Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice.

Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function. We demonstrated that Notch3em1Ecan mice harboring Notch3 mutations analogous to those found in LMS are osteopenic because of enhanced bone resorption. To determine the contribution of specific cell lineages to the phenotype, we created a conditional-by-inversion (Notch3COIN) model termed Notch3em2Ecan in which Cre recombination generates a Notch3INV allele expressing a NOTCH3 mutant lacking the PEST domain. Germ line Notch3COIN inversion caused osteopenia and phenocopied the Notch3em1Ecan mutant, validating the model. To induce the mutation in osteocytes, smooth muscle and endothelial cells, Notch3COIN mice were bred with mice expressing Cre from the Dmp1, Sm22a and Cdh5 promoters, respectively, creating experimental mice harboring Notch3INV alleles in Cre-expressing cells and control littermates harboring Notch3COIN alleles. Notch3COIN inversion in osteocytes led to femoral and vertebral cancellous bone osteopenia, whereas Notch3COIN inversion in mural Sm22a or endothelial Cdh5-expressing cells did not result in a skeletal phenotype. In conclusion, introduction of the LMS mutation in osteocytes but not in vascular cells causes osteopenia and phenocopies Notch3em1Ecan global mutant mice.

Role of nuclear factor of activated T cells in chondrogenesis osteogenesis and osteochondroma formation.

PURPOSE: Nuclear factor of activated T cells (NFATc) are transcription factors that play a function in the immune response and in osteoclast differentiation. In the present work, we define the function of NFATc2 in chondrogenic and osteogenic cells. METHODS: Nfatc2loxP/loxP and Nfatc1loxP/loxP;Nfatc2loxP/loxP conditional mice were crossed with Prx1-Cre transgenics to inactivate Nfatc2 singly and with Nfatc1. Femurs and vertebrae were examined by microcomputed tomography (µCT) X-Ray images and histology and analyzed for the presence of osteochondromas. RESULTS: µCT demonstrated that Prx1-Cre;Nfatc2∆/∆ female mice had transient osteopenia and male mice did not have a cancellous or a cortical bone phenotype when compared to control mice. In contrast, the dual inactivation of Nfatc1 and Nfatc2 in Prx1-expressing cells resulted in cancellous osteopenia and small bones at 1 month of age in both sexes. Nfatc1;Nfatc2 deleted mice exhibited a ~ 50% decrease in bone volume and connectivity. Total bone area, periosteal and endocortical bone perimeters and femoral length were reduced indicating smaller bones. As the mice matured, the shortening of the femoral length persisted, but the osteopenic phenotype resolved and cancellous femoral bone of 4-month-old Nfatc1;Nfatc2 deleted mice was not different from controls although male mice had vertebral osteopenia. In addition, Nfatc1;Nfatc2 deleted mice displayed distortion of the distal metaphysis and, as they matured, the articular presence of mineralized tumors with the appearance of osteochondromas. CONCLUSION: Our studies reveal that NFATc1 and NFATc2 are necessary for optimal bone homeostasis and the suppression of osteochondroma formation.

Comparative transcriptome analysis of inner blood-retinal barrier and blood-brain barrier in rats.

Although retinal microvessels (RMVs) and brain microvessels (BMVs) are closely related in their developmental and share similar blood-neural barriers, studies have reported markedly different responses to stressors such as diabetes. Therefore, we hypothesized that RMVs and BMVs will display substantial differences in gene expression levels even though they are of the same embryological origin. In this study, both RMVs and BMVs were mechanically isolated from rats. Full retinal and brain tissue samples (RT, BT) were collected for comparisons. Total RNA extracted from these four groups were processed on Affymetrix rat 2.0 microarray Chips. The transcriptional profiles of these tissues were then analyzed. In the present paper we looked at differentially expressed genes (DEGs) in RMVs (against RT) and BMVs (against BT) using a rather conservative threshold value of ≥ ± twofold change and a false discovery rate corrected for multiple comparisons (p < 0.05). In RMVs a total of 1559 DEGs were found, of which 1004 genes were higher expressed in RMVs than in RT. Moreover, 4244 DEGs between BMVs and BT were identified, of which 1956 genes were ≥ twofold enriched in BMVs. Using these DEGs, we comprehensively analyzed the actual expression levels and highlighted their involvement in critical functional structures in RMVs and BMVs, such as junctional complex, transporters and signaling pathways. Our work provides for the first time the transcriptional profiles of rat RMVs and BMVs. These results may help to understand why retina and brain microvasculature show different susceptibilities to stressors, and they might even provide new insight for pharmacological interventions.

