A novel Asp380Ala mutation in the GLC1A/myocilin gene in a family with juvenile onset primary open angle glaucoma

Glaucoma describes a clinically and genetically heterogeneous group of diseases that result in optic neuropathy and progressive loss of visual fields. A gene for juvenile onset primary open angle glaucoma JOAG) has recently been mapped to 1q21-31. Mutations in the trabecular meshwork induced glucocorticoid response gene (TIGR, also known as myocilin or the GLC1A locus) have been found to cause both juvenile and later onset primary open angle glaucoma. Family TCD-POAG1 is a Spanish kindred, which segregates JOAG in an autosomal dominant fashion. This family was found to be linked to the previously identified GLC1A locus on chromosome 1q. Direct sequencing of the TIGR/myocilin gene showed a heterozygous A to C transition in codon 380, resulting in the substitution of alanine for aspartic acid (Asp380Ala). This substitution created a StyI restriction site, which segregated with the JOAG phenotype and permitted rapid screening of all members of the family. This restriction site was not present in 60 controls.     

Sequence effects, health profiles, and the QALY model: in search of realistic modeling

In limbs with combined shortening with angulation or malrotation, deformity may be quickly or slowly corrected before lengthening with external fixation. We examined a series of 35 patients with 40 limbs that underwent acute deformity correction and subsequent gradual lengthening. The average deformity corrected was 19 degrees, with subsequent average lengthening of 4.1 cm. Good radiographic callus formation was noted in 34 of the 40 segments studied. The magnitude of deformity correction had no effect on the quality of lengthened bone, incidence of complications, or the healing index. Skeletally mature segments had statistically significant decreased bone formation (p = 0.001), increased prevalence of callus complications (p = 0.001), and a higher healing index (p = 0.003). Based on this experience, it is our conclusion that immediate correction and lengthening is suitable in children and adolescents who have malaligned and shortened lower extremities. Because of poorer results in older patients, we believe that other techniques should be considered in adults.     

Communication in general practice: recognition and treatment of mental illness

The scope of the present review is to describe epidemiology, classification, symptomatology and treatment of diabetic peripheral somatic neuropathy and autonomic neuropathy. Special attention is paid to the use of local anaesthetic agents in painful diabetic neuropathy. Denervation hypersensitivity is a characteristic of autonomic neuropathy in diabetic patients. The pathophysiology behind this phenomenon is elucidated in this review and most recent studies related to diabetic encephalopathy are reviewed. References for this review were acquired via a MedLine and MedLars literature search.     

Rat group I metabotropic glutamate receptors inhibit neuronal Ca2+ channels via multiple signal transduction pathways in HEK 293 cells

We have shown previously that metabotropic glutamate receptors with group I-like pharmacology couple to N-type and P/Q-type calcium channels in acutely isolated cortical neurons using G proteins most likely belonging to the Gi/Go subclass. To better understand the potential mechanisms forming the basis for group I mGluR modulation of voltage-gated calcium channels in the CNS, we have examined the ability of specific mGluRs to couple to neuronal N-type (alpha1B-1/alpha2delta/beta1b) and P/Q-type (alpha1A-2/alpha2delta/beta1b) voltage-gated calcium channels in an HEK 293 heterologous expression system. Using the whole cell patch-clamp technique where intracellular calcium is buffered to low levels, we have shown that group I receptors inhibit both N-type and P/Q-type calcium channels in a voltage-dependent fashion. Similar to our observations in cortical neurons, this voltage-dependent inhibition is mediated almost entirely by N-ethylmaleimide (NEM)-sensitive heterotrimeric G proteins, strongly suggesting that these receptors can use Gi/Go-like G proteins to couple to N-type and P/Q-type calcium channels. However, inconsistent with the apparent NEM sensitivity of group I modulation of calcium channels, modulation of N-type channels in group I mGluR-expressing cells was only partially sensitive to pertussis toxin (PTX), indicating the potential involvement of both PTX-sensitive and -resistant G proteins. The PTX-resistant modulation was voltage dependent and entirely resistant to NEM and cholera toxin. A time course of treatment with PTX revealed that this toxin caused group I receptors to slowly shift from using a primarily NEM-sensitive G protein to using a NEM-resistant form. The PTX-induced switch from NEM-sensitive to -resistant modulation was also dependent on protein synthesis, indicating some reliance on active cellular processes. In addition to these voltage-dependent pathways, perforated patch recordings on group I mGluR-expressing cells indicate that another slowly developing, calcium-dependent form of modulation for N-type channels may be seen when intracellular calcium is not highly buffered. We conclude that group I mGluRs can modulate neuronal Ca2+ channels using a variety of signal transduction pathways and propose that the relative contributions of different pathways may exemplify the diversity of responses mediated by these receptors in the CNS.     

Human group C rotavirus in children with diarrhea in the Federal District, Brazil

BACKGROUND: A family history of atopy is a poor predictor of sensitization to inhalant allergens and allergic disease during childhood. We recently identified early sensitization to food allergens, especially hen's egg, as a valuable predictor of subsequent sensitization to inhalant allergens. OBJECTIVE: (1) Whether prediction will be improved by in vitro allergy tests at 1 year of age in combination with family history and medical history data. (2) Comparison with the capacities of in vitro tests to predict sensitization to aeroallergens. METHODS: Of an observational birth cohort study (MAS) 49 children who were sensitized to inhalant allergens at 5 years of age and 116 non-sensitized controls were included in the present study. For the prediction of sensitization to inhalant allergens the following prognostic factors were evaluated: atopic family history (FH), atopic dermatitis (AD) during the first year of life, two in vitro allergy tests for specific IgE to common food allergens at 1 year of age (fx5 [Pharmacia] and single allergen specific tests (sIgE) for four allergens) and 'high' total serum IgE, defined by three different cut off points. RESULTS: The combination of medical history data and laboratory tests resulted in the best predictive discrimination. The positive predictive values (PPV) were higher if sensitization to food was detected by single allergen specific tests (PPV: 66%/75%/100% corresponding to the three evaluated risk groups) than by the qualitative fx5 (PPV: 46%/65%/100%). The negative predictive values were equal for both tests (69 and 92% for the two low risk groups). High total serum IgE had low predictive capacity. CONCLUSION: During infancy the prediction of sensitization to inhalant allergens should be based on medical history data and allergy tests determining sensitization to food allergens. The in vitro tests improve the predictive discrimination, but the individual risk profile of the child must be considered for a reliable and valid prediction.     

