A strategy for producing predicted polymorphs: catemeric carbamazepine form V

A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II

Current challenges in the provision of ambulance services in New Zealand

Emergency Medical Services (EMS) in New Zealand has been serving the society since the first ambulance in 1892. Since then it has developed rapidly following national health system reforms and changes in lifestyle that increase demands and expectations from local communities. Today, the system provides high-quality pre-hospital emergency care. This article will briefly introduce some of the issues facing EMS that will impact the future of this crucial system in New Zealand. These issues include demands because of an aging population funding, double crewing, and volunteerism, registration, and unified standards

Purification of matrix Gla protein from a marine teleost fish, Argyrosomus regius: Calcified cartilage and not bone as the primary site of MGP accumulation in fish

Matrix Gla protein (MGP) belongs to the family of vitamin K-dependent, Gla-containing proteins, and in mammals, birds, and Xenopus, its mRNA was previously detected in extracts of bone, cartilage, and soft tissues (mainly heart and kidney), whereas the protein was found to accumulate mainly in bone. However, at that time, it was not evaluated if this accumulation originated from protein synthesized in cartilage or in bone cells because both coexist in skeletal structures of higher vertebrates and Xenopus. Later reports showed that MGP also accumulated in costal calcified cartilage as well as at sites of heart valves and arterial calcification. Interestingly, MGP was also found to accumulate in vertebra of shark, a cartilaginous fish. However, to date, no information is available on sites of MGP expression or accumulation in teleost fishes, the ancestors of terrestrial vertebrates, who have in their skeleton mineralized structures with both bone and calcified cartilage. To analyze MGP structure and function in bony fish, MGP was acid-extracted from the mineralized matrix of either bone tissue (vertebra) or calcified cartilage (branchial arches) from the bony fish, Argyrosomus regius,(1) separated from the mineral phase by dialysis, and purified by Sephacryl S-100 chromatography. No MGP was recovered from bone tissue, whereas a protein peak corresponding to the MGP position in this type of gel filtration was obtained from an extract of branchial arches, rich in calcified cartilage. MGP was identified by N-terminal amino acid sequence analysis, and the resulting protein sequence was used to design specific oligonucleotides suitable to amplify the corresponding DNA by a mixture of reverse transcription-polymerase chain reaction (RT-PCR) and 5'rapid amplification of cDNA (RACE)-PCR. In parallel, ArBGP (bone Gla protein, osteocalcin) was also identified in the same fish, and its complementary DNA cloned by an identical procedure. Tissue distribution/accumulation was analyzed by Northern blot, in situ hybridization, and immunohistochemistry. In mineralized tissues, the MGP gene was predominantly expressed in cartilage from branchial arches, with no expression detected in the different types of bone analyzed, whereas BGP mRNA was located in bone tissue as expected. Accordingly, the MGP protein was found to accumulate, by immunohistochemical analysis, mainly in the extracellular matrix of calcified cartilage. In soft tissues, MGP mRNA was mainly expressed in heart but in situ hybridization, indicated that cells expressing the MGP gene were located in the bulbus arteriosus and aortic wall, rich in smooth muscle and endothelial cells, whereas no expression was detected in the striated muscle myocardial fibers of the ventricle. These results show that in marine teleost fish, as in mammals, the MGP gene is expressed in cartilage, heart, and kidney tissues, but in contrast with results obtained in Xenopus and higher vertebrates, the protein does not accumulate in vertebra of non-osteocytic teleost fish, but only in calcified cartilage. In addition, our results also indicate that the presence of MGP mRNA in heart tissue is due, at least in fish, to the expression of the MGP gene in only two specific cell types, smooth muscle and endothelial cells, whereas no expression was found in the striated muscle fibers of the ventricle. In light of these results and recent information on expression of MGP gene in these same cell types in mammalian aorta, it is likely that the levels of MGP mRNA previously detected in Xenopus, birds, and mammalian heart tissue may be restricted toregions rich in smoot Our results also emphasize the need to re-evaluate which cell types are involved in MGP gene expression in other soft tissues and bring further evidence that fish are a valuable model system to study MGP gene expression and regulation.NIAMS NIH HHS [AR25921]info:eu-repo/semantics/publishedVersio

Association of Residential Mobility Over the Life Course With Nonaffective Psychosis in 1.4 Million Young People in Sweden