Workplace-related risk of tick bites in military personnel stationed in Northern Germany.

PURPOSE: There are more than 500,000 employees in Germany alone who are at risk of being bitten by a tick at their workplace and thus also at risk of being infected with Borrelia burgdorferi s.l. or the tick-borne meningoencephalitis virus. So far, there are only a small number of studies on the risk of tick bites in Central Europe, in particular, for military personnel during relevant training activities. METHODS: During a total of 36 months of training in 2008/2009 and from 2012 to 2014, the number of tick bites and any resulting diseases of 1156 recruits under comparable conditions of exposure and prevention were documented based on their medical records. The incidence of tick bites was calculated with each recruit's individual exposure time for field training. RESULTS: There were a total of 66 tick bites during an exposure time of 317,059 h of field training (0.21 tick bites per 1000 h of training). The risk of tick bites was found to have a seasonal dependency. In 6 out of the 66 cases in which someone was bitten, the patients consulted a physician for a follow-up examination, and in one of these cases the bite resulted in an infection requiring treatment. CONCLUSIONS: It turns out that there is a rather low but relevant risk of being exposed to tick bites for military personnel during their field training. Under the given study conditions, months with a high risk of tick bites can be distinguished from months with a low risk of tick bites, which is of vital importance, in particular, for guidance and prevention.

[The use of sunglasses during leisure time and work : Lack of prevention of sun-induced eye damage]. / Die Nutzung von Sonnenbrillen in Freizeit und Beruf : Defizite in der Prävention sonnenbedingter Augenschäden.

OBJECTIVE: This study aimed at collecting representative national data on the use of sunglasses on sunny summer days during leisure time or work as well as identifying population and professional groups with a pronounced lack of preventive measures to avoid sun-induced eye damage. MATERIAL AND METHODS: Within the representative National Cancer Aid Monitoring, data on the use of sunglasses during leisure time was assessed among 3000 individuals aged 14-45 years in 2015, as well as on the use during outdoor work among 485 workers aged 14-45 years in 2016. Associations between the use of sunglasses and sociodemographic characteristics were assessed with the χ2-test. Additionally, descriptive and bivariate methods were used to assess connections between the use of sunglasses at work and each professional group. RESULTS: While more than half of the general population normally or often wear sunglasses on a sunny summer day, only one third of outdoor workers do so. While approximately every seventh individual surveyed never wears sunglasses during leisure time, among outdoor workers it is one out of three. The use during leisure time increases with age. DISCUSSION: Use of sunglasses during work could be supported by targeted information on UV-induced eye damage by ophthalmologists and company physicians with additional support from accident insurances and employers. Concerning preventive measures occupational groups such as landscapers, farmers and bricklayers who are strongly exposed to sunlight but rarely wear sunglasses are important groups.

[Lichen ruber planus : Better understanding, better treatment!] / Lichen ruber planus : Besser verstehen, besser behandeln!

