Smooth muscle dysfunction in resistance arteries of the staggerer mouse, a mutant of the nuclear receptor RORalpha

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the RORalpha gene. RORalpha plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1+/-1.2 and 87.0+/-0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional RORalpha is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that RORalpha might be involved in the differentiation of SMCs in mesenteric arteries.     

Structural characterization, physicochemical properties, and thermal stability of three crystal forms of nifedipine

In this study the single-crystal X-ray structure of the solvated species (nifedipine)2. 1,4-dioxane is reported for the first time. Included solvent molecules are located in isolated cavities in the crystal, yielding a very stable solvate. Desolvation of this species involves complete disruption of the crystal structure at the relatively high temperature of 150-153 degrees C, i.e., 50 degrees above the boiling point of 1,4-dioxane, and yields a monoclinic polymorph (Modification I) with a melting point of 174 degrees C. When exposed to an aqueous medium for 48 h, the solvate transformed into a dihydrate. The aqueous solubilities of the above species were in the order: 1,4-dioxane solvate >or= Modification I > dihydrate. The solubility of nifedipine was increased sixfold when transformed into an amorphous form by quenched fusion. This amorphous form was relatively stable at room temperature but converted to Modification I when suspended in water at pH 1. The fused materials also converted to Modification I through an intermediate, Modification III, within 6 days when kept at 40 degrees C for 6 days. XRPD analysis showed that grinding increased the crystallinity of the amorphous form due to partial transformation to Modification I. The pulverized amorphous powder was more stable at 40 degrees C and was approximately three times as soluble as Modification I.     

Rectal cancer in Luxembourg : a national population-based data report, 1988–1998

Background  

Morphologic criteria which might help to support the need for a preventive strategy for early detection of rectal cancer were analysed. Population-based data on rectal adenomas with high-grade dysplastic changes (n = 199) and invasive adenocarcinomas (n = 912) registered by the national Morphologic Tumour Registry (MTR) and diagnosed in a central department of pathology in Luxembourg between 1988 and 1998 were considered.     

Reovirus tenosynovitis in a flock of layer breeders

The present paper describes a reovirus infection with clinical course in a flock of layer breeders. Lameness and tenosynovitis of flexor tendons were observed in approximately 15% of the cockerels and 3% of the hens from 17 weeks of age onwards. Affected birds did not die; on the contrary, most of them recovered clinically within a period of 8 weeks. Two other breeds of layer parents that were housed in close contact with the affected flock did not develop clinical signs, although serology indicated that infection with reovirus had taken place. These field observations constitute the first report of clinical reovirus tenosynovitis in layer parents and indicate different susceptibilities of layer parent breeds in developing clinical signs following reovirus infection.     

Overview of national guidelines for infrastructure and staffing of radiotherapy. ESTRO-QUARTS: work package 1.

BACKGROUND AND PURPOSE: The aim of this study was to collect the available guidelines for infrastructure and staffing throughout Europe and to develop general guidelines. MATERIALS AND METHODS: Questionnaires were sent to representatives in all European countries. Countries were divided into three groups, based on the GDP per capita (low, medium and high resource countries). Based on the results, general guidelines were developed. RESULTS: 41 countries (93.2%), representing over 99% of the European population responded. Guidelines for the number of linear accelerators and personnel were available in about 40% of the countries. For accelerators, the average was 1 per 183,000 inhabitants in the high, 1 per 284,000 in the medium and 1 per 500,000 in the low resource countries. For radiation oncologists, it varied between 1 per 150-400 patients (average: 250) and there was no clear difference between high, medium and low resource countries. For physicists, the average was 1 per 530 patients for high and 1 per 610 for medium or low resource countries. Guidelines for other equipment and staffing are highly dependent on local habits and complexity of the treatments. CONCLUSION: An accurate overview of existing guidelines for radiotherapy infrastructure and staffing is obtained. It is suggested to have one linear accelerator per 450 patients, one radiation oncologist per 200-250 patients and one physicist per 450-500 patients (or one per linac). It should be stressed, however, that these are only crude guidelines and that the actual needs heavily depend on population structure, cancer incidence and treatment strategies, which differ between the various countries.     

