carrier. This man's leucocyte DNA showed one normal allele and one allele of approximately 100 repeats. His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats. His affected son has repeat sizes of 1040 and 540. These data suggest that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion. We also show that in all informative carrier father to affected child transmissions, with the notable exception of the premutation carrier, the expansion size decreases.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Synaptic interactions between crista hair cells in the statocyst of the squid Alloteuthis subulata.

Intracellular injections of the fluorescent dye Lucifer yellow into the various cell types within the anterior transverse crista segment of the statocyst of squid revealed that the primary sensory hair cells and both large and small first-order afferent neurons have relatively simple morphologies, each cell having a single, unbranched axon that passes directly into the small crista nerve that innervates the anterior transverse crista. However, the small first-order neurons have short dendritic processes occurring in the region of the sensory hair cells. The secondary sensory hair cells have no centripetal axons, but some have long processes extending from their bases along the segment. Simultaneous intracellular recordings from pairs of the different cell types in the anterior transverse crista segment demonstrated that electrical coupling is widespread; secondary sensory hair cells are coupled electrically along a hair cell row, as are groups of primary sensory hair cells. Secondary sensory hair cell also are coupled to neighboring small first-order afferent neurons. However, this coupling is rectifying in that it only occurs from secondary sensory hair cells to first-order afferent neurons. Direct electrical stimulation of the small crista nerve to excite the efferent axons revealed efferent connections to both the primary sensory hair cells and the small first-order afferent neurons. These efferent responses were of three types: excitatory or inhibitory postsynaptic potentials and excitatory postsynaptic potentials followed by inhibitory postsynaptic potentials. The functional significance of the cell interactions within the crista epithelium of the statocyst of squid is discussed and comparisons drawn with the balance organs of other animals.

Action Potentials↗
PubMed1998

Molecular Basis of beta-Thalassemia in Indonesia: Application to Prenatal Diagnosis.

Background: To facilitate an effective prevention program, the beta-thalassemia mutations in the different ethnic groups in Indonesia were characterized. Methods and Results: The amplification refractory mutation system and artificially created restriction site were used to detect seven known mutations previously described in the Indonesian population. Other mutant alleles were identified by chemical cleavage mismatch, double-stranded sequencing, and Southern blotting. With these methods 78% of beta-thalassemia mutant alleles have been detected so far. Thirteen different beta-thalassemia mutations were characterized, nine of which had previously been described in the Jakarta population. The most frequent mutation is HbE (29%), followed by IVS1-nt5 (19%), and Cd 35 (8%). The frequencies of the other mutations varied from 4% to less than 1%. Two large gene deletions, Filipino beta-deletion and Hb Lepore, were identified in patients from the eastern part of Indonesia. Conclusions: The ethnicity and clinical hematology of cases in the region should be considered in the screening strategy for carriers and antenatal diagnosis of beta-thalassemia in Indonesia. Direct sequencing proved to be the appropriate method for detecting the unknown mutations, and Southern blotting had to be used for large deletions.

Journal Article↗
PubMed1997

Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS: We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS: In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION: Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.

Alleles↗
PubMed1997

Sonographic and maternal serum screening abnormalities in fetuses affected by spinal muscular atrophy.

Fetuses with degenerative neurological disorders or metabolic diseases rarely exhibit sonographic abnormalities. As a result, prenatal diagnosis, when available, requires invasive testing. Prenatal diagnosis of spinal muscular atrophy (SMA) can be made by testing chorionic villi or amniocytes. Indirect genotype analysis by use of single- and multi-locus polymorphic microsatellites of the region 5q11.2-q13.3 is used. We present two cases of SMA that manifested at 11 and 16 weeks' gestation by the presence of abnormal ultrasound findings. Each case also had abnormal maternal serum screening.

Chorionic Gonadotropin↗