Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes

OBJECTIVE: To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. METHODS: All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed. RESULTS: Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). CONCLUSION: Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.     

Epidemiology of macrolide and lincosamide resistance in species of staphylococci in a general hospital

During a 1-year period resistance to macrolides and lincosamides among staphylococci in a general hospital was studied. The macrolide-lincosamide resistance phenotype was found in 36.7% of coagulase-negative and in 3.7% of coagulase-positive species. Isolates showing this phenotype were more abundant from indwelling artificial devices, blood, respiratory tract and sterile fluids. The surgery and intensive care units of the hospital provided the highest proportion of such strains. Methicillin resistance was present in 13.9% of the staphylococci but no relationship between methicillin and macrolide-lincosamide resistance was observed.     

Eye-movement recording in freely moving animals

A new method is described for precise recording of eye movements in freely moving animals using Hall-effect devices. This inexpensive system, of small size and low weight, allows the analysis of horizontal and vertical components of saccadic eye movements, optokinetic nystagmus, slow tracking movements, eye vergence, etc., in unrestrained animals. A set of Hall-effect devices mounted in the skull is used to sense variations in the position of high-power miniature magnets fixed to the eye sclera. The output of the Hall-effect devices is amplified by operational amplifiers and collected through an analog-to-digital converter to be displayed on-line in a personal computer and stored for later analysis by specific software. Some examples of simultaneous body- and eye-movement recordings obtained in freely moving goldfish in different experimental situations are presented. This method would be useful in the recording of eye and gaze movements under natural conditions and for behavioural studies in freely moving animals.     

Anion exchanger 2 is critical for CD8+ T cells to maintain pHi homeostasis and modulate immune responses

Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pH_i). Subsequent pH_i regulation may involve HCO₃^? extrusion through Cl^?/HCO₃^? exchangers and/or Na⁺‐HCO₃^? co‐transporters with acid‐loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8⁺ T‐cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na⁺‐independent Cl^?/HCO₃^? anion‐exchange activity). Here we report that CD8⁺ T cells but not CD4⁺ T cells or other lymphocyte populations, are crucially dependent on Ae2 for pH_i regulation. While total lymphocytes (including isolated CD4⁺ T cells) exhibit Ae1 expression and Na⁺‐HCO₃^? co‐transport with acidifying potential, CD8⁺ T cells lack these acid‐loading mechanisms. In Ae2‐KO mice, CD4⁺ but not CD8⁺ T cells upregulate these potential Ae2 surrogates. As a consequence, Ae2‐KO CD8⁺ T cells exhibit alkalinized pH_i, and dramatically increase their pH_i upon CD3 stimulation. Moreover, stimulated Ae2‐deficient CD8⁺ T cells show enhanced intracellular production of IL‐2 and membrane expression of its receptor IL‐2Rα, together with increased cell proliferation and activation. These findings demonstrate that CD8⁺ T cells are critically dependent on Ae2 for pH_i homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8⁺ T‐cell responses.     

Selective tolerization of Th1-like cells after nasal administration of a cholera toxoid-LACK conjugate

Recent reports have suggested that after infection of BALB/c mice with Leishmania major, CD4+ T cells responding to a single antigen, LACK (Leishmaniahomologue of receptors for activated C kinase), drive the differentiation of other responding T cells to the Th2 phenotype and so allow lesion development to occur. Transgenic mice expressing LACK in the thymus are tolerant to LACK and thus resolve infection with L. major. The oral administration of soluble protein to mice has been shown to result in the peripheral tolerance of antigen-specific CD4+ T cells. We therefore sought to tolerize LACK reactive T cells in non-transgenic BALB/c mice in order to determine the effectiveness of this tolerization approach as an alternative to standard vaccination protocols againist L. majorinfection. Surprisingly, oral or nasal administration of up to 8 mg of recombinant LACK did not affect the outcome of infection. We therefore conjugated LACK to cholera toxin β subunit (CTB-LACK) which has previously been shown to improve the effectiveness of oral tolerance to conjugated antigens. Nasal administration of as little as 12 μg of CTB-LACK effectively diminished the capacity of mice to mount a subsequent proliferative response to LACK and further delayed the onset of lesion development in infected mice. However, pretreatment with CTB-LACK did not prevent the eventual onset and progression of disease in these mice. An examination of cytokine responsiveness to LACK after tolerization with CTB-LACK revealed that while the Th1 response to LACK was suppressed, Th2 cytokine production was unaffected. Similar experiments using an ovalbumin-CTB conjugate suggested that this selective tolerance of Th1 cells was not specific to the LACK protein but may be an effect common to CTB-conjugated proteins.     

