Biomedical subjects
Publications and source records attributed to S Hall.
A-pacemaker that had been implanted correctly was found at follow-up to have "flipped over" as a result of a fall from a ladder. Symptomatic pectoral muscle stimulation ceased immediately when the generator was manually flipped back into the correct position.
Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a loss of neurones, which affects about 1 in 5000 live births. Genetic factors have been implicated in the aetiology of this disease in about 20% of cases and a dominant pattern of inheritance has been revealed in several families. The pathogenesis of the aganglionosis is often attributed to a failure of migration of neural crest cells, although this has not been proven. Recently, mutations in a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in the endothelin receptor-B gene (ENDR-B) have both been linked to familial Hirschsprung's disease in humans. Moreover, certain mutant mouse strains--namely piebald lethal and lethal spotted--exhibit striking similarities to the human condition. The mutation which gives rise to piebald lethal has now been found to be in the ENDR-B gene, and the mutation associated with lethal spotted occurs in the gene for endothelin-3 (ET-3), a ligand for ENDR-B. Two transgenic mouse lines have been developed which also reflect the human disease: ret-k-, which has a loss of function mutation of the ret gene, and ENDR-B null. In addition, the introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice has made it possible to study directly the fate of enteric neuroblasts which are affected by "Hirschsprung's-like" mutations. Here, we review the possible roles of RET and endothelin in the normal development of the enteric nervous system, and the significance of their mutated forms in the pathogenesis of familial aganglionosis. This review focuses on recent advances in our understanding of the genetic basis of the lesions which have been implicated in congenital forms of Hirschsprung's disease. Disruption of these genes in the mouse, either by transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of greater understanding of both the cellular and developmental bases of the human disease.
Single-strand conformational polymorphism analysis of the lipoprotein lipase promoter identified a T-->G transition at position -93. The frequency in healthy white men was 3.4% (n = 1575). There was an 83% allelic association between -93T-->G and Asp9-->Asn (D9N); all N9 mutations occurred on a -93G allele, but not all -93G mutations occurred on an N9 allele. It was thus possible to assess the effect on plasma triglyceride (Tg) levels of the rare -93G mutation in the presence of the wild-type D9. Carriers of the -93G, with genotype TG/DD, had significantly lower Tg levels than TT/DD individuals (1.36 versus 1.78 mmol/L, P = .01); carriers of both mutations (TG/DN) had the highest Tg levels (1.93 mmol/L). When the group was stratified above and below the sample mean for body mass index (BMI), carriers of the -93G on a D9 allele (TG/DD) were "protected" against the Tg-raising effect of obesity, as assessed by BMI. In Afro-Caribbeans (n = 91), the carrier frequency of -93G was 18-fold higher (63%), with weaker (17%) allelic association between -93G and N9. In vitro, the -93G promoter had 24% higher activity than the -93T in a rat smooth muscle cell line and 18% higher activity in a human adrenal cell line. A protein identified by band-shift assays bound to the -93G but not to the -93T allele, which may explain the lower Tg levels in -93G carriers.
Objective data are necessary for the design of clinical pathways of total hip replacement (THR) surgery. The functional recovery and timing for hospital discharge was studied in a consecutive series of 65 patients undergoing primary THR. The Modified Barthel Index (MBI) was serially measured after surgery to assess the recovery of functional independence. A MBI score of 90 out of a maximum of 100 is required before patients are fit for hospital discharge. The length of hospital stay varied from 5 days to 39 days. Fifty-eight percent of patients were fit for discharge by day 8, and 42% required 10 days or longer (mean = 14.2 days) in hospital. Patients in these two groups differed significantly with respect to age, the number of associated comorbidities, preoperative and early MBI scores, and muscle strength parameters. These data suggest that there is wide variability in patients presenting for primary THR. One single clinical pathway may not accommodate this patient variability, whereas two clinical pathways (one with a day 8 and another with an extended [day 10 +] time frame) may be more appropriate.
