International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature.
In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, endothelins mediate their actions via only two receptor types that have been cloned and classified as the ET(A) and ET(B) receptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of endothelin. A selective ET(A) receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp-]; FR139317, N- [(hexahydro-1-azepinyl)carbonyl]L-Leu(1-Me)D-Trp-3 (2-pyridyl)-D-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala(11,15)]Ac-ET-1((6-21))), and IRL1620 [Suc-(Glu(9), Ala(11,15))-ET-1((8-21))] are widely used synthetic ET(B) receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ET(B) antagonists have also been developed. They are generally less potent than ET(A) antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ET(B) receptor. Radioligands highly selective for either ET(A) ((125)I-PD151242, (125)I-PD164333, and (3)H-BQ123) or ET(B) receptors ((125)I-BQ3020 and (125)I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals.


Consumption of ultra-processed foods associated with weight gain and obesity in adults: A multi-national cohort study.
There is a worldwide shift towards increased consumption of ultra-processed foods (UPF) with concurrent rising prevalence of obesity. We examined the relationship between the consumption of UPF and weight gain and risk of obesity. This prospective cohort included 348 748 men and women aged 25-70 years. Participants were recruited between 1992 and 2000 from 9 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Two body weight measures were available, at baseline and after a median follow-up time of 5 years. Foods and drinks were assessed at baseline by dietary questionnaires and classified according to their degree of processing using NOVA classification. Multilevel mixed linear regression was used to estimate the association between UPF consumption and body weight change (kg/5 years). To estimate the relative risk of becoming overweight or obese after 5 years we used Poisson regression stratified according to baseline body mass index (BMI). After multivariable adjustment, higher UPF consumption (per 1 SD increment) was positively associated with weight gain (0·12 kg/5 years, 95% CI 0·09 to 0·15). Comparing highest vs. lowest quintile of UPF consumption was associated with a 15% greater risk (95% CI 1·11, 1·19) of becoming overweight or obese in normal weight participants, and with a 16% greater risk (95% CI 1·09, 1·23) of becoming obese in participants who were overweight at baseline. These results are supportive of public health campaigns to substitute UPF for less processed alternatives for obesity prevention and weight management.


Computed tomographic analysis of hemifacial spasm: narrowing of the posterior fossa as a possible facilitating factor for neurovascular compression.
Hemifacial spasm can be caused by vascular compression of the facial nerve at the root exit zone from the brainstem. Several case reports suggest that narrowing of the cerebellopontine angle cistern caused by Paget's disease, abnormal elevation of the petrous bone caused by hyperplasia, or contralateral acoustic neurinoma may increase the chance of vascular compression of the facial nerve. Therefore, posterior fossa narrowness has been evaluated in 34 patients with hemifacial spasm by measuring the petrous angle and pons diameter index to elucidate whether narrowing of the posterior fossa can act as a facilitating factor for neurovascular compression. The petrous angle in the hemifacial spasm group was significantly smaller than that in the control group, which consisted of 33 patients with an unruptured supratentorial aneurysm, and the pons diameter index in the hemifacial spasm group was significantly greater than that in the control group. These results indicate that the cerebellopontine angle cistern of patients with hemifacial spasm is narrower resulting in more crowded cranial nerves and vascular structures compared with patients without hemifacial spasm. The narrowness of the cerebellopontine angle cistern may be a possible factor in facilitating neurovascular compression in hemifacial spasm.


Effects of demineralization depth on microtensile bond strength to human dentin.
To evaluate the effect of different phosphoric acid concentrations (10% and 37%) on the microtensile bond strengths (microTBS) of three dentin adhesive systems with different solvents (ethanol, acetone, or none). Eighteen third molars divided into six groups were ground flat to expose superficial dentin, which was polished to 600-grit. The bonding procedure was initiated using either of two phosphoric acid gels (10% and 37%). Three adhesive systems - Single Bond (SB), Prime & Bond NT (NT), and One Coat Bond (OC) - with different solvents (ethanol, acetone, or none, respectively) were used. After adhesive application, a cylinder of composite resin was built up. After 24 h water storage, each tooth was serially sectioned into thin rectangular sections (or "sticks") parallel to the long axis and with a mean cross-sectional area of 0.4 mm2. microTBS were determined using an Instron universal testing machine. Data were analyzed using two-way ANOVA and Duncan's test. Mean bond strengths ranged from 66.1 MPa for 10%/ H3PO4 and SB to 43.8 MPa for 37% H3PO4 and OC. SB and OC tended to have slightly higher bond strengths when 10% H3PO4 was used. NT with 37% H3PO4 had a significantly higher microTBS (54.6 MPa) than NT with 10% H3PO4 (44.4 MPa). Etching dentin with 37% H3PO4 resulted in a significantly higher mean microTBS for the acetone-based adhesive NT. For both the ethanol- and water-based adhesive (SB) and the solvent-free adhesive (OC), acid concentration did not significantly affect bond strength.


Lidar calibration technique using laboratory-generated aerosols.
A new calibration technique for continuous-wave Doppler lidars that uses an aerosol scattering target has been developed. Calibrations with both single- and many-particle scattering were performed at the same lidar operating conditions as in atmospheric measurements. The calibrating targets, simulating atmospheric aerosols, were laboratory-generated spherical silicone oil droplets with known complex refractive indices and sizes, hence with known single-particle backscatter cross sections as obtained from Mie theory. Measurements of lidar efficiency with the conventional hard target calibration method were consistently higher by a factor of ~2 than measurements with the aerosol calibration technique. This result may have important implications for lidar backscatter estimates both for aerosol modeling efforts and for optimal design of future lidar systems. The aerosol calibration method provides a validation of basic lidar theory for particle scattering for coherent detection.


Chemopreventive effects of dietary flaxseed oil on colon tumor development.
Fatty acid composition of dietary fat, primarily the levels of omega-3 and omega-6 polyunsaturated fatty acids, has shown profound effect on colon tumor development in animal studies. Fats containing omega-6 fatty acids (for example, corn oil) enhanced and omega-3 fatty acids (for example, fish oil and mustard oil) reduced chemically induced colon tumors in rats. The purpose of this study was to investigate the effects of dietary flaxseed oil (containing alpha-linolenic acid, an omega-3 polyunsaturated fatty acid) on azoxymethane-induced colon tumor in rats and how it compared with the dietary corn oil-treated group. Male Fischer rats, separated into 2 groups of 30, were assigned to the AIN-93M diet, which was supplemented with either 15% corn oil or 15% flaxseed oil. Carcinogenesis was initiated with subcutaneous injections of azoxymethane (15 mg/kg) once a week for three consecutive weeks. Thirty-five weeks after initiation, the rats were sacrificed under ether anesthesia. Blood was collected by cardiac puncture. The gastrointestinal tract was isolated and flushed with ice-cold normal saline. The site, size, and number of tumors were recorded. The incidence and multiplicity of the tumors in the colon were determined. The fatty acid composition in the serum, colon, and tumors was estimated by using gas chromatography-flame ionization detection. Colon tumor incidence was found to be 100% and 54%, whereas multiplicity was found to be 3.1 and 0.7 tumors per rat in corn oil- and flaxseed oil-treated groups, respectively. Tumor size was significantly larger in the corn oil-treated group than in the flaxseed oil group. Colon and serum samples of the corn oil group showed an increase in the omega-6 fatty acid levels, whereas the flaxseed oil group exhibited an increase in the omega-3 fatty acid levels. The results indicate that dietary flaxseed oil, containing high levels of omega-3 fatty acids, is effective in preventing colon tumor development when compared with dietary corn oil containing omega-6 fatty acids in rats.


Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review.
To systematically review the literature on reported adverse effects (AE) associated with use of topical nonsteroidal antiinflammatory drugs (NSAID) in older adults with osteoarthritis (OA). A systematic search of Medline (1950 to November 2009), Scopus, Embase, Web of Science, Cochrane databases, Dissertation and American College of Rheumatology meeting abstracts was performed to identify original randomized controlled trials, case reports, observational studies, editorials, or dissertations reporting AE from topical NSAID in older adults with OA. Information was sought on study and participant characteristics, detailed recording of application site, and systemic AE as well as withdrawals due to AE. The initial search yielded 953 articles of which 19 met eligibility criteria. Subjects receiving topical NSAID reported up to 39.3% application site AE, and up to 17.5% systemic AE. Five cases of warfarin potentiation with topical agents were reported, 1 resulting in gastrointestinal bleeding. In formal trials, the withdrawal rate from AE ranged from 0 to 21% in the topical agents, 0 to 25% in the oral NSAID, and 0 to 16% in the placebo group. Although topical NSAID are safer than oral NSAID (fewer severe gastrointestinal AE), a substantial proportion of older adults report systemic AE with topical agents. The withdrawal rate due to AE with topical agents is comparable to that of oral NSAID. Given the safety profile and withdrawal rates described in this study, further data are needed to determine the incremental benefits of topical NSAID compared to other treatment modalities in older adults with OA.