Lipid emulsions potently increase transgene expression in hepatocytes after adenoviral transfer.

Elimination of Kupffer cells by cytotoxic clodronate liposomes increases transgene expression in the liver after adenoviral transfer. Here, we demonstrate that empty l-alpha-phosphatidylcholine liposomes block uptake of vectors in the reticuloendothelial cells of the liver and increase human apolipoprotein (apo) A-I (approved gene symbol apo A-I) expression in C57BL/6 (1.3-fold) and Balb/c mice (3.1-fold) to the same extent as clodronate liposomes (1.5- and 3.4-fold, respectively). A similar elevation of human apo A-I levels was induced by the lipid emulsion Intralipid (1.5- and 2.8-fold in C57BL/6 and Balb/c mice, respectively). Not only Kupffer cells but also hepatic sinusoidal endothelial cells (HSEC) constitute the reticuloendothelial cells of the liver. The uptake of adenoviral vectors 1 h after transfer in C57BL/6 mice was 2.9-fold lower in Kupffer cells than in HSEC. In contrast, Kupffer cell uptake in Balb/c mice was 2.6-fold higher than in HSEC. Vector uptake in reticuloendothelial cells of the liver was reduced and transgene expression was increased in splenectomized and Rag2-deficient Balb/c mice but not in splenectomized and Rag1-deficient C57BL/6 mice. In conclusion, lipid emulsions for parenteral clinical use block uptake of adenoviral vectors by the reticuloendothelial cells of the liver and potently increase transgene expression.     

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

PurposeHaploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS.MethodsWe report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status.ResultsThe expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes.ConclusionWe refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.     

Immunoassay of low concentrations of albumin in urine by latex particle counting

We describe here a nonisotopic immunoassay, based on particle-counting technology, for the determination of urinary albumin. The assay takes only 35 min and has been fully automated on the IMPACT (Acade Diagnostic Systems, Brussels, Belgium) machine. The system measures albumin within a linear range between 6.25 and 50 mg/L and has a detection limit of 0.4 mg/L. Analytical recoveries at three concentrations ranged between 96% and 102%. Within-run precision ranged from 1.6% to 9.5%. The method was compared with a commercial nephelometric immunoassay system and a correlation coefficient of 0.996 was found for 216 urine samples. No antigen excess affects the shape of the curve in our system, whereas in nephelometry a 3 g/L solution of albumin starts to decrease the dose-response curve.     

Rabies exposure in international travelers: do we miss the target?

BackgroundLittle data exist about the spatial distribution of the risk for travelers of being injured by a potentially rabid animal.MethodsOver the last 14 years, animal-associated injuries in 424 international travelers presenting to a travel medicine clinic in Marseille, southern France, were investigated.ResultsThe majority of cases were reported from North Africa (41.5%) and Asia (22.2%). Most countries where at-risk injuries occurred (Algeria, Morocco, Tunisia, Thailand, and Turkey) were those for which travelers do not usually seek advice at a specialized travel clinic, because these countries are not at risk for specific travel-associated diseases like malaria or yellow fever. The probability of travelers being attacked by each animal species varied significantly according to the destination country. Dogs were more frequently involved in Algeria, cats in Tunisia and the Middle East, and non-human primates in sub-Saharan Africa, Madagascar, and Asia.ConclusionsWe suggest that rabies pre-exposure vaccination should be offered to individuals traveling regularly to North Africa to visit their relatives and who are at high risk of exposure to potentially rabid animal attacks. Pre-travel advice when addressing rabies prevention should consider the specific epidemiology of animal-related injuries in the traveled country, as well as the traveler's characteristics. Travelers should be advised about which species of animal are potentially aggressive in their destination country so that they can more easily avoid risk-contacts.     

Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases

Background  

The presentation and causes of adult meningitis in South Africa have changed substantially as a result of HIV. Knowledge of aetiology and laboratory findings in patients presenting with meningitis are important in guiding management. We performed a retrospective study to determine these findings in a setting of high HIV and TB prevalence in Cape Town.