Benign Intracranial Hypertension following Corticosteroid Withdrawal in Childhood

In an 18-month period seven children who were treated for a variety of neurological and non-neurological diseases, and in whom the corticosteroid or corticotrophin dosage was reduced, developed a syndrome indistinguishable from “benign intracranial hypertension.” The total duration and rate of reduction of corticosteroid dosage and perhaps an underlying susceptibility to cerebral oedema appear to be important factors in this syndrome. Usually patients can be treated without the need for special neuroradiological studies. Possibly mild forms of this condition are not uncommon, but its pathogenesis is still uncertain.     

Insulin binding to liver plasm membranes in the obese hyperglycemic (ob/ob) mouse. Demonstration of a decreased number of functionally normal receptors.

In previous studies, the insulin resistance of the obese hyperglycemic mouse (ob/ob) was found to be associated with decreased insulin binding to liver, fat, and lymphocytes. The present study demonstrates that the insulin receptors in the liver membranes of the ob/ob mouse are decreased in number, but are indistinguishable from normal by other criteria including affinity, kinetics of association and dissociation, temperature dependence of binding, and biological specificity of the binding reaction. The receptor in liver membranes of the ob/ob mouse is also indistinguishable with respect to insulin receptor site-site interactions. Degradation of both insulin and of receptor sites was studied and did not account for differences observed in binding. We conclude that the insulin receptor from the ob/ob mouse is a functionally normal receptor and that its presence in diminished number accounts for the observed decrease in insulin binding to liver plasma membranes.     

Shade as a thermoregulatory resource for captive chimpanzees

In nature, the thermoregulatory strategies of species have evolved in response to the environmental conditions in which they live. Primates display extensive behavioural flexibility but few have examined the role of this behavioural flexibility with regard to thermoregulation. Chimpanzees, under free-living conditions, utilise natural vertical light/thermal gradients in rainforest canopies as a means of thermoregulation, moving along the gradient to maintain homoeostasis. In contrast, captive chimpanzees are often housed at latitudes outside their natural range under conditions that do not allow for this natural behavioural thermoregulation. We investigated the use of shade by captive chimpanzees as a behavioural thermoregulatory strategy at the Johannesburg Zoo, South Africa. We performed behavioural observations over the austral winter/spring period on a group of captive chimpanzees recording their behaviour in relation to shade use. Despite experiencing temperatures in Johannesburg below or just within their thermoneutral zone, chimpanzees consistently spent more time in shade than in direct sun. This pattern of shade use was most pronounced for the hotter midday period than for other times, was not dependent on the overall availability of shade within the enclosure and was not predicted by mean daily or hourly temperatures nor thermal maxima or minima. Instead, ultraviolet radiation and humidity levels appear to predict the observed patterns of shade utilisation and these findings suggest that chimpanzees in captivity adopt a sun-avoidance strategy, possibly as a result of the rapid heat gain associated with their dark skin and pelage. The findings suggest that chimpanzees are flexible when responding to the thermal challenges associated with housing outside of their natural environment.     

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ K_i,app/PI3Kα K_i,app = 57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.     

Lasting effects of maternal behaviour on the distribution of a dispersive stream insect

1. Predicting population dynamics at large spatial scales requires integrating information about spatial distribution patterns, inter-patch movement rates and within-patch processes. Advective dispersal of aquatic species by water movement is considered paramount to understanding their population dynamics. Rivers are model advective systems, and the larvae of baetid mayflies are considered quintessential dispersers. Egg laying of baetids along channels is patchy and reflects the distribution of oviposition sites, but larvae are assumed to drift frequently and far, thereby erasing patterns created during oviposition. Dispersal kernels are often overestimated, however, and empirical tests of such assumptions are warranted because of the pivotal role distribution patterns can have on populations. 2. We tested empirically whether the egg distribution patterns arising from oviposition behaviours persisted and were reflected in the distribution patterns of larval Baetis rhodani. In field surveys, we tested for associations between egg mass and larval densities over 1 km lengths of four streams. A control species, the mayfly Ephemerella ignita, was employed to test for covarying environmental factors. We estimated drift rates directly to test whether larvae dispersed between riffles (patches of high egg mass density) and whether drift rates were density-dependent or density-related - expected outcomes if drift erases patterns established by maternal behaviours. 3. Positive associations between egg masses and larval benthic densities were found for neonate and mid-stage larvae of Baetis, but not the control species, suggesting persistence of the patchy distribution patterns established at oviposition. Drift rates were high, and riffles were net exporters of neonate and mid-stage larvae, but drift rates were unrelated to benthic densities and few drifters reached the next riffle. Riffles were sinks for large larvae, suggesting ontogenetic shifts in habitat use, but little long-distance dispersal. 4. Overall, the results suggest that most neonate and mid-stage larvae of B. rhodani remain close to the natal riffle, and late-stage larvae disperse shorter distances than routinely assumed. The persistence of maternal effects on distribution patterns well into juvenile life of an allegedly iconic disperser suggests that traditional models of how dispersal influences the population dynamics of many lotic invertebrates may be incorrect.     

Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a highly conserved sequence

The dengue viruses (DENVs) exist as numerous genetic strains that are grouped into four antigenically distinct serotypes. DENV strains from each serotype can cause severe disease and threaten public health in tropical and subtropical regions worldwide. No licensed antiviral agent to treat DENV infections is currently available, and there is an acute need for the development of novel therapeutics. We found that a synthetic small interfering RNA (siRNA) (DC-3) targeting the highly conserved 5' cyclization sequence (5'CS) region of the DENV genome reduced, by more than 100-fold, the titers of representative strains from each DENV serotype in vitro. To determine if DC-3 siRNA could inhibit DENV in vivo, an "in vivo-ready" version of DC-3 was synthesized and tested against DENV-2 by using a mouse model of antibody-dependent enhancement of infection (ADE)-induced disease. Compared with the rapid weight loss and 5-day average survival time of the control groups, mice receiving the DC-3 siRNA had an average survival time of 15 days and showed little weight loss for approximately 12 days. DC-3-treated mice also contained significantly less virus than control groups in several tissues at various time points postinfection. These results suggest that exogenously introduced siRNA combined with the endogenous RNA interference processing machinery has the capacity to prevent severe dengue disease. Overall, the data indicate that DC-3 siRNA represents a useful research reagent and has potential as a novel approach to therapeutic intervention against the genetically diverse dengue viruses.