Lichen ruber, also called lichen ruber planus or lichen planus (LP), is a noncontagious inflammatory skin disease. LP is the main representative and namesake of the group of lichenoid diseases, which are characterized by small papules often accompanied by severe itching. With 65% of cases, LP is primarily a disease of the mucous membranes. In 20% of the cases, the disease is found on the skin and mucous membranes; skin involvement alone is seen in only about 10% of cases. Cutaneous LP has a very favorable 1­year prognosis of almost 80% healing as opposed to the mucosa and the adnexal organs. Histologically, keratinocytes with vacuolar degeneration, leaving behind apoptotic Kamino bodies and the characteristic band-shaped lymphocytic infiltrate at the dermatoepithelial junction, are common to lichenoid diseases. The horny layer is firm and compact and the stratum granulosum is thickened as a correlate of the Wickham stripes. The molecular pathogenesis, still partially hypothetical, assumes trigger factors leading to the presentation of intrinsic or foreign antigens. The triggered inflammation becomes independent in the sense of a classical cell-mediated autoimmune disease. Other autoimmune diseases are often associated with LP. Classical anti-inflammatory-immunosuppressive therapeutic concepts dominate with systemic retinoids ranking first in the highest evidence class for cutaneous LP with limitations in treatment of both mucosal and adnexal LP. More recently, interesting and new complementary phototherapeutics have been identified.

[Postmenopausal lichen planopilaris also known as fibrosing frontotemporal alopecia Kossard : An evidence-oriented practical guide to treatment from the University of the Saarland, Hair Research Center of the Dr. Rolf M. Schwiete Foundation]. / Postmenopausaler Lichen planopilaris alias fibrosierende frontotemporale Alopezie Kossard : Ein evidenzorientierter "practical guide to treatment" des Haarforschungszentrums der Dr. Rolf M. Schwiete Stiftung an der Universität des Saarlandes.

Postmenopausal lichen planopilaris (PLPP), also known as fibrosing frontotemporal alopecia Kossard (FFAK), is a not uncommon inflammatory scalp disease affecting approximately 5% of patients at specialized hair centers. The overall incidence of sporadic occurrence is believed to be just under 1% in the older, predominantly female, general population. Since the disease is often undiagnosed, it is statistically likely to be underrepresented. It especially occurs in postmenopausal women who are in the 6th and 7th decade of life (90%), but also in about 10% of premenopausal women, and in men it is documented only in isolated cases. The result is a permanent scarring hair loss accentuated at the front hairline with backward movement towards the neck mostly accompanied by a typical loss of the eyebrows. The disease therefore often leads to significant mental distress and social anxiety in those affected. This is the basis for a compelling need to develop evidence-based therapeutic concepts. While numerous retrospective case series have characterized the phenomenology of FFAK very well, to date there are no randomized controlled trials on evidence-based therapy. Here, we present the Homburger Evidence-Oriented Therapy Algorithm, which is oriented along the available case series evidence: It may (1) serve as a therapy guide for practice and (2) can be used as a basis for working out reliable data based on study evidence. The article contains detailed practical information on photo documentation, biopsy and histological processing up to the practical implementation of, for example, intralesional steroid therapy as well as information on selection criteria for suitable systemic therapies.

Reproductive activity triggers accelerated male mortality and decreases lifespan: genetic and gene expression determinants in Drosophila.

Reproduction and aging evolved to be intimately associated. Experimental selection for early-life reproduction drives the evolution of decreased longevity in Drosophila whereas experimental selection for increased longevity leads to changes in reproduction. Although life history theory offers hypotheses to explain these relationships, the genetic architecture and molecular mechanisms underlying reproduction-longevity associations remain a matter of debate. Here we show that mating triggers accelerated mortality in males and identify hundreds of genes that are modulated upon mating in the fruit fly Drosophila melanogaster. Interrogation of genome-wide gene expression in virgin and recently mated males revealed coherent responses, with biological processes that are upregulated (testis-specific gene expression) or downregulated (metabolism and mitochondria-related functions) upon mating. Furthermore, using a panel of genotypes from the Drosophila Synthetic Population Resource (DSPR) as a source of naturally occurring genetic perturbation, we uncover abundant variation in longevity and reproduction-induced mortality among genotypes. Genotypes displayed more than fourfold variation in longevity and reproduction-induced mortality that can be traced to variation in specific segments of the genome. The data reveal individual variation in sensitivity to reproduction and physiological processes that are enhanced and suppressed upon mating. These results raise the prospect that variation in longevity and age-related traits could be traced to processes that coordinate germline and somatic function.