Derivation of oocytes from mouse embryonic stem cells.
Continuation of mammalian species requires the formation and development of the sexually dimorphic germ cells. Cultured embryonic stem cells are generally considered pluripotent rather than totipotent because of the failure to detect germline cells under differentiating conditions. Here we show that mouse embryonic stem cells in culture can develop into oogonia that enter meiosis, recruit adjacent cells to form follicle-like structures, and later develop into blastocysts. Oogenesis in culture should contribute to various areas, including nuclear transfer and manipulation of the germ line, and advance studies on fertility treatment and germ and somatic cell interaction and differentiation.


Effect of shaft stiffness and sole flexibility on perceived comfort and the plantar pressures generated when walking on a simulated underground coal mining surface.
The structural features of work boots worn by underground coal miners affect comfort, foot motion and, in turn, loading of the plantar surface of miners' feet. Although shaft stiffness and sole flexibility appear to be boot design features that could influence perceived comfort and plantar pressures, no study has systematically altered these boot design features to truly understand how they affect these parameters. This study aimed to systematically investigate the effect of changes to shaft stiffness and sole flexibility on perceived comfort and plantar pressures when 20 males walked on a simulated gravel coal mining surface under four different work boot conditions. There were no significant effects of shaft stiffness or sole flexibility on perceived comfort. However, shaft stiffness and sole flexibility each significantly affected the plantar pressures generated under the medial midfoot, heel, middle metatarsals and hallux and, in combination, affected plantar pressures generated beneath the lateral midfoot, medial and lateral metatarsals and lesser toes. Participants preferred a boot with a flexible shaft combined with a stiff sole, citing properties such as fit, moveability, walking effort and support to explain why they perceived one boot as more comfortable than another. We therefore recommend that underground coal mining work boots should be designed to incorporate different flexibility and stiffness between the shaft and sole of the boot to optimise foot movement and, in turn, walking efficiency.


Effective photothermal chemotherapy with docetaxel-loaded gold nanospheres in advanced prostate cancer.
Multifunctional gold nanospheres (MGNs)-loaded with docetaxel (MGN@DTX) were prepared and evaluated for therapeutic efficacy in nude mice bearing human prostate cancer xenografts. MGNs were prepared from PEGylated hollow gold nanospheres (HGNs) coated with folic acid and DTPTT chelate. Then, the effect of radiolabelled MGNs ((99m)Tc-MGNs) on PC-3 cell apoptosis was assessed by flow cytometry, while their binding affinity to these cells was evaluated by cell binding assays. Next, biodistribution of (99m)Tc-MGNs in xenograft bearing mice was measured by SPECT imaging. Also, DTX loading and release rates were estimated in MGN@DTX. Finally, in vitro stability in human serum and cytotoxicity of MGN@DTX were assessed, as well as their antitumor effect in xenograft bearing mice. (99m)Tc-MGNs (97.69% purity) showed good binding affinity to PC-3 cells, a specific recognition blocked by excess folic acid. Interestingly, MGN@DTX remained stable in human serum for 24 h, and exhibited higher mean cytotoxicity after NIR laser irradiation than free DTX. By day 28, tumor inhibition rates were higher in the MGN@DTX + NIR laser irradiation group compared with the DTX and MGNs + NIR laser irradiation groups. Loading chemotherapeutic drugs into MGNs can increase antitumor potency, reduce normal cell damage and decrease drug resistance, thus representing a promising approach for advanced prostate cancer treatment.


Comparison of pain-relieving effects of fentanyl versus ketorolac after eye amputation surgery.
To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant.


Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD).
Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.


Vaginal pessaries for pelvic organ prolapse and urinary incontinence: a multiprofessional survey of practice.
Vaginal pessaries may offer symptomatic improvement for women with pelvic organ prolapse (POP) or urinary incontinence (UI). This study aimed to investigate multidisciplinary perspectives on vaginal pessary use in clinical practice and to understand the service organisation of vaginal pessary care for women with these conditions. A pretested, anonymous survey was e-mailed to members of the Royal College of Obstetrics and Gynaecology, the Association for Continence Advice and the Association of Chartered Physiotherapists in Women's Health in the UK. A total of 678 respondents, from medical, nursing and physiotherapy professions, consented to survey participation and provided useable data (response rate 20.7 %). Doctors were significantly more likely to report involvement in pessary care than nurses or physiotherapists. Respondents were optimistic about the success of pessary treatment; however, a lower proportion reported using pessaries for UI than for prolapse. The majority of respondents used ring pessaries and shelf pessaries, most recipients were older women, and commonly an indication for fitting a pessary was that the woman was unfit for surgery. More than 15 % of respondents providing pessary care had not received training. Follow-up services for women with pessaries varied considerably. The variation in pessary care delivery and organisation requires further study in order to maximise efficiency and effectiveness. The development of nurse- or physiotherapist-led models of care may be appropriate, but the effectiveness of such models requires testing. Furthermore, to potentially improve outcomes of pessary care, a greater understanding of the availability, content and process of training may be warranted.


Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis in US clinical practice.
Accumulating evidence suggests that not all cancer chemotherapy patients who receive first-cycle pegfilgrastim prophylaxis continue to receive it in subsequent cycles and that these patients may be subsequently at higher risk of febrile neutropenia (FN). Additional evidence from US clinical practice is warranted. Data from two US private healthcare claims repositories were employed. The source population comprised adults who received "intermediate-risk" or "high-risk" chemotherapy regimens for solid cancers or non-Hodgkin's lymphoma and first-cycle pegfilgrastim prophylaxis. From the source population, all patients who did not receive second-cycle pegfilgrastim prophylaxis ("comparison patients") were matched (1:1) to those who received it ("pegfilgrastim patients") based on cancer, regimen, and propensity score. Odds ratios (OR) for FN-broad and narrow definitions-during the second chemotherapy cycle were estimated for comparison patients versus pegfilgrastim patients using generalized estimating equations. A total of 2245 comparison patients (5.3 % of source population) were matched to pegfilgrastim patients; cohorts were well-balanced on baseline characteristics. Second-cycle FN incidence proportions for comparison and pegfilgrastim patients were 3.8 versus 2.2 % based on broad definition and 2.6 versus 0.8 % based on narrow definition; corresponding OR were 1.7 (95 % CI 1.2-2.5, p = 0.002) and 3.5 (95 % CI 2.0-6.0, p < 0.001). Results were similar within cancer/regimen-subgroups and were robust when using alternative methods for confounding adjustment. In this retrospective evaluation of cancer chemotherapy patients who received first-cycle pegfilgrastim prophylaxis in US clinical practice, a clinically relevant minority did not receive second-cycle prophylaxis. Second-cycle FN odds among this subset were significantly higher than they were among those who continued prophylaxis.


Inhibition of αvβ3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles.
Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for αvβ3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. We find that SEVs secreted from MDA-MB-231 breast cancer cells carry αvβ3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of αvβ3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content. In summary, our findings demonstrate for the first time a key role of αvβ3 integrin in cell-cell communication through SEVs. Video Abstract.


[Neonatal adaptive phenomenon: secretion of beta-lipotropin, and beta-endorphin in the first week of life].
beta Lipotrophin and beta Endorphin plasma levels have been measured in 35 newborns subdivided in 5 groups of 12, 24, 48, 72 and 168 hours of life, 10 umbilical mixed blood samples were also evaluated. After plasma extraction (3 ml) and G-75 Sephadex column chromatography, the peptides were measured by two specific RIAs. beta LPH and beta EP levels were high in umbilical cord plasma (241.0 +/- 43.3 and 70.0 +/- 8.5 pg/ml respectively). A progressive decrement was then observed until the 72th hour of life (28.1 +/- 13.2 and 8.7 +/- 4.8 pg/ml respectively) but the elevated levels found at 24th hour demonstrate an active synthesis and release from fetal and neonatal pituitary. After a slight and transient decreased activity during the first week of life, the statistically significant increase of both beta LPH and beta EP observed at seven day indicate that at this moment pituitary function is restored.


