Streptozotocin, Type I Diabetes Severity and Bone

As many as 50% of adults with type I (T1) diabetes exhibit bone loss and are at increased risk for fractures. Therapeutic development to prevent bone loss and/or restore lost bone in T1 diabetic patients requires knowledge of the molecular mechanisms accounting for the bone pathology. Because cell culture models alone cannot fully address the systemic/metabolic complexity of T1 diabetes, animal models are critical. A variety of models exist including spontaneous and pharmacologically induced T1 diabetic rodents. In this paper, we discuss the streptozotocin (STZ)-induced T1 diabetic mouse model and examine dose-dependent effects on disease severity and bone. Five daily injections of either 40 or 60 mg/kg STZ induce bone pathologies similar to spontaneously diabetic mouse and rat models and to human T1 diabetic bone pathology. Specifically, bone volume, mineral apposition rate, and osteocalcin serum and tibia messenger RNA levels are decreased. In contrast, bone marrow adiposity and aP2 expression are increased with either dose. However, high-dose STZ caused a more rapid elevation of blood glucose levels and a greater magnitude of change in body mass, fat pad mass, and bone gene expression (osteocalcin, aP2). An increase in cathepsin K and in the ratio of RANKL/OPG was noted in high-dose STZ mice, suggesting the possibility that severe diabetes could increase osteoclast activity, something not seen with lower doses. This may contribute to some of the disparity between existing studies regarding the role of osteoclasts in diabetic bone pathology. Examination of kidney and liver toxicity indicate that the high STZ dose causes some liver inflammation. In summary, the multiple low-dose STZ mouse model exhibits a similar bone phenotype to spontaneous models, has low toxicity, and serves as a useful tool for examining mechanisms of T1 diabetic bone loss

Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection

Ischemic tolerance defines transient resistance to lethal ischemia gained by a prior sublethal noxious stimulus (i.e., preconditioning). This adaptive response is thought to be an evolutionarily conserved defense mechanism, observed in a wide variety of species. Preconditioning confers ischemic tolerance if not in all, in most organ systems, including the heart, kidney, liver, and small intestine. Since the first landmark experimental demonstration of ischemic tolerance in the gerbil brain in early 1990's, basic scientific knowledge on the mechanisms of cerebral ischemic tolerance increased substantially. Various noxious stimuli can precondition the brain, presumably through a common mechanism, genomic reprogramming. Ischemic tolerance occurs in two temporally distinct windows. Early tolerance can be achieved within minutes, but wanes also rapidly, within hours. Delayed tolerance develops in hours and lasts for days. The main mechanism involved in early tolerance is adaptation of membrane receptors, whereas gene activation with subsequent de novo protein synthesis dominates delayed tolerance. Ischemic preconditioning is associated with robust cerebroprotection in animals. In humans, transient ischemic attacks may be the clinical correlate of preconditioning leading to ischemic tolerance. Mimicking the mechanisms of this unique endogenous protection process is therefore a potential strategy for stroke prevention. Perhaps new remedies for stroke are very close, right in our cells

The re-entry of disordered phases in a crystalline polymer poly-4-methyl-pentene-1

In situ x-ray expts. are reported on a cryst. polymer, poly(4-methylpentene-1) (I) as a function of pressure (P) and temp. (T) carried out under isothermal and isobaric conditions. At room temp., when the cryst. tetragonal phase (Ct) of I is subjected to pressure, it passes through a range of mesomorphic phases leading to complete amorphization. The melting temp. (Tm) gradually increases with P up to 3Kb where the trend reverses on further increase in P leading to a decrease in Tm. This, combined with the pressure-induced amorphization at room temp. raises the possibility of reentrant of 2 widely sepd. regions of disordered phases (along the T axis) in the P-T phase diagram. This effect, namely a reentrant of disordered phases, i.e. disordering setting in on isobaric cooling, at appropriately elevated P, was in fact obsd. exptl. In the course of the above expts. a new hexagonal crystal (Ch) phase was identified lying between Ct and the low T disordered phase along the T axis of P-T phase diagram. This Ch phase is attainable along 2 routes with basically different characteristics. Also, there is a triple point where the liq., Ct, and Ch phases are in equil. Recently similar observations were reported for inorg. materials such as silicates, phosphates, sulfates, and ice-water (the latter at low T and high P), so that the newly recognized behavior pattern seems to be of wider generality beyond the subject of polymers. [on SciFinder (R)