Evaluación de la posición condilary del espacio articular en atm de individuos chilenos con trastornos temporomandibulares / Assessment of tmj condylar position and joint space in chilean individuals with temporomandibular disorders

La importancia de la relación cóndilo-fosa en la articulación temporomandibular (ATM) aún no es clara, sin embargo algunos autores asocian la posición no céntrica del cóndilo de la mandíbula en la fosa mandibular con trastorno temporomandibular (TTM). Además, otros autores sugieren que la evaluación del espacio articular es una herramienta diagnóstica para la evaluación de las alteraciones de ATM. El objetivo de este estudio fue evaluar la posición condilar y el espacio articular de ATM en individuos chilenos con TTM utilizando tomografía computarizada cone-beam. Fueron seleccionados 19 pacientes de la Unidad de Trastornos Cráneo Cervico Mandibulares-Universidad de Talca, con diagnóstico de TTM según el Research Diagnostic Criteria for Temporomandibular Disorders. Para la evaluación de la posición condilar se utilizó la técnica de Pullinger & Hollender y para la evaluación de los espacios articulares anterior (EAA), superior (EAS) y posterior (EAP) se utilizó la técnica de Ikeda & Kawamura. Un 39,47% de los cóndilos se presentaron en posición posterior, 34,21% en posición central y un 26,31% en posición anterior. Para cóndilos en posición central encontramos: EAA=1,57 mm; EAS=2,20 mm; EAP= 1,54 mm. Para cóndilos en posición posterior encontramos: EAA= 2,18 mm; EAS= 2,02 mm; EAP= 0,98 mm. Para cóndilos en posición anterior encontramos: EAA= 1,00 mm; EAS= 1,89 mm y EAP= 2,07 mm. Concluimos que individuos con diagnóstico de TTM presentan las regiones anatómicas predisponientes a las alteraciones articulares con espacios articulares disminuidos cuando comparados con sujetos asintomáticos. La posición posterior fue la más común en individuos con TTM, sin embargo hubo gran variabilidad en la posición condilar, por ello sugerimos que una posición no centralizada del cóndilo no está necesariamente asociada con la presencia de TTM. Concluimos además que en individuos con TTM los cóndilos ubicados en posición central y posterior presentan EAP disminuido en comparación con individuos sanos.

The importance of the condyle-fossa relationship in the temporomandibular joint (TMJ) is not yet fully clear, however, some authors associate the non-central position of the head of the mandible in the mandibular fossa with temporomandibular disorder (TMD). Furthermore, other authors suggest that assessment of joint space is a diagnostic tool for assessing the TMJ alterations. The aim of this study was to evaluate the TMJ condylar position and joint space in Chilean individuals with TMD using cone-beam computed tomography. We selected 19 patients of "Unidad de Trastornos Cráneo Cervico Mandibulares (UCRACEM) - Universidad de Talca, Chile", who had a diagnosis of TMD according to the Research Diagnostic Criteria for Temporomandibular Disorders. The assessment of condylar position was performed using Pullinger & Hollender technique and to evaluate the anterior joint space (AJS), superior joint space (SJS) and posterior joint space (PJS) was used Ikeda & Kawamura technique. Posterior condylar position was found in 39.47% of condyles, central condylar position in 34.21% and anterior condylar position in 26.31%. To condyles in central position we found: AJS = 1.57 mm; SJS = 2.20 mm; PJS = 1.54 mm. To condyles in posterior position we found: AJS = 2.18 mm; SJS = 2.02 mm; PJS = 0.98 mm. To condyles in anterior position we found: AJS = 1.00 mm; SJS = 1.89 mm and PJS = 2.07 mm. We conclude that individuals diagnosed with TMD present anatomical regions predisposing to joint disorders with joint spaces diminished when compared with asymptomatic subjects. Furthermore, the posterior condylar position was the most common in individuals with TMD, however there was great variability in condylar position, therefore we suggest that a non-centralized position of the condyle is not necessarily associated with the presence of TMD. We further conclude that in individuals with TMD the condyles located in central and posterior position present EAP decreased compared with healthy individuals.