[Characteristics of meningococcal meningitis in children in France].
In France, meningococcal meningitis account for 50% of bacterial meningitis in children. The GPIP/ACTIV (Groupe de Pathologie Infectieuse Pédiatrique and Association Clinique et Thérapeutique Infantile du Val de Marne) set up an active surveillance network to analyze the epidemiological, clinical and biological features of meningococcal meningitis. From 2001 to 2007, 252 French paediatric wards working with 166 microbiology laboratories enrolled all children (0-18 years old) with bacterial meningitis. Risk factors, signs and symptoms, vaccination status, cerebrospinal fluid analysis, treatments and case fatality rate were recorded. During the period of the study, 1344 meningococcal meningitis were reported among 2951 (45.5%) bacterial meningitis. Mean age was 4.4 years (+/-4.7, median 2.5) and 2/3 cases occurred in children under 5 years (68.5%). Serogroup B (59.1%) was preponderant following by serogroup C (28.9%). 25% of children had received an antibiotic treatment 24hours before lumbar puncture. A shock was reported in 31.3% of cases. Cerebrospinal fluid culture was positive in 73% of cases. All N. meningitidis isolates were susceptible to cefotaxime and ceftriaxone while 41.6% and 25.7% showed reduced susceptibility to penicillin and amoxicillin respectively. Two cases of meningitis due to isolates of serogroups C and B were reported in two children that were respectively vaccinated using A+C plain saccharide vaccine or two doses of MenBvac vaccine. All patients had received beta-lactamin. Global case fatality rate was 6.6% but was higher (9.9%) for serogroup C than for serogroup B (5.5%) (p=0,007). This study is among the largest series of microbiologically documented meningococcal meningitis to date (more than 1300 cases). In France, meningococal is responsible for 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could lessen considerably the burden of meningococal meningitis.


Analysis of genes of tetrahydrofolate-dependent metabolism from cultivated spirochaetes and the gut community of the termite Zootermopsis angusticollis.
The hindguts of wood-feeding termites are the sites of intense, CO2-reductive acetogenesis. This activity profoundly influences host nutrition and methane emissions. Homoacetogens previously isolated from diverse termites comprised novel taxa belonging to two distinct bacterial phyla, Firmicutes and Spirochates. Little else is known about either the diversity or abundance of homoacetogenic species present in any given termite or the genetic details underlying CO2-reductive acetogenesis by Spirochaetes. A key enzyme of CO2-reductive acetogenesis is formyltetrahydrofolate synthetase (FTHFS). A previously designed primer set was used to amplify FTHFS genes from three isolated termite-gut spirochaetes. Sequencing DNA flanking the FTHFS gene of Treponema strain ZAS-2 revealed genes encoding two acetogenesis-related enzymes, methenyltetrahydrofolate cyclohydrolase and methylenetetrahydrofolate dehydrogenase. Although termite-gut spirochaetes are only distantly related to clostridia at the ribosomal level, their tetrahydrofolate-dependent enzymes appear to be closely related. In contrast, homologous proteins identified in the non-homoacetogenic oral spirochaete Treponema denticola were only distantly related to those from clostridia and the termite-gut treponemes. Having demonstrated their utility with spirochaete pure cultures, the FTHFS primers were used to construct a 91-clone library from the termite-gut community DNA. From this, 19 DNA and eight amino acid FTHFS types were identified. Over 75 % of the retrieved clones formed a novel, coherent cluster with the FTHFS homologues obtained from the termite-gut treponemes. Thus, FTHFS gene diversity in the gut of the termite Zootermopsis angusticollis appears to be dominated by spirochaetes. The homoacetogenic capacity of termite-gut spirochaetes may have been acquired via lateral gene transfer from clostridia.


Propolis modulates miRNAs involved in TLR-4 pathway, NF-κB activation, cytokine production and in the bactericidal activity of human dendritic cells.
Dendritic cells (DCs) are antigen-presenting cells, essential for recognition and presentation of pathogens to T cells. Propolis, a resinous material produced by bees from various plants, exhibits numerous biological properties, highlighting its immunomodulatory action. Here, we assayed the effects of propolis on the maturation and function of human DCs. DCs were generated from human monocytes and incubated with propolis and LPS. NF-κB and cytokines production were determined by ELISA. microRNA's expression was analysed by RT-qPCR and cell markers detection by flow cytometry. Colony-forming units were obtained to assess the bactericidal activity of propolis-treated DCs. Propolis activated DCs in the presence of LPS, inducing NF-kB, TNF-α, IL-6 and IL-10 production. The inhibition of hsa-miR-148a and hsa-miR-148b abolished the inhibitory effects on HLA-DR and pro-inflammatory cytokines. The increased expression of hsa-miR-155 may be correlated to the increase in TLR-4 and CD86 expression, maintaining LPS-induced expression of HLA-DR and CD40. Such parameters may be involved in the increased bactericidal activity of DCs against Streptococcus mutans. Propolis modulated the maturation and function of DCs and may be useful in the initial steps of the immune response, providing a novel approach to the development of DC-based strategies and for the discovery of new immunomodulators.


Effect of deoxynivalenol on apoptosis, barrier function, and expression levels of genes involved in nutrient transport, mitochondrial biogenesis and function in IPEC-J2 cells.
This study was conducted to determine the effect of 200 ng mL-1 and 2000 ng mL-1 deoxynivalenol (DON) on apoptosis, barrier function, nutrient transporter gene expression, and free amino acid variation as well as on mitochondrial biogenesis and function-related gene expression in the intestinal porcine epithelial cell line J2 (IPEC-J2) for 6 h, 12 h, and 24 h. Exposure to 200 ng mL-1 DON inhibited the cell viability and promoted cell cycle progression from the G2/M phase to the S phase (P < 0.05). The data showed that the IPEC-J2 cell content of free amino acids, such as valine, methionine, leucine, and phenylalanine, was increased (P < 0.05) after treatment for 6 h; the aspartate, threonine, and lysine contents increased (P < 0.05) after treatment for 12 h; and the aspartate, serine, glycine, alanine, isoleucine, leucine, and lysine contents decreased (P < 0.05) after treatment for 24 h. The expression levels of barrier function genes, including zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 1 (CLDN1), showed a significant reduction (P < 0.05). Moreover, the expression levels of differently regulated nutrient transporter genes, including B0,+ amino acid transporter (B0,+AT) and sodium-glucose transporter 1 (SGLT1) genes, showed a significant decrease (P < 0.05), while the Na+-dependent neutral amino acid transporter 2 (ASCT2) and glucose transporter type 2 (GLUT2) showed a significant increase (P < 0.01). The expression levels of cytokine genes, including IL-8, and IL-1β genes, showed a significant increase (P < 0.05). Furthermore, the expression levels of mitochondrial biogenesis and function-related genes, including mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF), mitochondrial single-strand DNA-binding protein (mt SSB) and mitochondrial polymerase r (mt polr), NADH dehydrogenase subunit 4 (ND4) and cytochrome c oxidase (CcOX) IV, CcOX V and cytochrome c (Cyt c), mammalian silencing information regulator-2α (SIRT-1), glucokinase and citrate synthase (CS), showed a significant increase (P < 0.05). Taken together, the present study indicated that 200 and 2000 ng mL-1 DON could affect proliferation and cell cycle progression from the G2/M phase to the S phase and could mediate the expression levels of differently regulated barrier function, nutrient transport, and mitochondrial biogenesis and function-related genes.


Pulmonary surfactant-associated protein A enhances the surface activity of lipid extract surfactant and reverses inhibition by blood proteins in vitro.
Although a monolayer of dipalmitoylphosphatidylcholine, the major component of pulmonary surfactant, is thought to be responsible for the reduction of the surface tension at the air-liquid interface of the alveolus, the participation of unsaturated and anionic phospholipids and the three surfactant-associated proteins is suggested in the generation and maintenance of this surface-active monolayer. We have examined the effects of surfactant-associated protein A (SP-A) purified from bovine lavage material on the surface activity of lipid extract surfactant (LES), an organic extract of pulmonary surfactant containing all of the phospholipids and SP-B and SP-C, but lacking SP-A. Measurements of the surface tension during dynamic compression were made on a pulsating bubble surfactometer. Addition of SP-A to LES reduces the number of pulsations required to attain surface tensions near zero at minimum bubble radius. This increase in surface activity is dependent upon the presence of Ca2+ in the assay mixture. Maximal enhancement is observed at or below 1% of the lipid concentration (w/w). The addition of two blood proteins, fibrinogen and albumin, at physiological concentrations to LES causes severe inhibition of surface activity. Addition of SP-A in the presence of Ca2+ completely counteracts the inhibition by fibrinogen. The amount of SP-A required for full reversal of this inhibition was less than 0.5% of the lipid concentration. Complete reversal of inhibition by albumin was also observed, even though there was a approximately 5000-fold molar excess of inhibitor. Addition of lysophosphatidylcholine also inhibits LES; however, SP-A has no effect on this inhibition.


Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance.
The nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome. We generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD. TAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure. Our data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.


