A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.
Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans.


Voice over Internet protocol for the orthodontic practice: a sensible switch from plain old telephone service.
Voice over Internet protocol (VoIP) is a revolutionary new technology that is causing a stir in the telecommunications industry and threatening the existence of traditional telephone service providers. Based on a simple method of converting analog audio signals into digital data before being transmitted over the Internet, VoIP has gained immense popularity among consumers. The technology is now regarded as an alternative to traditional telephone service for the orthodontic office. When the economics are considered, it is cost-effective, especially for a busy orthodontic practice where the call volumes both in and out are always high. VoIP has the potential to reduce costs, break the barriers between local vs long-distance calling, and make life easier for the office staff. However, deploying VoIP requires a cautious and thought-out process. Users should fully understand the risks and benefits before switching from the public switched telephone network. VoIP customers and service providers are vulnerable to many of the same impersonation-based attacks by those who attempt toll fraud, and identity and information theft. In this article, VoIP is introduced to orthodontic practitioners, who might be unfamiliar with this technology. Internet protocol based private branch exchange systems that are currently marketed as open-source technologies are also reviewed. Additionally, VoIP is compared with the traditional public switched telephone network technology and evaluated for its potential applications in an orthodontic office for both increased efficiency and cost savings.


The role of Algerian Ephedra alata ethanolic extract in inhibiting the growth of breast cancer cells by inducing apoptosis in a p53- dependent pathway.
Ephedra alata, a member of the Ephedraceae family, was used to treat different diseases and it might be shown a strong efficacy to inhibit cancer cell lines. Due to the limited research available about this plant, the objective of this research was to evaluate the antioxidant, cytotoxic and apoptotic effects of Ephedra alata ethanolic extract (EAEE), against different human cancer cell lines. EAEE inhibited the growth of the liver (HepG2), breast (MCF-7), and colon cancer cells (Caco-2). MCF-7 cells with an IC50 of 153 µg/ml, were the most sensitive to the extract. Furthermore, exploration using flow cytometry using Annexin V-FITC/PI assay demonstrated that EAEE caused death for all human cancer cells mainly through apoptosis. Very interestingly, qRT-PCR analysis using the ΔΔCt method revealed that four genes, Bax, p21, RB1, and TP53 were up-regulated in MCF-7 cells treated either with EAEE or S-FU drug. These findings let us believe that the mechanism by which EAEE kills breast cancer cells seems to be apoptosis via a P53-dependent manner, which involved intrinsic pathways through the induction of Bax, p21, and RB1. EAEE exhibits good biological properties in contradiction of HepG-2, MCF-7, and Caco-2 cell lines. This study appoints for the first time that EAEE increases the expression in MCF-7 cells of p53 and three more genetic traits that control cellular proliferation and apoptosis. Therefore, this plant could serve as a potential source to find new pro-apoptotic drugs for cancer treatment.


GABA and bicuculline-induced blood pressure changes in spontaneously hypertensive rats.
The brain GABAergic system was previously shown to influence blood pressure (BP) maintenance in rats which may in part be accomplished by disruption of the central renin-angiotensin system (RAS). We examined the potential role of GABA in sustaining the high BP exhibited by the spontaneously hypertensive rat (SHR) model of human essential hypertension. Intracerebroventricular (i.c.v.) infusion of GABA produced decreases in BP in members of three rat strains, including Wistar-Kyoto (WKY) and Sprague-Dawley normotensive controls and SHR. The SHR were significantly more sensitive to GABA than the normotensive strains. Next, the GABA receptor antagonist bicuculline (BMI) was infused i.c.v. and produced increases in BP in members of each strain. Finally, i.c.v. pretreatment with the specific angiotensin receptor antagonist [Sar1, Thr8]AII (sarthran), blocked subsequent GABA-induced decreases in BP in members of all three strains, and there was a trend toward sarthran attenuation of BMI-induced increases in BP. These results encourage the hypothesis that the hypotensive effects produced by central application of GABA are mediated by the brain angiotensin system.


Arsenic extraction from solid phase using a dissimilatory arsenate-reducing bacterium.
We investigated the feasibility of a novel bioremedial strategy for arsenic-contaminated soil using a dissimilatory arsenate-reducing bacterium (DARB), Bacillus sp. SF-1. SF-1 was able to effectively extract arsenic from various arsenic-laden solids, via the reduction of solid-phase arsenate to arsenite, which is much less adsorptive than arsenate. The strain can be an easy-to-handle, and cost-effective bioremedial agent.


The CDC25 "Start" gene of Saccharomyces cerevisiae: sequencing of the active C-terminal fragment and regional homologies with rhodopsin and cytochrome P450.
The CDC25 Start gene whose product appears to be required for traversing the Go phase of the cell cycle in Saccharomyces cerevisiae, has been previously cloned (J. Daniel and G. Simchen (1986), Curr Genet 10:643-646). By nucleotide sequencing of an active subclone, we found that only a region of the gene that codes for the C-terminal portion of the CDC25 protein was required for full suppression of the cdc25 mutation. The codon usage in this region indicates a poor translation of the transcript compared to genes encoding abundant proteins. The derived CDC25 protein fragment contains two regions of homology, one with the rhodopsin family, the other with the cytochrome P450 family. Strikingly, these two regions of homology are adjacent on the CDC25 protein. In view of the likely involvement of the CDC25 protein in the regulation of adenylate cyclase activity, a working hypothesis is proposed that accounts for the observed homologies.


