Biomedical subjects
Publications and source records attributed to J Hopkin.
A young man, engaged in a head shaking competition presented with headache, nausea and vomiting. Imaging revealed a subdural haematoma and ipsilateral arachnoid cyst. This novel mechanism of trauma underscores the predisposition to haemorrhage in patients with arachnoid cysts, even with minor trauma. Aetiology, imaging and possible treatment options are discussed.
Duchenne muscular dystrophy (DMD) results from mutations in the dystrophin gene. One-third of cases arise from point mutations, which are heterogeneous and difficult to detect. The aims of this study of dystrophin point mutation analysis were to assess its technical feasibility in a routine diagnostic laboratory, and to estimate its costs and clinical benefits. The methods used were a laboratory based study using reverse transcription-polymerase chain reaction (RT-PCR) and a protein truncation test, and a mathematical model to estimate costs and clinical benefits. None of the cases analyzed had an identifiable dystrophin deletion or duplication. They were 12 males affected with DMD and two obligate female carriers; two female carriers of known dystrophin point mutations were also analyzed. Point mutations were detected in six out of 12 males, but in none of the female carriers. Assuming a sensitivity of 50% the model predicts significant clinical benefits of point mutation analysis over linkage analysis, including a reduction in the number of prenatal diagnoses (by 0.77 per family), terminations of pregnancy (by 0.18 per family), and terminations of unaffected fetuses (by 0.16 per family). The mean cost of point mutation analysis to prevent the termination of an unaffected fetus is 6220 US dollars.
Cardiac abnormalities, cardiomyopathy and skeletal muscle weakness have been described in female carriers of the Xp21 (Duchenne and Becker) muscular dystrophies (J Neurol 1975;209(4):279-285; Br Med J 1969;2:418-420; J AmMed Assoc 1996;275(17):1335-1338; Neurology 1980;30(5):497-501; Neuromusc Disord 1999;9:347-351; Arch Neurol 1989;46:673-675). We have screened volunteers from our Xp21 genetics register and found the prevalence of previously unrecognized, clinically relevant, abnormalities in this group to be less than previously reported. We studied 91 women (56 carriers and 35 controls), aged between 18 and 69 years, from our local population known to the Oxford Regional Genetics Register. Our study included controls, with the investigators being blind to the subject's genetic status. The prevalence of previously unrecognised cardiac abnormalities on echocardiogram and ECG was 18% (10/56). Seven percent (4/56) of carriers had cardiomyopathy, defined by significant LV dilatation and decreased shortening fraction. In most cases, subjects with abnormal cardiac findings were asymptomatic. Echocardiography was more frequently abnormal than electrocardiography, but in many subjects the measurements of left ventricular dimensions were only just outside the normal ranges. The prevalence of skeletal muscle weakness was 12% (7/56). It was usually recognized by the individual, although not previously volunteered, but was mild and did not substantially affect activities of daily living.
PURPOSE: This report evaluates treatment outcomes associated with the use of Gore-Tex (GT; W.L. Gore & Associates, Flagstaff, AZ) vein graft tubing as a conduit for repair of inferior alveolar nerve (IAN) and lingual nerve (LN) continuity defects. PATIENTS AND METHODS: Six patients (5 female and 1 male) with painful dysesthesia secondary to injuries of the IAN (n = 3) or LN (n = 3) underwent surgical exploration and resection of pathologic tissue. Reconstruction of the resultant continuity defects was performed using 3-mm diameter GT tubing sutured to the epineurium of the proximal and distal nerve trunks. Nerve reconstruction was performed an average of 20 months after injury (range, 4 to 48 months). Patients were tested before and after surgery with the following tests: subjective pain level using an analogue scale, sharp stimulus, touch, cold sensation, directional sense, and 2-point discrimination. RESULTS: Four patients reported no change in subjective pain level, and 2 patients had minimal decrease in pain. Two patients reported some sensation to sharp stimulus, and 1 patient was hypersensitive. Three patients responded to touch, and 3 had no response. Four patients had no response to cold sensation, and 2 had a delayed response. Only 1 patient could detect brushstroke direction. Three patients had no response to 2-point discrimination, and 3 responded at greater than 20 mm. CONCLUSIONS: Use of GT tubing in this group of patients produced poor clinical outcomes and is not recommended for nerve reconstruction of IAN and LN continuity defects.