Quality of life in thalassemia: a comparison of SF-36 results from the thalassemia longitudinal cohort to reported literature and the US norms.

Thalassemia is a chronic, inherited blood disorder, which, in its most severe form, causes life-threatening anemia. Advances in treatment have led to increased life expectancy however the need for chronic blood transfusions and chelation therapy remains a significant burden for patients. Our study compared health related quality of life (HRQOL) from the Thalassemia Clinical Research Network's (TCRNs) Thalassemia Longitudinal Cohort (TLC) study to US norms and assessed association with clinical variables. There were 264 patients over age 14 who completed the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF36v2) baseline assessment. When compared to US norms, TLC patients had statistically significant (P < 0.05) worse HRQOL on five of the eight subscales (physical functioning, role-physical, general health, social functioning, and role-emotional) and on both summary scales (physical component summary and mental component summary). Women, older patients, and those with more disease complications and side effects from chelation reported lower HRQOL. In general, adolescents and adults with thalassemia report worse HRQOL than the US population, despite contemporary therapy. The SF-36 should become a standard instrument for assessing HRQOL in thalassemia to determine predictors of low HRQOL which may be better addressed by a multidisciplinary team.

[Current concepts for experimental micro-CT in small animals]. / Aktueller Stand der Mikro-CT in der experimentellen Kleintierbildgebung.

The number of publications describing the use of micro-computed tomography (microCT) for preclinical in vivo imaging of small animals has risen considerably within the last few years. The purpose of this review is to familiarize the reader with the basic principles of microCT, to present successful experimental approaches in order of the evaluated organ system, and to highlight limitations that need to be considered when planning microCT-based studies.

Interest in health information exchange in ambulatory care: a statewide survey.

OBJECTIVE: Assess the interest in and preferences of ambulatory practitioners in HIE. BACKGROUND: Health information exchange (HIE) may improve the quality and efficiency of care. Identifying the value proposition for smaller ambulatory practices may help those practices engage in HIE. METHODS: Survey of primary care and specialist practitioners in the State of Colorado. RESULTS: Clinical data were commonly (always [2%], often [29%] or sometimes [49%]) missing during clinic visits. Of 12 data types proposed as available through HIE, ten were considered "extremely useful" by most practitioners. "Clinical notes/consultation reports," "diagnosis or problem lists," and "hospital discharge summaries" were considered the three most useful data types. Interest in EKG reports, diagnosis/problem lists, childhood immunizations, and discharge summaries differed among ambulatory practitioner groups (primary care, obstetrics-gynecology, and internal medicine subspecialties). CONCLUSION: Practitioners express strong interest in most of the data types, but opinions differed by specialties on what types were most important. All providers felt that a system that provided all data types would be useful. These results support the potential benefit of HIE in ambulatory practices.

Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPbeta.

We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-Ras (Ha-Ras) induces CCAAT/enhance binding protein beta (C/EBPbeta) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpbeta-dependent inhibition of SIM2s, C/ebpbeta(-/-) mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpbeta isoforms decreased SIM2s mRNA levels in C/ebpbeta immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-Ras-transformed breast epithelial cells and identify SIM2s as a target of C/EBPbeta and NOTCH signaling.

Regular-to-chaotic tunneling rates using a fictitious integrable system.

We derive a formula predicting dynamical tunneling rates from regular states to the chaotic sea in systems with a mixed phase space. Our approach is based on the introduction of a fictitious integrable system that resembles the regular dynamics within the island. For the standard map and other kicked systems we find agreement with numerical results for all regular states in a regime where resonance-assisted tunneling is not relevant.

Clinical questions asked by medical students: a learning tool for dermatology rotations.