Does breastfeeding protect against allergic rhinitis during childhood? A meta-analysis of prospective studies.
The effect of breastfeeding on the development of allergic rhinitis and other atopic conditions has been assessed in many studies but remains controversial. To elucidate this issue, a systematic review was conducted of prospective studies that evaluated the association between exclusive breastfeeding during the first 3 mo after birth and allergic rhinitis. The 1966-2000 MEDLINE databases were searched and the reference lists of relevant articles were reviewed according to predetermined inclusion criteria. The methodological aspects of each study, duration and exclusivity of breastfeeding, outcome measures, control for potential confounding variables and other factors were assessed, and estimates of the association between breastfeeding and allergic rhinitis were abstracted independently by the investigators using a standardized approach. Six prospective studies met the inclusion criteria. The summary odds ratio for the protective effect of breastfeeding was 0.74 (95% confidence interval 0.54-1.01). The effect estimate in studies of children with a family history of atopy was 0.87 (95% confidence interval 0.48-1.58). Exclusive breastfeeding during the first 3 mo after birth protects against allergic rhinitis in children, both with and without a family history of atopy. The protective association, although of borderline statistical significance, was substantial. Larger prospective studies with strict methodology and longer periods of follow-up are needed.


International Collaboration and Spatial Dynamics of US Patenting in Central and Eastern Europe 1981-2010.
How did post-socialist transition and a parallel shift in international labor division restructure regional innovation systems in Central and Eastern Europe? This question is increasingly important, because current EU innovation policy is combined with regional development in Smart Specialization Strategies; however, spatial trends of innovation in Central and Eastern Europe are not fully understood which might lead to less than perfectly efficient policy. In this paper we describe the spatial dynamics of inventor activity in the Czech Republic, Hungary, Poland and Slovakia between 1981 and 2010 -a period that covers both the late socialist era and the post-socialist transition. Cleaning and analyzing the publicly available data from the United States Patent and Trademark Office we illustrate that Central and Eastern European patents made in international co-operations with partners outside the region receive more citations than those Central and Eastern European patents that lack international co-operation. Furthermore, the technological portfolio of the former patents has become increasingly independent from the technological portfolio of the latter class. A town-level analysis of the applicant-inventor ties reveals that inventors have started to work for foreign assignees in those towns where no innovation activity had been recorded before. However, the positive effect does not last long and patenting seems to be only periodic in the majority of these towns. Therefore, innovation policy in Central and Eastern European countries, as well as in other less developed regions, shall foster synergies between international and domestic collaborations in order to decrease regional disparities in patenting.


Enantioselective synthesis of (+)-brevipolide H.
The enantioselective synthesis of natural brevipolide H is reported for the first time. By way of Sharpless epoxidation of penta-1,4-dien-3-ol, both enantiomerically pure epoxides were converted to the corresponding olefins for cross metathesis. Subsequent transformations, including epoxide ring opening, esterifications, cyclopropanation, oxidation and ring-closing metathesis, provided the target molecule. This synthesis successfully addresses previous shortcomings in preparing brevipolides.


Hybrid Evolutionary Approaches to Maximum Lifetime Routing and Energy Efficiency in Sensor Mesh Networks.
Mesh network topologies are becoming increasingly popular in battery-powered wireless sensor networks, primarily because of the extension of network range. However, multihop mesh networks suffer from higher energy costs, and the routing strategy employed directly affects the lifetime of nodes with limited energy resources. Hence when planning routes there are trade-offs to be considered between individual and system-wide battery lifetimes. We present a multiobjective routing optimisation approach using hybrid evolutionary algorithms to approximate the optimal trade-off between the minimum lifetime and the average lifetime of nodes in the network. In order to accomplish this combinatorial optimisation rapidly, our approach prunes the search space using k-shortest path pruning and a graph reduction method that finds candidate routes promoting long minimum lifetimes. When arbitrarily many routes from a node to the base station are permitted, optimal routes may be found as the solution to a well-known linear program. We present an evolutionary algorithm that finds good routes when each node is allowed only a small number of paths to the base station. On a real network deployed in the Victoria & Albert Museum, London, these solutions, using only three paths per node, are able to achieve minimum lifetimes of over 99% of the optimum linear program solution's time to first sensor battery failure.


(n-3) fatty acids and cancer therapy.
Supplementing the diet of tumor-bearing mice or rats with oils containing (n-3) (omega-3) or with purified (n-3) fatty acids has slowed the growth of various types of cancers, including lung, colon, mammary, and prostate. The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, CPT-11, 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included (n-3) fatty acids. Some potential mechanisms for the activity of (n-3) fatty acids against cancer include modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, and estrogen signaling. In humans, (n-3) fatty acids have also been used to suppress cancer-associated cachexia and to improve the quality of life. In one study, the response to chemotherapy therapy was better in breast cancer patients with higher levels of (n-3) fatty acids in adipose tissue [indicating past consumption of (n-3) fatty acids] than in patients with lower levels of (n-3) fatty acids. Thus, in combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer. Used alone, an (n-3) supplement may be a useful alternative therapy for patients who are not candidates for standard toxic cancer therapies.


Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).
Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping. The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis. Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.


Effect of a walnut meal on postprandial oxidative stress and antioxidants in healthy individuals.
In vitro studies rank walnuts (Juglans regia) among the plant foods high in antioxidant capacity, but whether the active constituents of walnuts are bioavailable to humans remains to be determined. The intention of this study was to examine the acute effects of consuming walnuts compared to refined fat on meal induced oxidative stress. At issue is whether the ellagitannins and tocopherols in walnuts are bioavailable and provide postprandial antioxidant protection. A randomized, crossover, and controlled-feeding study was conducted to evaluate a walnut test meal compared to one composed of refined ingredients on postprandial serum antioxidants and biomarkers of oxidative status in healthy adults (n = 16) with at least 1 week between testing sessions. Following consumption of a low phenolic diet for one day and an overnight fast, blood was sampled prior to the test meals and at intervals up to 24 hours post ingestion and analyzed for total phenols, malondiadehyde (MDA), oxidized LDL, ferric reducing antioxidant power (FRAP), hydrophilic and lipophilic oxygen radical absorbance capacity (ORAC), uric acid, catechins and urinary excretion of phenylacetate metabolites and of urolithin A. Mixed linear models demonstrated a diet effect (P < 0.001) for plasma γ-tocopherol but not for α-tocopherol with the walnut meal. Following the walnut test meal, the incremental 5 hour area under the curve (AUC(0-5h)) was reduced 7.4% for MDA, increased 7.5% for hydrophilic and 8.5% for lipophilic ORAC and comparable for total phenols, FRAP and uric acid. Oxidized LDL was reduced at 2 hours after the walnut meal. Plasma concentrations of gallocatechin gallate (GCG), epicatechin gallate (ECG) and epicallocatechin gallate (EGCG) increased significantly at 1 hour after the walnut test meal. Quantities of urolithin-A excreted in the urine were significantly higher following the walnut meal. Compared to the refined control meal, the walnut meal acutely increased postprandial γ-tocopherol and catechins and attenuated some measures of oxidative stress.


Informed consent and incompetent medical patients.
The mentally incapacitated patient is frequently encountered in the general medical hospital. Incapacity is the clinical state in which a patient is unable to participate in a meaningful way in medical decisions. Mentally incapacitated patients relinquish the authority, that is the competent patient's right, to choose among professionally acceptable alternative treatments. Such patients, therefore, require a surrogate decision-maker. There are certain clinical situations in which questions of incapacity are especially important to consider. In a study for the President's Commission for the Study of Ethical Problems in Medical Biomedical and Behavioral Research, the most common problem in recognizing incapacity was found with previously capable patients who became transiently incapacitated during the course of hospitalization. Questions of incapacity or the authority of surrogate decision-makers also arose with comatose, mentally retarded, mentally ill, and physically handicapped patients. While standards to determine capacity remain unclear, a practical approach is to demonstrate that a patient is able to describe the physician's view of the situation and to understand the physician's opinion as to the best intervention. When a patient is deemed to be incapacitated, the physician should turn to family members, whenever possible, to make decisions.


Differences in physical performance based on the Geriatric Nutritional Risk Index in elderly female cardiac patients.
Little is known about differences in the risk of poor nutritional status as assessed by the Geriatric Nutritional Risk Index (GNRI) in relation to physical performance in elderly female cardiac inpatients. The present study aimed to determine both differences in physical performance based on the GNRI and physical performance cut-off values according to the GNRI in elderly female cardiac inpatients. We enrolled 105 consecutive female Japanese inpatients aged ≥65 years (mean age, 74.6 years) with cardiac disease in this cross-sectional study. We divided the patients into two groups according to GNRI: high-GNRI group (≥92 points) (n = 71) and low-GNRI group (<92 points) (n = 34). Handgrip strength (HG), knee extensor muscle strength (KEMS), gait speed (GS), and one-leg standing time (OLST) were assessed as indices of hospital physical performance and compared between the two groups to determine cut-off values of physical performance. After adjustment for age and left ventricular ejection fraction, HG, KEMS, GS, and OLST were significantly lower in the low-GNRI versus high-GNRI group. Cut-off values by ROC curve analysis were 16.2 kgf (AUC = 0.66; p < 0.001) for HG, 34.3 % of body weight (AUC = 0.62; p = 0.04) for KEMS, 1.24 m/s (AUC = 0.72; p < 0.01) for GS, and 8.28 s (AUC = 0.62; p = 0.04) for OLST. The risk of poor nutrition, as indicated by a low GNRI, might be a predictor of lower physical performance. Cut-off values determined in this study might be minimum target goals for physical performance that can be attained by elderly female cardiac inpatients.


