Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.     

Transverse stiffness: a method for estimation of myocardial wall stress

Determination of regional ventricular wall stress would allow quantification of both regional contractile state and its interplay with global function. Current methods for quantifying regional stress include mathematical modelling and measurements with strain gauges. Both methods are difficult to validate. We hypothesized that transverse stiffness (i.e., the ratio of indentation stress to strain as the ventricular wall is indented in the direction perpendicular to the wall) would be proportional to the stresses in the plane of the wall and could be used to estimate the latter. To test this hypothesis, 6 arterially perfused canine ventricular septa were mounted in an apparatus that could exert biaxial load in the plane of the wall. A servo system maintained the central third of the septa isometric during active contractions while the septa were paced at 30-60 pulses/min. In the center of the isometric region, a probe of 7 mm diameter indented the septa while the transverse indentation stress and strain were measured. For values of peak systolic in-plane stress from 0.56 to 2.6 g/mm2, the transverse stiffness varied from 1.2 to 11.7 g/mm2 and was linearly related to the in-plane wall stress in each septum (p less than 0.001, ANOVA). After cardioplegia, the transverse stiffness also correlated with passively applied wall stress for each dog (p less than 0.001). The slopes of the individual relations between transverse stiffness and wall stress from active contractions were similar to those from passively applied stress (mean +/- SEM; 1.82 +/- 0.36 versus 1.45 +/- 0.31, NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Making a working clinical diagnosis of HIV infection in infants in Zimbabwe

Objectives Clinical algorithms can be helpful in decisions about treatment and feeding options in infancy, but have had limited exposure to real data. This analysis uses data from a large clinical trial to test such algorithms, and thereby develop a successor which performs usefully in poor countries with high HIV‐prevalence. Methods The ZVITAMBO trial followed 14 110 mother‐baby pairs through infancy. 32% of mothers were HIV‐positive. Infants were HIV tested regularly using DNA PCR. Clinical signs were evaluated in terms of identifying HIV‐infection at 6 weeks, 6 and 12 months, using Zimbabwean, South African, and WHO generic adaptations of the WHO integrated management of childhood illness HIV algorithm. A modification, in which HIV‐exposed infants are first divided into being at least or less than median weight‐for‐age, was derived and evaluated. Results At 6 weeks 65% of all infected babies are less than median weight‐for‐age. Adding at least two clinical signs reduces sensitivity to 20% but those identified are 1.5 (95% CI 1.1–2.1) times more likely to die by 6 months than other infected infants. At 6 months, 86% of uninfected babies of HIV‐infected mothers can be identified by selecting those whose weight is greater than median or, if less than median, who exhibit <2 clinical signs. Conclusions In poor settings a simple clinical algorithm can identify children with probable HIV infection, especially those at risk of early death, who can then be referred for further testing and care, including highly active antiretroviral therapy. Most infants who are HIV‐uninfected can be identified at 6 months and provided with support to maintain infection‐free survival, including focussed infant‐feeding counselling.     

The time course of metonymic language text processing by older and younger adults

The influence of aging on the processing of figurative language was investigated by utilizing Frisson and Pickering's (Journal of Experimental Psychology: Learning, Memory, and Cognition, 25, 1366-1383, 1999) paradigm, monitoring eye fixation times to target words in sentences. First fixation times and total fixation times were analyzed for familiar and unfamiliar metonymies and literal control sentences. Frisson and Pickering found that processing figurative and literal expressions yielded similar patterns of eye fixations. In the current study, these methods and results were replicated and extended to include older adults' processing of metonymies. This investigation replicated their findings for young adults and found that older adults produced the same processing patterns as the younger adults.