BACKGROUND/AIMS: To determine whether having medical students answer self-generated patient-specific questions in a clinical setting promotes learning. METHODS: Medical students rotating through dermatology clinics at the Denver Veterans' Affairs (VA) Medical Center were asked to formulate and answer one clinical question arising during patient encounters, and to complete a survey regarding their findings and experience. RESULTS: 49% (44/89) of rotating medical students completed the exercise. Self-generated questions frequently addressed therapy (61%, 27/44), prognosis (13%, 6/44), etiology/risk factors (7%, 3/44), and harm (5%, 2/44). The most frequently used sources of clinical information were journal abstracts/articles (55%, 24/44), UpToDate (50%, 22/44), websites (27%, 12/44) and printed textbooks (25%, 11/44). Medical students rated the impact of answers they obtained on a Likert scale of 1 (strongly disagree) to 5 (strongly agree) for the following: can be used to assist in patient's care (mean 4.1), improved care (mean 3.7), improved communication (mean 4.4), improved confidence in care (mean 4.2), improved knowledge (mean 4.6), and will improve future care (mean 4.5). CONCLUSIONS: Medical students report increased knowledge, confidence and patient care skills after completing a self-directed formal exercise consisting of formulating and answering a patient-specific clinical question.

Cochrane Skin Group systematic reviews are more methodologically rigorous than other systematic reviews in dermatology.

BACKGROUND: The Cochrane collaboration aims to produce high-quality systematic reviews. It is not known whether the methods used in producing Cochrane Skin Group (CSG) reviews result in higher quality reviews than other systematic reviews in dermatology. OBJECTIVES: To determine how the methodological quality of dermatological CSG reviews published in The Cochrane Library and in peer-reviewed journals compare with non-Cochrane systematic reviews. METHODS: Two blinded investigators independently assessed review quality using the 10-item Oxman and Guyatt scale. RESULTS: Thirty-eight systematic reviews (17 Cochrane reviews published in The Cochrane Library, 11 Cochrane reviews published in peer-reviewed journals and 10 non-Cochrane reviews published in peer-reviewed journals) were examined. The Cochrane Library reviews included quality of life (11/17 vs. 1/10, P = 0.014) and adverse outcomes (14/17 vs. 2/10, P = 0.003) more often than non-Cochrane reviews published in peer-reviewed journals. Cochrane reviews published in both peer-reviewed journals and The Cochrane Library were more likely to include comprehensive search strategies (11/11 and 17/17 vs. 6/10, P-values = 0.04 and 0.01), take steps to minimize selection bias (11/11 and 16/17 vs. 3/10, P-values = 0.003 and 0.001) and appropriately assess the validity of all included trials (10/11 and 16/17 vs. 4/10, P-values = 0.04 and 0.007) than non-Cochrane reviews. Overall, Cochrane reviews published both in peer-reviewed journals and in The Cochrane Library were assigned higher quality scores by reviewers than non-Cochrane reviews (median = 6.0 and 6.5 vs. 4.5, P-values = 0.01 and 0.002). CONCLUSIONS: The Cochrane Library systematic review methodology leads to higher quality reviews on dermatological topics.

Statins and fibrates for preventing melanoma.