[Structure and ultrastructure of the ovary of Cichlasoma urophthalmus (Osteichthyes: Cichlidae)].
The study of the normal development, differentiation, structure and function of various components of developing follicles in the ovaries of numerous fish species have been a consistent focus of comparative reproduction. The structural and ultrastructural features of gonads from Cichlasoma urophthalmus have received scarce attention. In this work, we realized a descriptive study of female gonads of Cichlasoma urophthalmus. A total of 40 samples were collected in the Veracruz Alvarado Lagoon, Mexico in 2007-2008 period including the windy, dry and rainy seasons. Female gonads were extracted and a portion was fixed in 4% formaldehyde for treatment for routine histology hematoxylin and eosin (HE) and another part was processed for transmission electron microscopy (TEM). The gonads were fixed in 3% glutaraldehyde and 2% osmium tetroxide, followed by dehydrated in ethanol 50%, 70%, 80%, 95% and 100% for inclusion in Epon, thin sections were then prepared and were contrasted with lead citrate and uranyl acetate. The process of oocyte development can be divided into five distinct stages (formation of oocytes from oogonia, primary growth, lipid stage, vitellogenesis and maturation). In this work, we found that the primary growth stage is characterized by intense RNA synthesis and the differentiation of the vitelline envelope. Secondary growth starts with the accumulation of lipid droplets in the oocyte cytoplasm (lipid stage), which is then followed by massive uptake and processing of proteins into yolk platelets (vitellogenic stage). During the maturation stage, the lipid inclusions coalesce into a single oil droplet, and hydrolysis of the yolk platelets leads to the formation of a homogeneous mass of fluid yolk in mature eggs. In conclusion, further studies should elucidate structure and ultrastructural changes in the ovarian follicular components, in C. urophthalmus during different stages of oocyte growth.


Full control over the electric field using four liquid crystal arrays.
We present a femtosecond pulse shaper setup that is capable of shaping the phase, amplitude, and polarization simultaneously and independently. The modulator utilizes four liquid crystal arrays, a pair of half-wave plates, and a polarizer to gain full control of the electrical field. This is done in a common-path common-optic scheme without using interferometry. The functionality of the setup is demonstrated by using systematic parameter scans and example pulses.


Enhancing Executive Function and Neural Health in Bipolar Disorder through Reasoning Training.
Cognitive deficits in executive function and memory among individuals with bipolar disorder (BD) are well-documented; however, only recently have efforts begun to address whether such cognitive deficits can be ameliorated through cognitive training. This pilot study examined the effects of a top-down, cognitive reasoning training program in adults with BD on both brain and cognitive measures. Twenty-seven participants (11 males, 16 females), aged 21-70 years old, completed the study. Participants completed neurocognitive testing and functional magnetic resonance imaging (fMRI) before and after training, consisting of 8 h (2 h/week) of training in small groups. The training delivered information processing strategies that were implemented and applicable to a variety of daily living contexts. Results indicated that participants showed significant gains in the primary outcome measure of complex abstraction, also referred to as gist reasoning, as well as in untrained domains of executive function and memory. We found a significant increase in resting cerebral blood flow (CBF) in left inferior frontal gyrus after cognitive training. We also found that resting CBF in the right frontal middle gyrus correlated positively with performance on the measure of complex abstraction. This feasibility study provides promising evidence that short-term reasoning training can enhance cognitive performance and brain health in adults with BD. These data motivate further efforts to explore adjuvant therapeutics to improve cognitive performance and underlying brain systems in bipolar, as well as other psychiatric disorders. Clinicaltrials.gov Identifier: NCT02843282, http://www.clinicaltrials.gov/ct2/show/NCT02843282.


The mouse ADP-ribosylation factor-like 4 gene: two separate promoters direct specific transcription in tissues and testicular germ cell.
ADP-ribosylation factor-like protein 4 (ARL4) is a Ras-related GTPase that has been cloned from the 3T3-L1 preadipocyte cell line as an adipocyte-specific cDNA [Schürmann, Breiner, Becker, Huppertz, Kainulainen, Kentrup and Joost (1994) J. Biol. Chem. 269, 15683-15688]. The Arl4 gene maps to the proximal region of mouse chromosome 12 linked to Lamb1-1, Hfhbf1 and Sos2. Compared with all other known genes of Ras-related GTPases, the genomic organization of Arl4 is unusual in that its entire coding region, the 3' untranslated region (UTR) and most of the 5' UTR are located on a single exon. This structure suggests that Arl4 has evolved by retroposition of an Arf (ADP-ribosylation factor) or Arf-like gene. Isolation of the 5' UTR by rapid amplification of cDNA ends (RACE)-PCR revealed heterogeneous transcription initiation sites in alternative exons 1. Both 5'-flanking regions exhibited promoter activity when expressed in COS-7 cells, indicating that the expression of Arl4 is directed by two separate promoters. mRNA transcribed under the control of the downstream promoter was isolated by RACE-PCR from all investigated tissues. In contrast, the upstream promoter seems to drive specifically the expression of Arl4 in adult testis. Hybridization of rat testis in situ indicated that Arl4 is expressed in germ cells of puberal and adult testis, but not in prepuberal testis, suggesting that Arl4 is involved in sperm production.


Angiographic contrast media relax isolated rabbit aorta through an endothelium-independent mechanism that may not depend on the presence of the iodine atom.
Systemically administered iodinated angiographic contrast media evoke vasodilatation through mechanisms that are at present poorly understood. In the current investigation we have evaluated the role of the vascular endothelium in responses to an iso-osmolar formation of the non-ionic dimer iodixanol and a hyperosmolar formulation of the non-ionic monomer iopromide. Isolated rabbit aortic ring preparations with endothelium intact or removed by gentle abrasion were mounted in organ baths containing oxygenated Holman's solution, and cumulative concentration-response curves for relaxation to the contrast media were constructed after pre-constriction by phenylephrine (300 nM) in the presence of indomethacin to inhibit prostaglandin synthesis. Endothelial denudation did not influence the ability of either iodixanol or iopromide to relax the aortic ring preparations. Iopromide was significantly more potent than iodixanol when expressed in terms of iodine concentration (mg I ml-1), but both agents were equipotent when expressed in terms of molarity (mM). We conclude that relaxation of isolated rabbit aortic rings to iodixanol and iopromide under conditions where there is no fluid flow is endothelium-independent, and therefore not mediated by release of the potent endogeneous nitrovasodilator endothelium-derived relaxing factor (EDRF). Furthermore, their relaxant activity under the in vitro experimental conditions employed is attributable to a direct action on vascular smooth muscle by factors in addition to osmolality, and may depend on features that are not specifically associated with the presence of the iodine atom.


The First Decade with the Swedish Prescribed Drug Register - A Systematic Review of the Output in the Scientific Literature.
The aim of this study was to quantify and characterize the scientific output from the Swedish Prescribed Drug Register (SPDR) the first decade after its establishment. A systematic literature search was performed in Medline, EMBASE and PubMed (2005-2014). Additional publications were identified by personal knowledge, reference lists, contact with active authors and a citation search in Web of Sciences. Publications using SPDR data were included in the analysis and characterized regarding study type, presence of patient-level record linkage, target population and topic. A total of 719 publications were identified in the literature search and an additional 148 by other strategies. Three hundred and thirty-eight studies fulfilled the inclusion criteria. The majority were analytic (n = 166; 49.1%) or descriptive (n = 100; 29.5%). The remaining studies focused on validation (n = 20; 5.9%), health economics (n = 16; 4.7%) or miscellaneous (n = 36; 10.7%). The analytic studies investigating effects of drug exposure focused mainly on safety (n = 46) and/or effectiveness (n = 24). The first publications appeared in 2007 (n = 6), and in 2014, 90 articles using SPDR were published. Over the years, linkage with other registers using the personal identity number increased (0-88.9% of the publications). The population was often selected by age (49.7%), condition (45.0%) and/or drug (22.8%) and concerned predominantly psychiatric (29.0%) and cardiovascular (20.4%) diseases. In conclusion, this study illustrates that the establishment of a nationwide individual-based register on dispensed prescription drugs facilitates an encouraging development of pharmacoepidemiological research, both regarding the number of publications and the scientific level of the analyses.