Region-specific activation of microglial cells in the rat septal complex following fimbria-fornix transection

Studies of postlesional microglial activation may gain insight into microglia/neuronal interactions in processes of neurodegeneration. We compared the microglial response after axotomy of septohippocampal projection neurons with that seen after selective immunolesioning of cholinergic septohippocampal neurons with the immunotoxin 192 IgG-saporin. Using the microglial marker isolectin B₄ from Griffonia simplicifolia (GSA I-B₄), we found striking differences in the microglial response between these two lesion paradigms. Following axotomy of septohippocampal neurons by fimbria-fornix transection (ff-t), there was only a moderate and short-lasting microglial reaction in the medial septum (MS) in the early postlesion period. Prelabeling of septohippocampal neurons with Fluoro-Gold (FG) prior to axotomy revealed the survival of most neurons, and only very rarely were microglial cells observed that had phagocytosed FG-labeled debris. In the lateral septum (LS) containing the degenerating terminals of hippocamposeptal fibers transected by ff-t, a heavy reaction of lectin-labeled activated microglial cells associated with high phagocytotic activity was noticed. Unexpectedly, after a long survival time (6 months) following ff-t, we observed an increase in microglial GSA I-B₄ labeling in the MS. In contrast, an inverse pattern of the microglial response, i.e., a strong initial reaction in the MS and very little microglial activation in the LS, was observed after immunolesioning. Our results indicate that the microglial reaction in the MS following ff-t differs substantially from that seen in other models of axotomy. J. Comp. Neurol. 390:481–496, 1998. © 1998 Wiley-Liss, Inc.     

Effects of glutamic acid and related agents on horizontal cells in a marine teleost retina

Excitatory amino acids (EAAs) such as glutamic and aspartic acids, considered as the most likely neurotransmitters at the photoreceptor-horizontal cell synapse of teleost retinas, as well as agonists such as kainic acid and several of their antagonists, were applied to isolated and superfused retinas of the teleost Eugerres plumieri. Intracellular recordings from horizontal cells reveal that EAA receptors are of the kainate-quisqualate type. There is competitive inhibition between the agonist and anatogonist agents used, and under their combined effect, the synapse under study remains operational, in a functional state, able to modulate the horizontal cell membrane potential upon retinal illumination. © 1996 Wiley-Liss, Inc.     

The outcome of bacterial arthritis. A prospective community-based study

Objective. To assess the outcome and adverse prognostic factors of bacterial arthritis (BA). Methods. In a prospective community survey of BA, data were collected at the time of diagnosis and at a mean of 2 years later. A poor patient outcome was defined as death due to BA or severe overall functional deterioration. A poor joint outcome was defined as amputation, arthrodesis, prosthetic surgery, or severe functional deterioration. Possible prognostic factors were analyzed by univariate analysis. Results. BA was diagnosed in 154 patients, 121 adults and 33 children. One-half of the adults had a preexisting joint disease and 29% of the infected joints contained synthetic material. The patient outcome was poor in 21% of all patients, and the joint outcome was poor in 33% of the surviving patients. Adverse prognostic factors were an older age, preexisting joint disease, and an infected joint containing synthetic material. These factors were interrelated. There was no association between a poor outcome and young age, comorbidity, immunosuppressive medication, functional class, multiple infected joints, type of microorganism, or treatment delay. Conclusion. BA had a poor outcome in almost one-half of the patients. Patients who were older, had a preexisting joint disease, and/or had an infected joint containing synthetic material had the poorest prognosis.