Reliable expression and purification of highly insoluble transmembrane domains.
A general procedure for the reliable preparation of insoluble transmembrane domains has been developed. Improved expression schemes were developed by expressing the transmembrane domains of caveolin proteins 1, 2, and 3 as a fusion to the Trp leader protein. This construct readily formed inclusion bodies during overexpression, allowing high levels of protein to be achieved. Cleavage of the transmembrane domain away from the Trp leader carrier protein was performed with cyanogen bromide. The transmembrane domains were then purified using reverse-phase high-performance liquid chromatography with a C4 column and were eluted with a mixture of 1-butanol and acetic acid. Using this method, the 39-42 amino acid transmembrane domains from caveolin proteins 1, 2, and 3 were successfully purified to homogeneity. Further verification of this method was successfully done with Rfbp(18-51), another insoluble transmembrane domain.


Basic surgical training in Ireland: the impact of operative experience, training program allocation and mentorship on trainee satisfaction.
Application to the Irish basic surgical training (BST) program in Ireland has decreased progressively over the past 5 years. We hypothesised that this decline was secondary to dissatisfaction with training correlated with reduced operative experience and lack of mentorship among BSTs. An anonymous 15 question electronic survey was circulated to all BSTs appraising their impression of the operative experience available to them, their mentorship and their opinions of critical aspects of training. Fifty trainees responded to the survey. At the commencement of training 98 % (n = 43) intended to stay in surgery, decreasing to 79 % (n = 34) during the BST. Trainees who felt they had a mentor were three times more likely to be content in surgical training (OR 3.11; 95 % CI 0.94-10.25, P = 0.06). Trainees satisfied with their allocated rotation were more likely to be content in surgical training (OR 4.5; 95 % CI 1.03-19.6, P = 0.045). Individual trainee comments revealed dissatisfaction with operative exposure. Mentorship and satisfaction with allocated training rotation had a positive impact on trainee satisfaction and correlated with contentedness in surgical training. Operative experience is the main element that trainees report as lacking. This highlights the need for reform of the training system to improve current levels of mentorship and increase operative exposure to enhance its attractiveness to the best quality medical graduates.


Radioprotective Effect of Arbutin in Megavoltage Therapeutic X-irradiated Mice using Liver Enzymes Assessment.
Medical use of ionizing radiation has direct/indirect undesirable effects on normal tissues. In this study, the radioprotective effect of arbutin in megavoltage therapeutic x-irradiated mice was investigated using serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), and asparate amniotransferase (AST) activity measurements. In this analytical and experimental lab study, sixty mice (12 identical groups) were irradiated with 6 MV x-ray beam (2 and 4 Gy in one fraction). Arbutin concentrations were chosen 50, 100, and 200 mg/kg and injected intraperitoneal 2 hours before irradiation. Samples of peripheral blood cells were collected and serum was separated on the 1, 3, and 7 days post-x-radiation; in addition, the level of ALP, ALT, and AST were measured. Data were analyzed using one-way ANOVA, and Tukey HSD test. X-radiation (2 and 4 Gy) increased the ALT and AST activity levels on the 1, 3, and 7 days post- irradiation, but the ALP level significantly increased on the 1 and 7 days and decreased on the third day compared to the control group (P< 0.001). ALP, ALT and AST activity levels in "2 and 4 Gy x irradiation + distilled water" groups were significantly higher than "2 and 4 Gy irradiation + 50, 100, and 200 mg/kg arbutin" groups on the first and seventh day post-irradiation (P< 0.001). Arbutin is a strong radioprotector for reducing the radiation effect on the whole-body tissues by measuring ALP, ALT and AST enzyme activity levels. Furthermore, the concentration of 50 mg/kg arbutin showed higher radioprotective effect.


Swivel arm perimeter for visual field testing in different body positions.
To investigate the influence of body position on visual field results, a 'swivel arm perimeter' was built, based on a modified Octopus 1-2-3. Here, the measuring unit was detected from the control unit and mounted on a swivel arm, allowing its movement in all directions. The first results obtained with this device have indicated that its development was worthwhile.


Vascularized the greater trochanter grafting treatment cysts of the femoral neck.
Bone cyst is a common benign bone tumor lesion, it is characterized by a clear boundary appearing round or oval osteolytic area, cortical bone thinning, and sometimes it can be visible sclerotic margin. Limb long bone cysts occur more common shares, the current jaw bone cysts are also relatively common, and most patients are asymptomatic. Femoral neck bone cyst can lead to pain and pathologic fractures, which is one of the main reasons why patients are in treatment. Due to the lesion site and patients age specificity of femoral proximal bone cysts especially femoral neck bone cysts in young adults, treatment is necessary to completely remove the lesion to prevent cyst recurrence, but also as far as possible to restore function in patients with hip joint.


