Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: Importance in the control of blood pressure and hypertension.

In this review, we discuss genetic evidence supporting Guyton's hypothesis stating that blood pressure control is critically depending on fluid handling by the kidney. The review is focused on the genetic dissection of sodium and potassium transport in the distal nephron and the collecting duct that are the most important sites for the control of sodium and potassium balance by aldosterone and angiotensin II. Thanks to the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, three main classes of diuretic receptors (furosemide, thiazide, amiloride) and the main components of the aldosterone- and angiotensin-dependent signaling pathways were molecularly identified over the past 20years. This will allow to design rational strategies for the treatment of hypertension and for the development of the next generation of diuretics.

Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue.

Through analysis of mice with spatially and temporally restricted inactivation of Lpin1, we characterized its cell autonomous function in both white (WAT) and brown (BAT) adipocyte development and maintenance. We observed that the lipin 1 inactivation in adipocytes of aP2(Cre/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice resulted in lipodystrophy and the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice led to their replacement by newly formed Lpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formed Lpin1-positive adipocytes in aP2(Cre-ERT2/+)/Lp(fEx2)(-)(3/fEx2)(-)(3) mice protected these animals against WAT inflammation and hepatic steatosis induced by a high-fat diet. Loss of lipin 1 also affected BAT development and function, as revealed by histological changes, defects in the expression of peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, and UCP1, and functionally by altered cold sensitivity. Finally, our data indicate that phosphatidic acid, which accumulates in WAT of animals lacking lipin 1 function, specifically inhibits differentiation of preadipocytes. Together, these observations firmly demonstrate a cell autonomous role of lipin 1 in WAT and BAT biology and indicate its potential as a therapeutical target for the treatment of obesity.

Universality class of fiber bundles with strong heterogeneities

We study the effect of strong heterogeneities on the fracture of disordered materials using a fiber bundle model. The bundle is composed of two subsets of fibers, i.e. a fraction 0 ≤ α ≤ 1 of fibers is unbreakable, while the remaining 1 - α fraction is characterized by a distribution of breaking thresholds. Assuming global load sharing, we show analytically that there exists a critical fraction of the components αc which separates two qualitatively diferent regimes of the system: below αc the burst size distribution is a power law with the usual exponent Ƭ= 5/2, while above αc the exponent switches to a lower value Ƭ = 9/4 and a cutoff function occurs with a diverging characteristic size. Analyzing the macroscopic response of the system we demonstrate that the transition is conditioned to disorder distributions where the constitutive curve has a single maximum and an inflexion point defining a novel universality class of breakdown phenomena

Avalanche dynamics of fiber bundle models

We present a detailed analytical and numerical study of the avalanche distributions of the continuous damage fiber bundle model CDFBM . Linearly elastic fibers undergo a series of partial failure events which give rise to a gradual degradation of their stiffness. We show that the model reproduces a wide range of mechanical behaviors. We find that macroscopic hardening and plastic responses are characterized by avalanche distributions, which exhibit an algebraic decay with exponents between 5/2 and 2 different from those observed in mean-field fiber bundle models. We also derive analytically the phase diagram of a family of CDFBM which covers a large variety of potential avalanche size distributions. Our results provide a unified view of the statistics of breaking avalanches in fiber bundle models

Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection.

Principal mechanisms of resistance to azole antifungals include the upregulation of multidrug transporters and the modification of the target enzyme, a cytochrome P450 (Erg11) involved in the 14alpha-demethylation of ergosterol. These mechanisms are often combined in azole-resistant Candida albicans isolates recovered from patients. However, the precise contributions of individual mechanisms to C. albicans resistance to specific azoles have been difficult to establish because of the technical difficulties in the genetic manipulation of this diploid species. Recent advances have made genetic manipulations easier, and we therefore undertook the genetic dissection of resistance mechanisms in an azole-resistant clinical isolate. This isolate (DSY296) upregulates the multidrug transporter genes CDR1 and CDR2 and has acquired a G464S substitution in both ERG11 alleles. In DSY296, inactivation of TAC1, a transcription factor containing a gain-of-function mutation, followed by sequential replacement of ERG11 mutant alleles with wild-type alleles, restored azole susceptibility to the levels measured for a parent azole-susceptible isolate (DSY294). These sequential genetic manipulations not only demonstrated that these two resistance mechanisms were those responsible for the development of resistance in DSY296 but also indicated that the quantitative level of resistance as measured in vitro by MIC determinations was a function of the number of genetic resistance mechanisms operating in any strain. The engineered strains were also tested for their responses to fluconazole treatment in a novel 3-day model of invasive C. albicans infection of mice. Fifty percent effective doses (ED(50)s) of fluconazole were highest for DSY296 and decreased proportionally with the sequential removal of each resistance mechanism. However, while the fold differences in ED(50) were proportional to the fold differences in MICs, their magnitude was lower than that measured in vitro and depended on the specific resistance mechanism operating.