BACKGROUND: Effective treatment for advanced melanoma is lacking. While no drug therapy currently exists for prevention of melanoma, in vitro, case-control, and animal model evidence suggest that lipid-lowering medications, commonly taken for high cholesterol, might prevent melanoma. OBJECTIVES: To assess the effects of statin or fibrate lipid-lowering medications on melanoma outcomes. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (February 2003), CENTRAL (The Cochrane Library Issue 1, 2005), MEDLINE (to March 2003), EMBASE (to September 2003), CANCERLIT (to October 2002), Web of Science (to May 2003), and reference lists of articles. We approached study investigators and pharmaceutical companies for additional information (published or unpublished studies). SELECTION CRITERIA: Trials involving random allocation of study participants, where experimental groups used statins or fibrates and participants were enrolled for at least four years of therapy. DATA COLLECTION AND ANALYSIS: Three authors screened 109 abstracts of articles with titles of possible relevance. We then thoroughly examined the full text of 72 potentially relevant articles. We requested unpublished melanoma outcomes data from the corresponding author of each qualifying trial. MAIN RESULTS: We identified 16 qualifying randomised controlled trials (RCTs) (seven statin, nine fibrate). Thirteen of these trials (involving 62,197 participants) provided data on incident melanomas (six statin, seven fibrate). A total of 66 melanomas were reported in groups receiving the experimental drug and 86 in groups receiving placebo or other control therapies. For statin trials this translated to an odds ratio of 0.90 (95% confidence interval 0.56 to 1.44) and for fibrate trials an odds ratio of 0.58 (95% confidence interval 0.19 to 1.82). Subgroup analyses failed to show statistically significant differences in melanoma outcomes by gender, melanoma occurrence after two years of participation in trial, stage or histology, or trial funding. Subgroup analysis by type of fibrate or statin also failed to show statistically significant differences, except for the statin subgroup analysis which showed reduced melanoma incidence for lovastatin, based on one trial only (odds ratio 0.52, 95% confidence interval 0.27 to 0.99). AUTHORS' CONCLUSIONS: The melanoma outcomes data collected in this review of RCTs of statins and fibrates does not exclude the possibility that these drugs prevent melanoma. There was a 10% and 42% reduction for participants on statins and fibrates, respectively, however these results were not statistically significant. Until further evidence is established, limiting exposure to ultraviolet radiation remains the most effective way to reduce the risk of melanoma.

Circadian periodicity of cerebral blood flow revealed by laser-Doppler flowmetry in awake rats: relation to blood pressure and activity.

Cardiovascular parameters such as arterial blood pressure (ABP) and heart rate display pronounced circadian variation. The present study was performed to detect whether there is a circadian periodicity in the regulation of cerebral perfusion. Normotensive Sprague-Dawley rats (SDR, approximately 15 wk old) and hypertensive (mREN2)27 transgenic rats (TGR, approximately 12 wk old) were instrumented in the abdominal aorta with a blood pressure sensor coupled to a telemetry system for continuous recording of ABP, heart rate, and locomotor activity. After 5-12 days, a laser-Doppler flow (LDF) probe was attached to the skull by means of a guiding device to measure changes in brain cortical blood flow (CBF). After the animals recovered from anesthesia, measurements were taken for 3-4 days. The time series were analyzed with respect to the midline estimating statistic of rhythm (i.e., mean value of a periodic event after fit to a cosine function), amplitude, and acrophase (i.e., phase angle that corresponds to the peak of a given period) of the 24-h period. The LDF signal displayed a significant circadian rhythm, with the peak occurring at around midnight in SDR and TGR, despite inverse periodicity of ABP in TGR. This finding suggests independence of LDF periodicity from ABP regulation. Furthermore, the acrophase of the LDF was consistently found before the acrophase of the activity. From the present data, it is concluded that there is a circadian periodicity in the regulation of cerebral perfusion that is independent of circadian changes in ABP and probably is also independent of locomotor activity. The presence of a circadian periodicity in CBF may have implications for the occurrence of diurnal alterations in cerebrovascular events in humans.

Experimental approaches to evaluate endothelin-A receptor antagonists.

A large body of evidence suggests a substantial role of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Recently bosentan, an ET receptor antagonist, has received approval by the Food and Drug Administration (FDA) for use in pulmonary artery hypertension. The ET system may also be involved in cerebrovascular disorders such as stroke and, most notably, development of cerebral vasospasm following subarachnoid hemorrhage. The pathophysiological mechanisms contributing to the development of a cerebral vasospasm after subarachnoid hemorrhage may be taken as a paradigm to explore mechanisms leading to secondary ischemic brain damages in a variety of insults such as stroke and trauma. The present review provides the evidence to evaluate ET receptor antagonists for potential prophylactic and therapeutic use in patients suffering from subarachnoid hemorrhage. The rationale to develop selective ETA receptor antagonists is given with respect to basic and applied studies. This may be useful to better define the desired profile of action of a given compound, and it may also help to design appropriate preclinical and clinical trials, most desirably in close cooperation with pharmaceutical companies and neurosurgical departments.