Previous studies have demonstrated that activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) associated with opioid and non-opioid drug withdrawal syndromes. Using an in vivo voltammetric approach, we have examined the role of nitric oxide (NO), which mediates NMDA receptor function, in this withdrawal-induced LC hyperactivity. In the anaesthetized rat, acute morphine treatment (10 micrograms, i.c.v.) suppressed (55.7 +/- 4.4% of baseline) the catechol oxidation current (CA-OC) recorded from the LC using differential normal pulse voltammetry (DNPV). A subsequent intravenous injection of naloxone (2 mg/kg, i.v.) reversed the drug-induced inhibition of LC response and produced an increase (118.9 +/- 2.3% of baseline) in CA-OC above baseline, indicative of an acute withdrawal response. Systemic (100 mg/kg) and intracerebroventricular (i.c.v.) (100 micrograms) pretreatment of animals with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) blocked the naloxone-induced LC withdrawal response without influencing the inhibitory effect of morphine on LC activity. In animals chronically infused with morphine (15 micrograms/h, i.c.v., 5 days) a naloxone challenge (2 mg/kg, i.v.) produced significant increase (253.7 +/- 19.3% of baseline) in CA-OC signal. This LC withdrawal response was significantly reduced by pretreatment with L-NAME (100 micrograms, i.c.v.) or N omega-nitro-L-arginine (L-NOARG 10 micrograms, i.c.v.). In unanaesthetized animals pretreated with chronic morphine, systemic (100 mg/kg) and central L-NAME (100 micrograms) pretreatment suppressed some of the behavioural signs of withdrawal precipitated by naloxone (10 mg/kg) injection. As doses of the NOS inhibitors used in this study have previously been reported to produce significant inhibition of brain NOS activity, their effect on opioid withdrawal response most likely is due to NOS inhibition. The results of this study indicate that NO plays an intermediary role in the LC neuronal hyperactivity associated with both acute and chronic morphine withdrawal.
We have examined the role of K+ channels in mediating vasorelaxation produced by bacterial lipopolysaccharide (LPS) in endothelial-denuded strips of rat aorta precontracted with phenylephrine (1 microM). Salmonella typhosa LPS (0.1 microgram/ml) caused significant relaxation of tension which peaked at approximately 4hr. The K+ channel blocker, tetraethylammonium chloride (TEA; 10 mM), fully reversed these relaxations whether applied before or after long term exposure to LPS. L-arginine, the substrate for nitric oxide synthase, caused large relaxations in tissues incubated with LPS that were markedly inhibited by TEA. In contrast, TEA or L-arginine had little effect on phenylephrine contractions in control tissues. Furthermore, the inducible nitric oxide synthase inhibitor, aminoguanidine (0.4 mM), reversed the effects of LPS and blocked responses to TEA. These results suggest that activation of K+ channels, possibly Ca-activated K+ channels, through induction of the nitric oxide synthase pathway, may well be responsible for endotoxin-mediated hyporeactivity to vasoconstrictor agents in vascular smooth muscle.
BACKGROUND: Studies of cocaine-dependent subjects have shown that re-exposure to environmental cues previously associated with cocaine use produces a strong conditioned response characterised by autonomic hyperarousal and increases in subjective measures of cocaine craving. METHODS: To evaluate the role of dopamine release by such cues, 20 cocaine-dependent inpatients were randomised in a single-dose, crossover, placebo-controlled design, to haloperidol (4 mg by mouth) and placebo. Plasma homovanillic acid (HVA, a dopamine metabolite), adrenocorticotropic hormone (ACTH), and cortisol were assayed before and after cue exposure. Craving and anxiety were measured before and after cues with visual analogue scales for desire to use cocaine now and for mood changes. FINDINGS: Cocaine cues significantly increased anxiety, ACTH, cortisol, and HVA. Increases in anxiety and craving resulting from cue exposure were significantly antagonised by pretreatment with haloperidol. INTERPRETATION: It has long been hypothesised that increases in extracellular concentrations of dopamine mediate the acute reinforcing effects of cocaine. Our data suggest that dopamine release may also mediate some of the conditioned responses to cocaine cues.
The performance of 53 healthy older adults (age 60-92) was examined on the Continuous Visual Memory Test (CVMT) and the Visual-Motor Integration Test (VMI). Subjects were divided into the following 3 groups: age 60-69, age 70-79, and age 80-92. Findings for the 60-69 and 80-92 age groups are considered tentative due to small sample size (n = 14 and 8 respectively). Preliminary data for the three age groups on the CVMT and the VMI are presented. On the CVMT, an unsatisfactorily large percentage of subjects were classified as impaired using the cutoffs provided in the CVMT manual, particularly on the delayed recognition measure and for all scores in the age 80-92 group. These preliminary findings suggest that the CVMT may not be an appropriate measure of nonverbal memory for older adults. The subjects' performance on the VMI suggests that this test is an adequate measure of graphomotor constructional ability in older adults and appears to be sensitive to aging effects. The VMI shows promise as an objective measure of graphomotor constructional ability in healthy older adults, and potentially, for individuals with neurological disease.