Expression and function of HLA-B27 in lipid-linked form: implications for cytotoxic T lymphocyte-induced apoptosis signal transduction.
Major histocompatibility complex (MHC) class I antigen-restricted cytotoxic T lymphocytes (CTL) kill their target cells not only by inducing irreversible membrane damage but also by triggering a programmed suicide cascade (apoptosis) in target cells. Recent evidence suggests that MHC class I antigens are involved in apoptosis signal transduction in T cells. Therefore, it is possible that MHC class I antigens are also responsible for CTL-induced signal transduction in target cells leading to apoptosis. To test this hypothesis, we have expressed HLA-B27 in Chinese hamster ovary (CHO) cells in a phosphatidyl inositol (PI) anchored form. The expressed Pl-anchored HLA-B27 (PI-B27), a 42-kDa molecule which can be cleaved off the cell surface by PI-specific phospholipase C, can function as an MHC restriction and antigen presentation element for specific CTL. Furthermore, PI-B27 transfectant CHO cells undergo rapid DNA fragmentation when pulsed with the appropriate peptide and treated with specific CTL, suggesting that the cytoplasmic and transmembrane domains of the heavy chain of class I MHC molecules are not required in CTL-induced apoptosis signal transduction in target cells.


Efficacy of poly(adenosine diphosphate-ribose) polymerase inhibition in extracorporeal shock wave-induced renal injury.
Extracorporeal shock wave lithotripsy (ESW) induces renal damage by excessive production of free oxygen radicals. Free Oxygen radicals cause cellular injury by inducing nicks in DNA. The enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) involved in the process of repair of DNA in damaged cells. However, its activation in damaged cells can lead to adenosine triphosphate depletion and death. Thus, we designed a study to evaluate the efficacy of 3-aminobenzamide (3-AB), a PARP inhibitor, against extracorporeal shock wave induced renal injury. Twenty-four Sprague-Dawley rats were divided into three groups: control, ESW, ESW + 3-AB groups. All groups except control group were subjected to ESW procedure. ESW + 3-AB group received 20 mg/kg/day 3-aminobenzamide intraperitoneally at 2 h before ESW and continued once a day for consecutive 3 days. The surviving animals were sacrificed at the 4th day and their kidneys were harvested for biochemical and histopathologic analysis. Blood samples from animals were also obtained. Serum ALT and AST levels, serum neopterin and tissue oxidative stress parameters were increased in the ESW group and almost came to control values in the treatment group (p < 0.05, ESW vs. ESW + 3-AB). Histopathological injury score were significantly lower in treatment group than the ESW group (p < 0.05, ESW vs. ESW + 3-AB). Our data showed that PARP inhibition protected renal tissue against ESW induced renal injury. These findings suggest that it would be possible to improve the outcome of ESW induced renal injury by using PARP inhibitors as a preventive therapy.


Medicare Part D and quality of prescription medication use in older adults.
In 2006, the US Centers for Medicare and Medicaid Services implemented Medicare Part D to provide outpatient prescription drug insurance to disabled and older adults. In creating Part D, a key provision to address quality included medication therapy management (MTM) programmes designed to increase proper and safe use of medications among targeted Part D beneficiaries. A preponderance of evidence shows that Part D has increased medication affordability and accessibility; however, what remains less clear is whether it has improved the quality of medication use and optimized health outcomes. Now in its sixth year, Part D is undergoing its first major revision, with the gradual elimination of the coverage gap by 2020. Therefore, now is a good time to review the accumulated evidence on the impact of Part D and MTM programmes on the quality of medication use to help inform future policy decisions and research directions. In this review, we found that Part D's net effect on quality of medication use has mainly been positive. Cost-related medication nonadherence improved moderately and there were fewer than expected treatment interruptions. However, vulnerable subgroups, such as sicker and dual-eligible beneficiaries, experienced lags in improvement. Beneficiaries who entered the coverage gap consistently experienced interruptions and displayed worsening medication adherence after entering the gap, with generic-only gap drug coverage offering limited benefit. Such findings can serve as baseline information as the coverage gap phases out. Limited availability of data is the greatest barrier to research into Part D. Part D's overall effect on health outcomes and adverse medical events, such as hospitalizations, is inconclusive because of inadequate evidence to date. Similarly, no evaluation of quality of medication use is available with respect to utilization management strategies and MTM programmes delivered under Part D. Future research will need to further examine the added value of Part D and address whether Part D optimizes health outcomes in the Medicare population. As the current economic recession increases the pressure to cut costs, the effect of future spending restrictions, such as restrictions on coverage subsidies, will also be of special concern.


The prevalence and phenomenology of self-injurious and aggressive behaviour in genetic syndromes.
Self-injurious and aggressive behaviours are reported as components of some behavioural phenotypes but there are few studies comparing across syndrome groups. In this study we examined the prevalence of these behaviours and the associated person characteristics in seven genetic syndromes. Questionnaire data on self-injury and aggression, mood, hyperactivity, autism spectrum disorder and repetitive behaviour were collected on Angelman (AS, n=104), Cornelia de Lange (CdLS, 101), Cri du Chat (CdCS, 58), Fragile X (FXS, 191), Lowe (LS, 56), Prader-Willi (PWS, 189) and Smith-Magenis (SMS, 42) syndromes. A significantly higher prevalence of self-injury was evident in CdCS, CdLS, FXS, PWS, LS and SMS. The prevalence of aggression was significantly heightened in AS and SMS. Self-injury was associated with repetitive and impulsive behaviour in CdLS, FXS, PWS and LS. Impulsivity and overactivity were significantly higher in those showing aggression across all syndrome groups. These data quantify the risk for self-injury and aggression in the syndromes studied with implications for early intervention. The associations between these behaviours and person characteristics both within and between syndromes warrant further research.


Validation of PhenX measures in the personalized medicine research project for use in gene/environment studies.
The purpose of this paper is to describe the data collection efforts and validation of PhenX measures in the Personalized Medicine Research Project (PMRP) cohort. Thirty-six measures were chosen from the PhenX Toolkit within the following domains: demographics; anthropometrics; alcohol, tobacco and other substances; cardiovascular; environmental exposures; cancer; psychiatric; neurology; and physical activity and physical fitness. Eligibility criteria for the current study included: living PMRP subjects with known addresses who consented to future contact and were not currently living in a nursing home, available GWAS data from eMERGE I for subjects where age-related cataract, HDL, dementia and resistant hypertension were the primary phenotypes, thus biasing the sample to the older PMRP participants. The questionnaires were mailed twice. Data from the PhenX measures were compared with information from PMRP questionnaires and data from Marshfield Clinic electronic medical records. Completed PhenX questionnaires were returned by 2271 subjects for a final response rate of 70%. The mean age reported on the PhenX questionnaire (73.1 years) was greater than the PMRP questionnaire (64.8 years) because the data were collected at different time points. The mean self-reported weight, and subsequently calculated BMI, were less on the PhenX survey than the measured values at the time of enrollment into PMRP (PhenX means 173.5 pounds and BMI 28.2 kg/m2 versus PMRP 182.9 pounds and BMI 29.6 kg/m2). There was 95.3% agreement between the two questionnaires about having ever smoked at least 100 cigarettes. 139 (6.2%) of subjects indicated on the PhenX questionnaire that they had been told they had a stroke. Of them, only 15 (10.8%) had no electronic indication of a prior stroke or TIA. All of the age-and gender-specific 95% confidence limits around point estimates for major depressive episodes overlap and show that 31% of women aged 50-64 reported symptoms associated with a major depressive episode. The approach employed resulted in a high response rate and valuable data for future gene/environment analyses. These results and high response rate highlight the utility of the PhenX Toolkit to collect valid phenotypic data that can be shared across groups to facilitate gene/environment studies.


Forces and stress in second order Møller-Plesset perturbation theory for condensed phase systems within the resolution-of-identity Gaussian and plane waves approach.
The forces acting on the atoms as well as the stress tensor are crucial ingredients for calculating the structural and dynamical properties of systems in the condensed phase. Here, these derivatives of the total energy are evaluated for the second-order Møller-Plesset perturbation energy (MP2) in the framework of the resolution of identity Gaussian and plane waves method, in a way that is fully consistent with how the total energy is computed. This consistency is non-trivial, given the different ways employed to compute Coulomb, exchange, and canonical four center integrals, and allows, for example, for energy conserving dynamics in various ensembles. Based on this formalism, a massively parallel algorithm has been developed for finite and extended system. The designed parallel algorithm displays, with respect to the system size, cubic, quartic, and quintic requirements, respectively, for the memory, communication, and computation. All these requirements are reduced with an increasing number of processes, and the measured performance shows excellent parallel scalability and efficiency up to thousands of nodes. Additionally, the computationally more demanding quintic scaling steps can be accelerated by employing graphics processing units (GPU's) showing, for large systems, a gain of almost a factor two compared to the standard central processing unit-only case. In this way, the evaluation of the derivatives of the RI-MP2 energy can be performed within a few minutes for systems containing hundreds of atoms and thousands of basis functions. With good time to solution, the implementation thus opens the possibility to perform molecular dynamics (MD) simulations in various ensembles (microcanonical ensemble and isobaric-isothermal ensemble) at the MP2 level of theory. Geometry optimization, full cell relaxation, and energy conserving MD simulations have been performed for a variety of molecular crystals including NH3, CO2, formic acid, and benzene.