Coma in fulminant pneumococcal meningitis: new MRI observations

We report a 45-year-old man with fulminant pneumococcal meningitis. Fluid attenuated inverse ratio MR images showed the ravaging consequences of occlusive vasculopathy and a transient purulent basal exudate. Bilateral thalamic lesions may have explained the failure to awaken despite appropriate antibiotic therapy.     

Selection dynamics in autocatalytic systems: templates replicating through binary ligation

The theory of autocatalytic binary ligation is reviewed within the context of a consistently applied Michaelis-Menten quasi-steady-state approximation to obtain explicit analytical results describing time-course data from experiments. A detailed protocol for the step-wise elucidation of a minimal set of experimental parameters is outlined. The kinetic equations are then generalized to cases of self- and cross-catalysis among an arbitrary number of different templates and applied to experiments involving just two templates. Depending on the values of various kinetic parameters such systems can display exclusionary Darwinian selection corresponding to an exponential growth law, selective coexistence or coexistence of all species characteristic of a parabolic growth law; the intermediate behaviour arises as a property of the full mechanism analysed here. Our results are applicable to the classical case of self-replicating nucleic acids and their analogues as well as to newly discovered self-replicating peptides.     

Factors involved in presentation of older people with thick melanoma

OBJECTIVE: To examine whether presentation of older people with thick melanoma is a result of the site and histological type or of their reduced ability to identify melanoma. DESIGN AND SETTING: Retrospective analysis of the Newcastle Melanoma Unit patient database. PATIENTS: 2154 patients with melanoma for whom complete data (histological type, thickness and site of melanoma) were available and who presented from February 1981 to April 1997. MAIN OUTCOME MEASURES: Histological type and site of melanoma in older (> or = 50 years) versus younger men and women; frequency with which these groups identified melanoma and the first changes of melanoma that were noticed. RESULTS: Patients aged > or = 50 years, particularly men, were more likely to present with thicker lesions. Older men and, to a lesser extent, older women were more likely to present with nodular melanoma, which were more frequent on the scalp and face in older, compared with younger, men, and scalp and back in older men compared with older women. Failure to identify melanoma was associated with older age, sites on the scalp and back and histological type of the lesion, but was independent of sex once histological type, age, site and thickness were taken into account. Multivariate analysis indicated that the association of older age of patients with failure to identify melanoma applied irrespective of the site, type and thickness of their melanoma. CONCLUSION: The higher frequency of thick melanoma in older people is accounted for by an increased proportion of nodular melanoma and decreased ability to recognise the changes of melanoma. These findings have important implications for examination of older patients by doctors and for design of strategies for early detection of melanoma in this age group.     

Intravenous electron-beam computed tomographic coronary angiography for segmental analysis of coronary artery stenoses

OBJECTIVES: We sought to identify and localize significant coronary stenoses on a segmental basis by electron-beam computed tomography (EBCT) and intravenous administration of a contrast agent. BACKGROUND: The clinical applicability and limitations of intravenous EBCT coronary angiography have not been defined. METHODS: EBCT was performed within 24 h of selective coronary angiography (SCA) in 28 patients (19 men and 9 women, mean [+/-SD] age 60 +/- 10 years). After examination for coronary calcium, EBCT coronary angiography was performed using overlapping slices (in-plane resolution 0.34 to 0.41 mm) with a nominal slice thickness of 1 mm. Based on quantitative analysis of SCA, lumen diameter narrowing > or = 50% (i.e., significant stenoses) was evaluated in 8 (major) or 12 (including side branches) coronary artery segments, using both two-dimensional (tomographic) and three-dimensional (volume) data sets. RESULTS: Of the 330 segments assessable by SCA, 237 (72%) were visualized by EBCT. The sensitivity (+/-SE) for detection of significant stenoses was 82 +/- 6%; specificity was 88 +/- 2%; positive and negative predictive values were 57 +/- 7% and 96 +/- 2%, respectively; and overall accuracy was 87 +/- 2%. If only eight (major) coronary artery segments were considered, 194 (88%) of 221 segments were visualized, and the overall accuracy was 90 +/- 2%. Seven (18%) of 38 significantly stenotic segments were classified as having < 50% stenoses by EBCT. Six of these segments (86%), but only 9 (29%) of the 31 correctly classified stenotic segments, were severely calcified (area > 20 mm2, p = 0.02). In 23 (12%) of 199 nonstenotic segments falsely classified as having > or = 50% stenosis by EBCT, the lumen diameter was significantly smaller than that of the segments correctly classified as negative (mean [+/-SD] 1.5 +/- 0.8 vs. 2.9 +/- 1.1 mm, p < 0.001). CONCLUSIONS: Intravenous EBCT coronary angiography allows for accurate segmental evaluation of significant disease in the major coronary arteries and may be of value for ruling out significant disease. The main determinant of false negative results is substantial segmental calcification, whereas the main determinant of false positive results is small vessel size.