A genetic association study was performed with coding variants of Fc epsilon RI beta in relation to atopic and non-atopic asthma in a Japanese population (n = 400). A coding variant of Gly237Glu in exon 7 of Fc epsilon RI beta gene showed association with atopic asthma (OR = 3.00, chi 2 = 5.10, p < 0.03), but not with non-atopic asthma; this was seen particularly in childhood asthma (OR = 3.92, chi 2 = 8.66, p < 0.005). This variant is also associated with very high total serum IgE levels (> mean + 3 SD, OR = 8.56, chi 2 = 46.2, p < 0.0001), but not any allergen specific IgE. However, Leu181lle, another variant of Fc epsilon RI beta related to atopy in British and Australian populations, was not found in this Japanese population. These results suggest that variants of Fc epsilon RI beta may be an important genetic cause of the atopic asthma.
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Muscle pathology, dystrophin expression and X-inactivation patterns were studied in the muscle of five asymptomatic females heterozygous for deletions in the dystrophin gene (non-manifesting carriers) and five symptomatic carriers (manifesting carriers). Muscle from the non-manifesting carriers showed an increase in the population of centrally nucleated fibres (9.0 +/- 2.8%; controls, 1.4 +/- 0.3%), frequent fibers with abnormally interrupted dystrophin staining (38 +/- 5%), and, in sections from three individuals, small numbers of dystrophin-negative fibers (1-4%). The amount of dystrophin measured by immunoblotting was reduced to 64 +/- 5% (P < 0.001 n = 5) of normal. The pattern of X-inactivation in muscle DNA was non-biased (50: 50-60: 40) in all cases. In the manifesting carriers both highly biased (90: 10) and non-biased patterns of X-inactivation were found, but no consistent relationship was apparent between the patterns of X-inactivation and the proportions of dystrophin-negative fibers. We conclude from studies of the non-manifesting carriers that the proportion of residual dystrophin is similar to the relative activation in muscle of the X-chromosome carrying the wild-type allele. Extreme bias of X-inactivation can be associated with early clinical symptoms and severe pathology. However, as non-manifesting and some manifesting adult carriers had identical patterns of X-inactivation, abnormalities in the distribution of dystrophin, as well as overall levels of expression, may be important for the development of myopathic pathology.
Surfactant protein D (SP-D) is a lung-specific protein, synthesized and secreted by lung epithelial cells. It belongs to group III of the family of C-type lectins; each member of this group has an unusual overall structure consisting of multiple globular 'head' regions (which contain the C-type lectin domains) linked by triple-helical, collagen-like, strands. This group includes the surfactant protein A (SP-A) and the serum proteins mannan-binding protein, conglutinin and collectin-43, all of which have been shown to bind to the C1q receptor found on a wide variety of cells, including macrophages. Both SP-D and SP-A have been shown to enhance oxygen radical production by alveolar macrophages. Although this strongly suggests a direct interaction between SP-D and a specific receptor on alveolar macrophages, it is still unclear whether SP-D binds to the same receptor used by SP-A and/or C1q. Human SP-D was isolated from amniotic fluid and was radiolabelled using 125I. Alveolar macrophages were isolated from human bronchioalveolar lavage fluid, and also from bovine lung washings, by differential adhesion to 24-well tissue-culture plates. The study was carried out using EDTA-containing buffers, to eliminate Ca(2+)-dependent C-type lectin binding, and was also carried out at 4 degrees C to eliminate possible internalization by the cells. 125I-SP-D showed specific binding to alveolar macrophages in both a time- and concentration-saturable manner. The binding was inhibited, by approx. 90%, on addition of a 200-fold excess of unlabelled SP-D. The apparent dissociation constant (Kd) was (3.6 +/- 1.3) x 10(-11) M, based on the assumption that native SP-D is assembled as a dodecamer of 12 identical polypeptides of 43 kDa to yield a protein of 516 kDa. C1q was also shown to bind alveolar macrophages (Kd 3 x 10(-6) M), but addition of C1q did not show inhibition of the binding of 125I-SP-D to the macrophages. We conclude that SP-D binds specifically to alveolar macrophages and the receptor involved is different from that utilized by C1q.