IMPORTANCE Residential mobility (changing residence) during childhood and early adolescence is a possible risk factor for several adverse health outcomes, including psychotic disorders. However, it is unclear whether sensitive periods to residential mobility exist over the life course, including in adulthood, or if greater moving distances, which might disrupt social networks, are associated with a greater psychosis risk. OBJECTIVE To examine the association between residential mobility over the life course and the risk of nonaffective psychosis. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included all people born in Sweden between January 1, 1982, and December 31, 1995, who were alive and resided in Sweden on their 16th birthday who were followed up until up to age 29 years (ending December 2011). Participants were followed until receiving a first diagnosis of an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) nonaffective psychotic disorder (F20-29), emigration, death, or the end of 2011, whichever was sooner. National register linkage provided exposure, outcome, and covariate data (complete data were available for 1 440 383 participants [97.8%]). EXPOSURES The exposures to distance moved and the number of residential moves were examined for participants at the following periods over the life course: 0 to 6 years, 7 to 15 years, 16 to 19 years, and 20 years and older. RESULTS This study included 1 440 383 participants, of whom 4537 (0.31%) had nonaffective psychotic disorder (median age, 20.9 [interquartile range, 19.0-23.3]). More frequent moves during childhood and adolescence were associated with an increased risk of nonaffective psychosis that showed dose-response associations independent of covariates. The most sensitive period of risk occurred during late adolescence; those who moved during each year between age 16 to 19 years had an increased adjusted hazard ratio (HR) of 1.99 (95% CI, 1.30-3.05) compared with those who never moved. One move during adulthood was not associated with psychosis risk (adjusted HR, 1.04; 95% CI, 0.94-1.14), but moving 4 or more times during adulthood was associated with increased risk (adjusted hazard ratio, 1.82; 95% CI, 1.51-2.23). Independently, moving greater distances before age 16 years was associated with an increased risk (adjusted HR, 1.11; 95% CI, 1.05-1.19), with evidence of a nonlinear threshold effect for moves longer than 30 km. The distance moved after age 20 years was associated with a decreased risk (adjusted HR, 0.67; 95% CI, 0.63-0.71). CONCLUSIONS AND RELEVANCE Children and adolescents with less disruption in their residential environments are less likely to experience psychotic disorders in early adulthood. Moves that may necessitate changes in school and social networks were most strongly associated with future risk

The influence of liver dysfunction on cyclosporine pharmacokinetics -A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs-

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7±7.1 per cent (mean±SD) and the ICG-K decreased by 61.3±9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9±8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4±20.8 per cent and the bioavailability of CsA decreased by 26.4±14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1±12.8 per cent and the ICG-K decreased by 65.6±3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9±10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9±15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic, metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects. © 1989 The Japan Surgical Society

Wilsonian Approach to Fluid/Gravity Duality

The problem of gravitational fluctuations confined inside a finite cutoff at radius $r=r_c$ outside the horizon in a general class of black hole geometries is considered. Consistent boundary conditions at both the cutoff surface and the horizon are found and the resulting modes analyzed. For general cutoff $r_c$ the dispersion relation is shown at long wavelengths to be that of a linearized Navier-Stokes fluid living on the cutoff surface. A cutoff-dependent line-integral formula for the diffusion constant $D(r_c)$ is derived. The dependence on $r_c$ is interpreted as renormalization group (RG) flow in the fluid. Taking the cutoff to infinity in an asymptotically AdS context, the formula for $D(\infty)$ reproduces as a special case well-known results derived using AdS/CFT. Taking the cutoff to the horizon, the effective speed of sound goes to infinity, the fluid becomes incompressible and the Navier-Stokes dispersion relation becomes exact. The resulting universal formula for the diffusion constant $D(horizon)$ reproduces old results from the membrane paradigm. Hence the old membrane paradigm results and new AdS/CFT results are related by RG flow. RG flow-invariance of the viscosity to entropy ratio $\eta /s$ is shown to follow from the first law of thermodynamics together with isentropy of radial evolution in classical gravity. The ratio is expected to run when quantum gravitational corrections are included.Comment: 34 pages, harvmac, clarified boundary conditio

New drugs for non-alcoholic steatohepatitis and HIV infection: great expectations with a great absent?

In recent years, there has been an increasing number of clinical trials for the treatment of non‐alcoholic steatohepatitis (NASH). People living with HIV (PLWH) are commonly excluded from these studies, usually due to concerns over drug‐drug interactions (DDI) associated with antiretroviral therapy (ART). The Steatohepatitis in HIV Emerging Research (SHIVER) Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between HIV and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of DDI between ART and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL‐3196), which are currently in phase III trials for the treatment of NASH, are reviewed. Finally, a model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a sub‐population within studies

Interactions between downslope flows and a developing cold-air pool

A numerical model has been used to characterize the development of a region of enhanced cooling in an alpine valley with a width of order (Formula presented.) km, under decoupled stable conditions. The region of enhanced cooling develops largely as a region of relatively dry air which partitions the valley atmosphere dynamics into two volumes, with airflow partially trapped within the valley by a developing elevated inversion. Complex interactions between the region of enhanced cooling and the downslope flows are quantified. The cooling within the region of enhanced cooling and the elevated inversion is almost equally partitioned between radiative and dynamic effects. By the end of the simulation, the different valley atmospheric regions approach a state of thermal equilibrium with one another, though this cannot be said of the valley atmosphere and its external environment.Peer reviewe