Diagnostic accuracy of ambulatory ECG monitoring in ischemic heart disease.
Fifty patients with precordial pain were evaluated by 24 hour ambulatory ECG monitoring during normal everyday activities, and by coronary arteriography. The monitoring was regarded as positive if deviation of the ST segment of 1 mm or more from the resting pattern was observed, or if major T wave inversion occurred. Comparison of the results of the two tests showed a good correlation. Among the 32 patients with positive abnormalities on ECG monitoring, 28 had severe coronary disease (greater than 60% obstruction). Among the 18 patients with negative monitoring, only three had severe coronary disease. All seven patients with major T inversion had significant coronary obstruction. The type of chest pain and the resting ECG were less indicative of coronary pathology. The good correlation demonstrated between the ambulatory ECG monitoring and coronary arteriograms validates the monitoring as a reliable tool for uncovering latent ischemic heart disease (IHD) and for evaluation of patients with established IHD.


Swallowing in moderate and severe phases of Alzheimer's disease.
To characterize the problems of feeding and swallowing in individuals with moderate and severe Alzheimer´s disease (AD) and to correlate these with functional aspects. Fifty patients with AD and their caregivers participated in this study. The instruments used were: Clinical Dementia Rating (CDR), Mini-Mental State Examination, Index of Activities of Daily Living, Assessment of Feeding and Swallowing Difficulties in Dementia, Functional Outcome Questionnaire for Aphasia, and Swallowing Rating Scale. Problems with passivity, distraction and refusal to eat were encountered in the CDR2 group. Distraction, passivity and inappropriate feeding velocity were predominant in the CDR3 group. The problems were correlated with communication, swallowing severity of AD individuals and caregiver schooling. Given the inexorable functional alterations during the course of the disease, it is vital to observe these in patients with a compromised feeding and swallowing mechanism. The present study supplies the instruments to orient caregivers and professionals.


Vitamin D3 supplementation alleviates rotavirus infection in pigs and IPEC-J2 cells via regulating the autophagy signaling pathway.
Vitamin D had an anti-infection effect and benefited to the intestinal health. Autophagy signaling pathway was regulated by vitamin D3 to inhibit the infection of human immunodeficiency virus type-1. Rotavirus (RV) was a major cause of the severe diarrheal disease in young children and young animals. Although evidence suggested that vitamin D3 attenuates the negative effects of RV infection via the retinoic acid-inducible gene I signaling pathway, little is known of its antiviral effect whether through the regulation of autophagy. The present study was performed to investigate whether vitamin D3 alleviates RV infection in pig and porcine small intestinal epithelial cell line (IPEC-J2) models via regulating the autophagy signaling pathway. RV administration increased the Beclin 1 mRNA abundance in porcine jejunum and ileum. 5000 IU/kg dietary vitamin D3 supplementation greatly up-regulated LC3-II/LC3-I ratios and PR-39 mRNA expression under the condition of RV challenged. The viability of IPEC-J2 was significantly inhibited by RV infection. Incubation with 25-hydroxyvitamin D3 significantly decreased the concentrations of RV antigen and non-structural protein 4 (NSP4), and up-regulated the mRNA expression of Beclin 1 and PR-39 in the RV-infected IPEC-J2 cells. And then, based on the 25-hydroxyvitamin D3 treatment and RV infection, LC3-II mRNA expression in cells was inhibited by an autophagy inhibitor 3-methyladenine (3-MA). Bafilomycin A1 (Baf A1, a class of inhibitors of membrane ATPases, inhibits maturation of autophagic vacuoles) treatment numerically enhanced the LC3-II mRNA abundance, but had no effect on NSP4 concentration. Furthermore, 25-hydroxyvitamin D3 decreased the p62 mRNA expression and increased porcine cathelicidins (PMAP23, PG1-5 and PR-39) mRNA expression in the RV-infected cells. Taken together, these results indicated that vitamin D3 attenuates RV infection through regulating autophagic maturation and porcine cathelicidin genes expression.


Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation.
The sequence of neural responses to exogenous arterial pressure manipulation remains unclear, especially for extramedullary sites. We used functional magnetic resonance imaging procedures to visualize neural responses during pressor (phenylephrine) and depressor (sodium nitroprusside) challenges in seven isoflurane-anesthetized adult cats. Depressor challenges produced signal-intensity declines in multiple cardiovascular-related sites in the medulla, including the nucleus tractus solitarius, and caudal and rostral ventrolateral medulla. Signal decreases also emerged in the cerebellar vermis, inferior olive, dorsolateral pons, and right insula. Rostral sites, such as the amygdala and hypothalamus, increased signal intensity as arterial pressure declined. In contrast, arterial pressure elevation elicited smaller signal increases in medullary regions, the dorsolateral pons, and the right insula and signal declines in regions of the hypothalamus, with no change in deep cerebellar areas. Responses to both pressor and depressor challenges were typically lateralized. In a subset of animals, barodenervation resulted in rises and falls of blood pressure that were comparable to these resulting from the pharmacological challenges but different regional neural responses, indicating that the regional signal intensity responses did not derive from global perfusion effects but from baroreceptor mediation of central mechanisms. The findings demonstrate widespread lateralized distribution of neural sites responsive to blood pressure manipulation. The distribution and time course of neural responses follow patterns associated with early and late compensatory reactions.


A preliminary analysis of aortic injuries in lateral impacts.
Injuries to the aorta are among the more serious injuries that result from vehicle impacts, and often may be fatal. This article examines the incidence of aortic injuries in the United States and United Kingdom by using two international databases of real-world crashes. The main outcome of interest was the level of risk associated with each principal direction of force for drivers and front-seat passengers with respect to sustaining aortic injuries. The results indicate that the risk of sustaining an injury to the aorta is greater for near-side crashes than for far-side crashes. Further it is apparent that, given a near-side crash, the risk of an aortic injury is greater on the left side of the body (and left side of the vehicle) than on the right. It also was found that the delta-V of crashes where occupants sustained an injury to the aorta was considerably higher than crashes where occupants did not sustain aortic injuries. It is speculated that the anatomical asymmetry of the thorax might play a role in the differences seen in injury risk associated with different impact directions. The results presented in this article could be of use to both the emergency physician treating patients involved in motor vehicle collisions as well as the engineer involved in occupant design countermeasures. Limitations and further planned research are discussed.


Mechanistic aspects of hydrazine-induced Pt colloid instability and monitoring aggregation kinetics with nanoparticle impact electroanalysis.
Here we investigate the mechanistic aspects of Pt nanoparticle (NP) aggregation in solutions typically used for detecting NP/electrode impacts by electrocatalytic amplification (ECA). We previously proposed a general mechanism for Pt colloid destabilization that involved the participation of both the hydrazine redox probe and the pH buffer species as coagulants. Herein the Pt NP coagulation and aggregation mechanisms were further investigated with microscopic kinetic NP concentration monitoring and zeta potential measurements using nanoparticle tracking analysis (NTA), as well as open circuit potential experiments with a citrate-treated polycrystalline Pt surface to assess electrical double layer potential. After considering the combined results of these experiments we propose that the colloidal stability of citrate-capped platinum nanoparticles involves much more than the typical physicochemical interactions predicted by DLVO theory. A structure based on intermolecular H-bonding in the citrate capping layer is the most plausible explanation for the exceptional stability of large Pt NPs in high ionic strength buffers. Thus, the mechanism of Pt NP aggregation includes specific reactive contributions from hydrazine. The catalytic decomposition of hydrazine, in particular, is thought to occur to some extent at the citrate-coated Pt surface while the citrate remains adsorbed. Evolved gases such as ammonia and possible surface bound intermediates from Pt-catalyzed decomposition of hydrazine may disrupt the stability of the citrate layer, causing colloidal instability and thus promoting Pt NP coagulation. In the closing section, we demonstrate nanoparticle impact electroanalysis by ECA detection as a method to quantify Pt NP concentration with adequate time resolution for monitoring the kinetics of Pt NP coagulation.