A case of dissection of intracranial cerebral arteries with segmental mediolytic "arteritis".

The intravital diagnosis of intracranial arterial dissection is not always possible due to atypic and non-specific clinical and radiological presentations. The postmortem pathological examination of cerebral blood vessels is therefore necessary to establish or confirm the presence of a dissecting aneurysm of intracranial arteries. Most of the described cases showed no significant underlying vascular pathology. Here we present the case of a 24-year-old women who died 5 days after admission to the hospital for a rapidly developing right-sided hemisyndrome. Neuroradiological examination had revealed ill-defined bifrontal hypodense lesions and angiographic findings were compatible with a dissection of the left extracranial internal carotid artery with embolic subocclusion of both anterior cerebral arteries. The pathological evaluation ruled out a thromboembolic occlusion of cerebral arteries and an extracranial internal carotid artery dissection but showed an extended dissecting process of variable age in the anterior circulation of the circle of Willis. The dissected vessels showed pathological changes characteristic of segmental mediolytic "arteritis" [Slavin and Gonzalez-Vitale 1976]. To our knowledge this is the first report on intracranial arteries being affected by this pathologic entity. Our case illustrates the importance of a postmortem examination of dissecting aneurysms of intracranial arteries. Careful serial section studies of dissected intracranial arteries in young subjects should be performed and may allow for a better understanding of the vascular pathology underlying the dissection processus.

Range expansion of the greater white-toothed shrew Crocidura russula in Switzerland results in local extinction of the bicoloured white-toothed shrew C-leucodon

The distribution limits of Crocidura russula (Hermann, 1780) and C. leucodon (Hermann, 1780) were investigated during an interval of 25 years in the bottom of the Rhone valley above Lake Geneva, Switzerland (total data set: 105 spatio-temporal occurrences, 1137 shrews). In 1975, the contact zone between the two species was situated in the region of Martigny. In 1999/2000, new sampling revealed three results: (1) The contact zone showed an upward shift of about 25 km. (2) In the expanded range of C. russula, the resident species has totally disappeared (confirmed by owl pellets analysis). (3) This demonstrates a dominance of C, russula over C. leucodon. Three hypotheses which may explain the range expansion of C. russula were evaluated: (1) habitat modification favouring linear dispersal due to the construction of a highway; (2) temporal event favoured by climate fluctuations, or (3) ongoing postglacial colonisation of Europe. Hypothesis 1 was rejected, because the progression of the shrews anticipated the construction. Hypothesis 3 received only weak support because range limits of C. russula in the region of Nice have been stable for thousands of years. Therefore hypothesis 2, admitting that ongoing climate change has facilitated range expansion, is the most probable.

P. W. White sur Sunbeam [500 cmc, concurrent de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57961

Prevalences of masked and white-coat hypertension in the Lausanne population: the Hercules Study

Background and Objectives: Few population-based data on the prevalences of masked and white-coat hypertension exist. We collected 24-hour ambulatory blood pressure (BP) and urine in a random subset of participants to the population-based CoLaus study. Methods: Clinic BP was measured using an Omron HEM 907 device and ambulatory BP (ABP) using a Diasys Integra device. Masked hypertension (MH) was defined as clinic BP < 140/90mm Hg and 24-hour ABP >¼135/85mmHg. White coat hypertension (WCH) was defined as clinic BP >¼ 140/90mm Hg and ABP <135/85mm Hg. Microalbuminuria was defined as present if urinary albumin excretion was > 20mg/min. Results: The 198 men and 213 women were aged (mean_SD) 56.2_10.7 and 57.2_10.3 years and had mean urinary excretion of 148_65 and 122_52 mmol/24 h for sodium and 70_24 and 5721 mmol/24 h for potassium, respectively. In men and women, the prevalences were 34.9% and 31.0% for clinic hypertension, 42.9% and 32.9% for ambulatory hypertension, 12.6% and 5.6% for MH, and 4.5% and 3.8% for WCH, respectively. The higher prevalence of MH in men was explained, in part, by higher alcohol consumption and smoking. Participants with MH tended to have higher microalbuminuria (13.5% vs 5.8%, P¼0.067). Participants with WCH had no microalbuminuria. Conclusions: In the Lausanne population aged 38 to 78 years, the prevalence of hypertension based on ABP was high, despite moderate dietary salt intake. Men had higher prevalence of MH then women. The prevalence of WCH was low and similar in men and women. MH tended to be associated with early kidney damage.

White Cane Update, Spring 1999

The White Cane Update newsletter includes information about the latest happenings at the Iowa Department for the Blind.

White Cane Update, Fall 1998

The White Cane Update newsletter includes information about the latest happenings at the Iowa Department for the Blind.

White Cane Update, Fall 2003

The White Cane Update newsletter includes information about the latest happenings at the Iowa Department for the Blind.

White Cane Update, Summer 2000

The White Cane Update newsletter includes information about the latest happenings at the Iowa Department for the Blind.