SGK1 in the kidney: disrupted sodium transport in diabetes and beyond

Renal complications of diabetes can be severe; however, the mechanisms that underlie the development and progression of diabetic nephropathy are poorly understood. Recent evidence suggests that the serum and glucocorticoid induced kinase-1 (SGK1) may be key to this process. SGK1 expression and function are increased in models of diabetes and polymorphisms of the SGK1 gene are associated with type 2 diabetes mellitus. A key regulator of sodium transport within the renal epithelium of the distal nephron, SGK1 was originally isolated as a glucocorticoid-sensitive gene that regulated the epithelial sodium channel (ENaC; known also as the sodium channel, nonvoltage-gated 1, SCNN1). It is now apparent that SGK1 modulates sodium re-absorption by a number of sodium transporters/channels throughout the length of the nephron including; the Na+/H+ exchange isoform 3 (NHE3), the Na+Cl- co-transporter (NCC) and the Na+/K+-ATPase. In addition, SGK1 is regulated by a diverse range of factors including; insulin, glucose, intracellular calcium, transforming growth factor-beta1, flow rate and osmolality. This brief review examines the evidence supporting an involvement of SGK1 in diabetic nephropathy and discusses how dysregulated sodium transport may account for the development of secondary hypertension associated with the condition. Furthermore, the article examines how aberrant SGK1 expression and activity may be responsible for the cellular changes seen in the damaged nephron

Retrospective cohort study of false alarm rates associated with a series of heart operations: the case for hospital mortality monitoring groups

OBJECTIVE: To examine the efficacy of different methods of detecting a high death rate and determining whether an increase in deaths after heart transplantation could be explained by chance. DESIGN:Retrospective analysis of deaths after heart transplantation. Seven methods were used: mortality above national average, mortality excessively above national average, test of moving average mortality, test of number of consecutive deaths, sequential probability ratio test (SPRT), cusum graph with v-mask, and CRAM chart. The national average mortality was not available and a rate of 15% was used instead as the benchmark. SETTING: Regional cardiothoracic unit. PARTICIPANTS: All 371 patients who received a heart transplant in the programme, 1986-2000. MAIN OUTCOME MEASURES: 30 day survival after transplantation. RESULTS: All methods provided evidence that the 30 day mortality had been high at some stage. The probability that the finding was a false positive depended on which test was used. At the end of the series the average mortality, sequential probability ratio, and cusum tests indicated a level of deaths higher than the benchmark while the remaining four tests yielded negative results. CONCLUSIONS:If the decision to test for outlying mortality is made retrospectively, in the light of the data, it is not possible to determine the false positive rate. Prospective on-site mortality monitoring with the CRAM chart is recommended as this method can quantify the death rate and identify periods when an audit of cases is indicated, even when data from other institutions are not available. A hospital mortality monitoring group can routinely monitor all deaths in the hospital, by specialty, using hospital episode statistics (HES) data and appropriate statistical methods

Functional expression of TRPV4 channels in human collecting duct cells: implications for secondary hypertension in diabetic nephropathy

Background. The Vanilloid subfamily of transient receptor potential (TRPV) ion channels has been widely implicated in detecting osmotic and mechanical stress. In the current study, we examine the functional expression of TRPV4 channels in cell volume regulation in cells of the human collecting duct. Methods. Western blot analysis, siRNA knockdown, and microfluorimetry were used to assess the expression and function of TRPV4 in mediating Ca2+-dependent mechanical stimulation within a novel system of the human collecting duct (HCD). Results. Native and siRNA knockdown of TRPV4 protein expression was confirmed by western blot analysis. Touch was used as a cell-directed surrogate for osmotic stress. Mechanical stimulation of HCD cells evoked a transient increase in [Ca2+]i that was dependent upon thapsigargin-sensitive store release and Ca2+ influx. At 48 hrs, high glucose and mannitol (25 mM) reduced TRPV4 expression by 54% and 24%, respectively. Similar treatment doubled SGK1 expression. Touch-evoked changes were negated following TRPV4 knockdown. Conclusion. Our data confirm expression of Ca2+-dependent TRPV4 channels in HCD cells and suggest that a loss of expression in response to high glucose attenuates the ability of the collecting duct to exhibit regulatory volume decreases, an effect that may contribute to the pathology of fluid and electrolyte imbalance as observed in diabetic nephropathy

Differential torsion theory

AbstractDifferential torsion theories are introduced and it is shown that for a hereditary torsion theory τ every derivation on an R-module M has a unique extension to its module of quotients if and only if τ is a differential torsion theory. Dually, we show that when τ is cohereditary, every derivation on M can be lifed uniquely to its module of coquotients

Stragegies for Attracting and Retaining Teachers

Attracting and retaining high quality teachers is a challenge for many school districts. This is especially true in a time of increased accountability and limited resources. This report details best practice in the training, hiring, improvement, and retention of high quality teaching staff. The authors explain how school leaders can attract quality teaching staff, provide effective new teacher induction programs, and establish procedures that will assist in retaining the best of the best teaching staff

Failures in the “Laboratories of Democracy” and Democratic Due Process as Constitutional Guardrails