Serological diagnosis of echinococcosis: the diagnostic potential of native antigens.
Human alveolar (AE) and cystic echinococcosis (CE) caused by the metacestode stages of Echinococcus multilocularis and E. granulosus, respectively, lack pathognomonic clinical signs. Diagnosis therefore relies on the results of imaging and serological studies. The primary goal of this study was to evaluate the efficacy of several easy-to-produce crude or partially purified E. granulosus and E. multilocularis metacestode-derived antigens as tools for the serological diagnosis and differential diagnosis of patients suspicious for AE or CE. The sera of 51 treatment-naïve AE and 32 CE patients, 98 Swiss blood donors and 38 patients who were initially suspicious for echinococcosis but suffering from various other liver diseases (e.g., liver neoplasia, etc.) were analysed. According to the results of enzyme-linked immunosorbent assays (ELISA), metacestode-derived antigens of E. granulosus had sensitivities varying from 81 to 97% and >99.9% for the diagnosis of CE and AE, respectively. Antigens derived from E. multilocularis metacestodes had sensitivities ranging from 84 to 91% and >99.9% for the diagnosis of CE and AE, respectively. Specificities ranged from 92 to >99.9%. Post-test probabilities for the differential diagnosis of AE from liver neoplasias, CE from cystic liver lesions, and screening for AE in Switzerland were around 95, 86 and 2.2%, respectively. Cross-reactions with antibodies in sera of patients with other parasitic affections (fasciolosis, schistosomosis, amebosis, cysticercosis, and filarioses) did occur at variable frequencies, but could be eliminated through the use of confirmatory testing. Different metacestode-derived antigens of E. granulosus and E. multilocularis are valuable, widely accessible, and cost-efficient tools for the serological diagnosis of echinococcosis. However, confirmatory testing is necessary, due to the lack of species specificity and the occurrence of cross-reactions to other helminthic diseases.


Dysregulated claudin-5 cycling in the inner retina causes retinal pigment epithelial cell atrophy.
Age-related macular degeneration (AMD) is the leading cause of central retinal vision loss worldwide, with an estimated 1 in 10 people over the age of 55 showing early signs of the condition. There are currently no forms of therapy available for the end stage of dry AMD, geographic atrophy (GA). Here, we show that the inner blood-retina barrier (iBRB) is highly dynamic and may play a contributory role in GA development. We have discovered that the gene CLDN5, which encodes claudin-5, a tight junction protein abundantly expressed at the iBRB, is regulated by BMAL1 and the circadian clock. Persistent suppression of claudin-5 expression in mice exposed to a cholesterol-enriched diet induced striking retinal pigment epithelium (RPE) cell atrophy, and persistent targeted suppression of claudin-5 in the macular region of nonhuman primates induced RPE cell atrophy. Moreover, fundus fluorescein angiography in human and nonhuman primate subjects showed increased retinal vascular permeability in the evening compared with the morning. These findings implicate an inner retina-derived component in the early pathophysiological changes observed in AMD, and we suggest that restoring the integrity of the iBRB may represent a novel therapeutic target for the prevention and treatment of GA secondary to dry AMD.


Potential success of near-total laryngectomy despite postoperative radiation therapy.
Advanced laryngeal cancers frequently require total laryngectomy (TL). Some of these cancers, however, are suitable for near-total laryngectomy (NTL). We review our experience with NTL over a 14-year period and compare the functional results with those obtained over the same period using TL followed by tracheoesophageal puncture (TEP). One particular interest was the results achieved when surgery was preceded or followed by radiation therapy. From January 1980 through December 1994, 22 patients underwent NTL. The mean age of the 19 men (86.4%) and 3 women (13.6%) was 61.1 +/- 9.9 years. Follow-up ranged from 4 to 109 months, with a mean of 26.5 months. The local control rate was 90.9% (i.e., 20 of the 22 patients). Over the same time period, 11 TEPs were performed in 7 men (63.6%) and 4 women (36.4%) who had a mean age of 60.4 +/- 7.2 years. Compared with the TEP group, the patients in the NTL group had higher mean scores for swallowing, aspiration, and voice quality evaluations, although the differences were not statistically significant. Notably, 21 of 22 patients (95.5%) received preoperative or postoperative radiotherapy. Complications in the NTL group included aspiration, dilated shunt appendix, and inadequate tracheopharyngeal shunt function. Slight modifications of the NTL technique, including routine entrance into the vallecula in uninvolved larynges, the use of contralateral pyriform mucosa flaps, and the performance of an H-flap tracheostomy are described. The NTL is a sound oncologic procedure for tumors causing vocal cord fixation, and it can be successful even when postoperative radiotherapy is administered. The quality of speech, the ease of swallowing, and the incidence of aspiration are similar to those in patients who have had a TEP following TL.


Recent advances and future prospects in choroideremia.
Choroideremia is a complex and rare disease that is frequently misdiagnosed due to its similar appearance to classic retinitis pigmentosa. Recent advances in genetic testing have identified specific genetic mutations in many retinal dystrophies, and the identification of the mutation of the CHM gene on the X chromosome 25 years ago has paved the way for gene replacement therapy with the first human trials now underway. This article reviews the epidemiological and pathological features of choroideremia and new prospects in imaging to monitor disease progression, as well as potential treatment approaches for choroideremia.


Environmental factors in the etiology of type 1 diabetes.
Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes.


The STELLAR trial protocol: a prospective multicentre trial for Richter's syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease.
Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter's syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton's tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. EudraCT: 2017-004401-40 , registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057 , registered on the 04-Mar-2019. ClinicalTrials.gov : NCT03899337 , registered on 02-April-2019.


Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.
Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.


Thiourea, a ROS scavenger, regulates source-to-sink relationship to enhance crop yield and oil content in Brassica juncea (L.).
In the present agricultural scenario, the major thrust is to increase crop productivity so as to ensure sustainability. In an earlier study, foliar application of thiourea (TU; a non physiological thiol based ROS scavenger) has been demonstrated to enhance the stress tolerance and yield of different crops under field condition. Towards this endeavor, present work deals with the effect of TU on photosynthetic efficiency and source-to-sink relationship of Indian mustard (Brassica juncea) for understanding its mode of action. The application of TU increased the efficiency of both PSI and PSII photosystems and vegetative growth of plant. The comparative analysis of sucrose to starch ratio and expression level of sugar transporters confirmed the higher source and sink strength in response to TU treatment. The biochemical evidence in support of this was derived from higher activities of sucrose phosphate synthase and fructose-1,6-bis-phosphatase at source; and sucrose synthase and different classes of invertases at both source and sink. This indicated an overall increase in photoassimilate level at sink. An additional contribution through pod photosynthesis was confirmed through the analysis of phosphoenol pyruvate carboxylase enzyme activity and level of organic acids. The increased photoassimilate level was also co-ordinated with acetyl coA carboxylase mediated oil biosynthesis. All these changes were ultimately reflected in the form of 10 and 20% increase in total yield and oil content, respectively under TU treatment as compared to control. Additionally, no change was observed in oil composition of seeds derived from TU treated plants. The study thus signifies the co-ordinated regulation of key steps of photosynthesis and source-to-sink relationship through the external application of TU resulting in increased crop yield and oil content.


A meta-analysis of diagnostic accuracy of three screening tools for insomnia.
Insomnia is a highly prevalent health complaint in the modern societies; however, insomnia remains under-diagnosed and under-treated. Although screening tools, including the Insomnia Severity Index (ISI), Athens Insomnia Scale (AIS), and Pittsburg Sleep Quality Index (PSQI), are widely used for assessing the risk of insomnia, the diagnostic properties have yet to be summarized in a systematic manner. To estimate and to compare the diagnostic accuracy of the ISI, AIS, and PSQI for insomnia screening. We systematically searched EMBASE, PubMed, PsycINFO, CINAHL and Chinese Electronic Periodic Services for data from their inception to May 20, 2015. Original articles that had assessed the sensitivity and specificity of the ISI, AIS, or PSQI against a reference standard in adult participants (age>18) were included. A total of 19 studies comprising 4693 participants were included. The pooled sensitivity for the ISI, AIS, and PSQI was 88% (95% confidence interval [CI]=0.79 to 0.93), 91% (0.87 to 0.93), and 94% (0.86 to 0.98), respectively. The pooled specificity was 85% (0.68 to 0.94), 87% (0.68 to 0.95), and 76% (0.64 to 0.85); and the pooled DORs was 41.93 (8.77 to 200.33), 67.7 (23.4 to 196.1), and 53 (15.5 to 186.2), respectively. The summary estimates did not differ significantly among the ISI, AIS and PSQI (all P>0.05). The current evidence indicates that the ISI, AIS, and PSQI yield comparable diagnostic properties for insomnia screening.