In this report, levels of the 3243 A to G mtDNA mutation associated with the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome were measured in different heteroplasmic tissues of subjects in a kindred including adults with variable clinical phenotypes and a fetus. The relative proportions of mutant mtDNA varied widely (0.03 to 0.67) between identical tissues of the six different subjects and between different tissues of the same subjects. In the one adult for whom sufficient data were available there was an apparent correlation between the distribution of mutant mtDNA and clinical presentation. A woman without neurological symptoms who died prematurely with a cardiomyopathy and lactic acidosis had higher proportions of mutant in heart (0.49, SD 0.02), skeletal muscle (0.56, SD 0.01), and liver (0.55, SD 0.12) than in other tissues studied (for example, kidney, 0.03, SD 0.01). A strikingly different result was found in a 24 week old fetus in whom there was little variation in heteroplasmy in different tissues (average proportion of mutant mtDNA in six tissues, 0.53, SD 0.02). These observations add cardiomyopathy to the growing list of presenting features of the 3243 mtDNA mutation. The unique results from the fetus suggest also that selection pressures acting on either wild type or 3243 mutant mtDNA (rather than variation from replicative segregation of the heteroplasmic mtDNA) may be responsible primarily for the variable levels of 3243 mutant mtDNA in different heteroplasmic tissues of adults.
A 36 year old primigravid woman presented with a "flu-like" illness and premature labour, followed by severe pneumonitis and hepatitis in the late second trimester of pregnancy. Progressive deterioration obliged an elective delivery of twins, stillborn at 25 weeks of gestation. Herpes virus isolated from one placenta, but not from any fetal tissue, was the only indication of a systemic herpes simplex infection in which there were no mucocutaneous lesions seen before or during the illness. There was no history of herpes simplex infection and antibody studies were not helpful initially for a diagnosis that was confirmed in retrospect. Double staining for viral DNA and antigen showed that the virus was present in host monocytes.
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Four of five patients with AIDS and pulmonary infection had syncopal reactions as a result of fine-needle aspiration of the lung; in one patient the reaction was fatal. Subsequently, in one of these patients and four further patients with AIDS or human immunodeficiency virus (HIV) infection, the autonomic nervous system proved to be abnormal. This preliminary evidence suggests HIV infection may be associated with an autonomic neuropathy, which may expose these patients to particular risk after invasive procedures.
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The authors review the literature on the rapid neuroleptization (titration) method with I.M. haloperidol. Most of the approximately 650 predominantly schizophrenic and manic patients represented in the studies calmed down rapidly on medication, and some demonstrated an early reduction in core psychotic symptoms. The initial doses varied widely, ranging from 1 to 30 mg, with a maximum total daily dosage of 100 mg. The medication seemed to have been well tolerated in all cases, with no reported major complications. The authors conclude that the method shows definite merit with agitated and belligerent patients. However, they make a number of specific recommendations for further research to clearly establish the effectiveness and safety of this method of neuroleptic administration.
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1. The effects of electrical stimulation and solutions containing a high concentration of potassium on the efflux of [(14)C] glycine from slices of rat spinal cord have been studied.2. Slices of cord were incubated with [(14)C] glycine which rapidly accumulated in the tissue. The slices were then superfused in a small chamber and the radioactivity released from the tissue was measured. After superfusion for 60 min, 98% of the radioactivity remaining in the tissue was present as unchanged glycine.3. The spontaneous efflux of [(14)C] glycine consisted of an initial rapid phase followed by a much slower release of [(14)C] glycine. After superfusion for 60 min, more than 65% of the radioactivity taken up during the incubation period was retained by the tissue.4. When the slices were depolarized by electrical stimulation or by solutions containing a high concentration of potassium (40 mM), a striking increase in the efflux of [(14)C] glycine was produced. This effect was not reduced by the absence of calcium ions in the superfusion medium.5. Electrical stimulation produced similar increases in the efflux of [(3)H] GABA and [(14)C] glutamate from slices of cord but had no significant effects on the efflux of [(3)H] alanine or [(14)C] urea.6. The results are consistent with the suggestion that glycine may be an inhibitory synaptic transmitter substance in the mammalian spinal cord.