In Dobbs v. Jackson Women’s Health Organization, the Supreme Court reversed decades of precedent supporting a substantive due process right to abortion under the Fourteenth Amendment, and purported to return the question of reproductive autonomy to the “democratic process” in the states. Justice Thomas, writing in concurrence, militated for reconsidering all of the Court’s substantive due process precedents. In today’s era of democratic backsliding, these are dangerous pronouncements with grave, if not existential, implications for democracy in the United States. The Dobbs majority hazardously asserted that state-level abortion legislation would, in fact, be the result of a democratic process. Further, because the law of democracy draws extensively from substantive due process, including where the Fourteenth Amendment “incorporates” textually enumerated constitutional rights against the states, the broader threat to substantive due process in the Dobbs majority opinion and Justice Thomas’s concurrence is also a direct threat to democracy itself. Although the literature on democracy and the literature on substantive due process are both individually voluminous, there is surprisingly limited scholarship focused specifically on both as interrelated topics. Building from democratic theory and John Hart Ely’s political process theory of judicial review, this Article seeks to begin elaborating on the important connections between democracy and substantive due process that help explain the legal and practical importance of each to the other. In doing so, it also attempts to lay the groundwork for an approach to substantive due process rooted in the Federal Constitution’s vision of democratic self-government for a diverse society

The immune response of the mouse to the tapeworm Hymenolepsis diminuta

Previous investigations have demonstrated that the cestode, Hymenolepis diminuta, is rejected immnologically from the mouse small intestine. This host-parasite relationship provides a model for the study of immunity to adult tapeworms which were formerly thought to be immunologically inert. The work described herein was undertaken to investigate the specific mechanisms underlying the response of the mouse to H. diminuta and to deter-mine the possible effect of the response on a physiological aspect o of the host-parasite relationship. Whole-body X-iradiation of the mouse was used extensively as a tool to deplete the immune response and induce suppression of worm rejection. Initial investigations using single cysticercoid infections of H. diminuta in random-bred mice indicated that effective suppression of worm rejection was achieved with either lethal or sublethal doses of X-irradiation. Succeeding investigations (which employed five- or six-cysticercoid infections in inbred mice to reduce variation), therefore, used only sublethal doses of irradiation to eliminate the necessity for subsequent reconstitution of the haemopoietic tissues. Growth of H. diminuta following irradiation given early in infection was found to be less than growth following irradiation given later in infection. The response inducing worm rejection was found to be biphasic with respect to radiation sensitivity; irradiation on or before day 8 post-infection effectively suppressed worm rejection, whilst irradiation on day 10 had no effect on the normal course of worm rejection . Restoration of the irradiation-depleted response was attempted using various combinations of lymphoid and bone-marrow cells, but reconstitution was not achieved using any of the cell combinations. It is suggested that X-irradiation induces a defect additional to simple depletion of small lymphoid elements and that, in particular, local antibody production in the intestine of infected mice be investigated following irradiation. The unresponsiveness of athymic nude mice and adult-thymectomised, irradiated, bone-marrow reconstituted mice to single H. diminuta infection demonstrates that the response inducing rejection of H. diminuta requires the presence of fully differentiated T cells. Total weight of worms recovered from nude mice infected with 10 cysticercoids of gr diminuta. was less than from single worm infections in nude mice, suggesting the presence of a threshold of immunological stimulation dependent on surface area of worm rather than on worm weight. The effect of intestinal inflammation, induced by Trichinella spiralis, on a concurrent infection with H. diminuta was investigated. It was demonstrated that no cross-immunity exists between the two parasites. The inflammatory response produced marked adverse effects, on H. diminuta manifested variously by reduced worm growth, destrobilation and worm rejection from both mice and rats. The severity of the effect on H. diminuta was shown to be dependent on the timing of acute inflammation with respect to development of H. diminuta. In the mouse, if severe inflammation occurred at, or shortly following the time of infection with H. diminuta then, although many H. diminuta established and survived for at least 2 days, they did not grow and the majority were subsequently expelled. If, however, H. diminuta was allowed xvi to establish for 5 or 6 clays prior to the appearance of severe inflammation, then although the worms destrobilated, most survived the inflammatory response. In the rat, growth of H. diminuta was stopped by the inflammatory response to Ta spiralis. However, when the inflammation subsided, worm growth recommenced and eventually returned to levels found in non-inflamed controls. It is suggested that future work should investigate the specific nature of this interaction and should include careful monitoring, not only of cellular and biochemical changes occurring during the inflammatory response, but also of host dietary intake during the response. Brief discussion is made of the possible sites of immune damage to H. diminuta and investigation of one such site, the transport of nutrients across the tapeworm tegument, is described. The transport of 14C-labelled glucose, acetate and methionine, which cross the tegument by separate pathways, was investigated. Transport of these substrates by worms from six-cysticercoid infections in mice was compared to transport by worms of similar weight from mice immunosuppressed with cortisone and from rats. Transport of methionine and acetate by H. diminuta from untreated mice was depressed compared to transport by worms from immunosup-pressed mice or rats. Uptake of glucose was similar, regardless of host type. The results are interpreted to demonstrate the selective blocking of membrane transport loci on the tegument of H. diminuta from mice by an immunological mediator. The thesis adds to current concepts of immune responses to adult cestodes and suggests many lines of further investigation

Higher derivations on rings and modules

Let τ be a hereditary torsion theory on Mod R and suppose that Q τ : Mod R → Mod R is the localization functor. It is shown that for all R-modules M, every higher derivation defined on M can be extended uniquely to a higher derivation defined on Q τ (M) if and only if τ is a higher differential torsion theory. It is also shown that if τ is a TTF theory and C τ : M → M is the colocalization functor, then a higher derivation defined on M can be lifted uniquely to a higher derivation defined on C τ (M)