Human papillomavirus (HPV) DNA detection in cervical specimens was correlated with cytologic and histologic diagnoses for 151 women who were referred to the Johns Hopkins Hospital colposcopy clinic for evaluation of an abnormal Pap smear. HPVs were identified as "high-risk" or "low-risk" by Hybrid Capture. The final disease status was categorized as high-grade squamous intraepithelial lesion (HSIL) by histology (n = 26), low-grade squamous intra-epithelial lesion (LSIL) by histology (n = 43), equivocal [histology negative, cytology atypical squamous cells of undetermined significance (ASCUS) or higher, n = 42], and negative (both histology and cytology negative, n = 40). Thirty-five percent of disease-negative women and 84% of the women with biopsy-proven or equivocal disease were HPV-positive. Ninety-two percent of the HPV-positive women harbored high-risk HPVs, either high-risk HPVs alone (77%) or high-risk HPVs along with low-risk HPVs (15%). High-risk HPVs predominated in disease-negative as well as disease-positive women. Collection of specimens with a cytobrush was more efficient for HPV DNA detection than collection by cervicovaginal lavage. Large amounts of HPV DNA correlated with presence of HSIL or LSIL. For detection of HSIL, considering only brush samples, the sensitivities of abnormal cytology (ASCUS or higher), of high-risk HPVs, and of the two combined were, respectively, 87, 93, and 100%; the corresponding specificities were 30, 30, and 20%. HPV DNA detection may be most beneficial in populations with low HPV prevalence.
This study examined the effects and aftereffects of naturally occurring upper respiratory tract illnesses on mood and performance. Twenty-six subjects (12 males, 14 females, mean age 23 years 10 months, age range 18-39 years) were tested once a week for a period of a month. Fifteen subjects were suffering from a common cold on the first week and the other 11 subjects were matched healthy controls. Subjects attended for an initial 3-h testing period that consisted of a set of practice trials and two test sessions involving mood rating and performance of a battery of tests measuring psychomotor functions, attention, and memory. Sessions 3, 4, and 5 took place 1, 2, and 3 weeks later, respectively. In addition to measuring mood and mental performance, symptom severity was rated on a subjective checklist. The results showed that subjects with a cold reported an increase in negative mood and that this was only significant in the first week. Impairments of psychomotor function (simple reaction time and tracking) were also observed at this time. Performance of sustained and selective attention tasks was also impaired in subjects with colds but this effect was only significant in the second week. Other functions such as working and semantic memory were unimpaired in subjects with colds at any point in the experiment. Overall, the present results confirm many of the earlier results obtained in studies of experimentally induced upper respiratory tract illnesses. Indeed, these results are both of great practical importance and theoretical interest and further studies must now elucidate the mechanisms underlying these effects.
This paper is part of a study attempting to identify parental perception of support necessary to care for their child with special needs. The existing literature has been analysed, revealing a paucity of studies relating to the parents' perception. The study gathered data from questionnaires administered to 25 randomly selected parents who have children with special needs, exploring multi-disciplinary support. The other method used was conducting three semi structured interviews, with parents known to the paediatric team in the locality being studied. The health professionals input, respite care and overall level of support have been studied from the questionnaires. The interviews highlighted many areas where the paediatric community nurse could fulfil some of the parents' support needs. The response rate was 19 questionnaires returned, covering 21 children, as two families had two children with special needs. The results indicate that half the parents were satisfied with the support they received, with the main groups giving support being education and relatives, followed by health and social services.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Almost 25% of patients with T-cell acute lymphoblastic leukemia (T-ALL) have tumor-specific rearrangements of the TAL1 gene. Although TAL1 expression has not been observed in normal lymphocytes, TAL1 gene products are readily detected in leukemic cells that harbor a rearranged TAL1 allele. Hence, it has been proposed that ectopic expression of TAL1 promotes the development of T-ALL. In this report, we show that TAL1 is expressed in the leukemic cells of most patients with T-ALL, including many that do not display an apparent TAL1 gene alteration. A polymorphic dinucleotide repeat in the transcribed sequences of TAL1 was used to determine the allele specificity of TAL1 transcription in primary T-ALL cells. Monoallelic expression of TAL1 was observed in the leukemic cells of all patients (8 of 8) bearing a TAL1 gene rearrangement. In the leukemic cells of patients without detectable TAL1 rearrangements, TAL1 transcription occurred in either a monoallelic (3 of 7 patients) or a biallelic (4 of 7 patients) fashion. Thus, TAL1 activation in these patients may result from subtle alterations in cis-acting regulatory sequences (affecting expression of a single TAL1 allele) or changes in trans-acting factors that control TAL1 transcription (affecting expression of both TAL1 alleles).
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Prenatal diagnosis of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria syndrome is described by the analysis of ornithine incorporation in second-trimester cultured amniotic fluid cells. An unaffected fetus was predicted and confirmed in the newborn child. This is the third reported prenatal diagnosis for this disorder and the second predicting an unaffected fetus.