Recognition memory with and without retrieval of context: an event-related potential study.
In two recognition memory tests subjects made initial old/new judgements and subsequently judged whether 'old' words had been presented auditorily or visually at study. Test words were presented visually in Experiment 1 and auditorily in Experiment 2. ERPs evoked at test by words correctly judged 'old' were separated according to whether they were correctly or incorrectly assigned to their study modality. In both experiments, ERPs to correctly assigned words were more positive than those evoked by words correctly judged to be new. This ERP old/new effect was absent for words incorrectly assigned to study modality in Experiment 1, and was observed over a restricted latency range in Experiment 2. The findings are consistent with the hypothesis that the old/new effect is associated with recognition memory based on recollection of the study episode, rather than familiarity.


Evaluation of drug-drug interaction screening software combined with pharmacist intervention.
Drug-drug interactions (DDI) in hospitalized patients are highly prevalent and an important source of adverse drug reactions. DI computerized screening system can prevent the occurrence of some of these events. To evaluate the impact of drug-drug interaction (DDI) screening software combined with active intervention in preventing drug interactions. The study was conducted at General Hospital of Vitória da Conquista (HGVC), Brazil. A quasi-experimental study was used to evaluate the impact of IM-Pharma, a locally developed drug-drug interaction screening system, coupled with pharmacist intervention on adverse drug events in the hospital setting. The proportion of patients co-prescribed two interacting drugs were measured in two phases, prior the implementation of IM-Pharma and during the intervention period. DDI rates per 100 patient days were calculated before and after implementation. Risk ratios were estimated by Poisson regression models. A total of 6,834 instances of drug-drug interactions were identified; there was an average of 3.3 DDIs per patient in phase one and 2.5 in phase two, a reduction of 24 % (P = 0.03). There was a 71 % reduction in high-severity drug-drug interaction (P < 0.01). The risk for all DDIs decreased 50 % after the implementation of IM-Pharma (P < 0.01), and for those with high-severity, the reduction was 81 % (P < 0.01). The performance of IM-Pharma combined with pharmacist intervention was positive with an expressive reduction in the risk of DDIs.


Distribution of immunoglobulin isotypes in the nonspecific B-cell response induced by infection with Plasmodium chabaudi adami and Plasmodium yoelii.
The nonspecific B-cell response induced by infecting mice with two nonlethal malaria parasites, Plasmodium chabaudi adami and Plasmodium yoelii, was analyzed in an isotype-specific reverse plaque assay. Our results showed different isotypic patterns in the two infections, although cells secreting immunoglobulin of all isotypes were increased to some extent. P. yoelii induced large increases in secreting cells of all isotypes; IgG2a-secreting cells were increased out of proportion to those of the other IgG classes. P. chabaudi induced large increases in secreting cells of all isotypes except IgG1. In addition, there was not a disproportionate increase in cells secreting IgG2a. The data show that these "polyclonal" responses are different during each infection. There are marked similarities between the distribution of "nonspecific isotypes" and the specific antibodies formed in each infection.


Highly effective synthesis of 5-hydroxymethylfurfural from lignocellulosic biomass over a green and one-pot reaction in biphasic system.
In this study, different types of lignocellulosic biomas were used as substrates for the conversion to 5-HMF via biphasic reaction system that is composed of a reaction phase (aqueous phase) and an extraction phase (organic phase) under the catalysis of various metal salts. Deep eutectic solvents (DESs), ionic liquid [BMIM]Cl, aqueous choline chloride, aqueous betaine hydrochloride, and ethylamine hydrochloride were used as the reaction phase in the combination of dimethyl sulfoxide (DMSO) as organic solvents. The highest yields of 5-HMF obtained from pineapple stems in reactions with DES were 40.98%, 37.26%, and 23.44% for ChCl:Lac, ChCl:OA, and EaCl:Lac, respectively. Moreover, the combination of dimethyl sulfoxide, betaine hydrochloride aqueous solution, and AlCl3·6H2O with the pineapple stem conversion system resulted in a maximum yield of 61.04% ± 0.55% of 5-HMF. This study also demonstrated that AlCl3·6H2O and betaine hydrochloride could be effectively reused four times, which indicates a green and effective process.


Particle induced X-ray emission study of blood samples of Indian Kala-azar patients.
Visceral leishmaniasis (VL) or Kala-azar (KA) is a neglected tropical disease caused by protozoan parasite, Leishmania sp. and is fatal, if left untreated. In this study, we measured trace elements (K, Fe, Cu, Zn, Br, Cl, S, Ca, Mn, Cr, Ni, As, Se, Rb and Sr) in the blood of Indian VL patients (32) by particle-induced X-ray emission (PIXE) study. Blood was collected from 36 subjects including healthy controls from Rambagh Kala-azar Hospital, Muzaffarpur, Bihar, India. PIXE experiment was carried out at the Institute of Physics, Bhubaneswar, India and data were analyzed by GUPIXWIN software. We observed first time the association of bromine with the disease. The results showed 48.47 % decrease in Br, 35.16 % decrease in Zn and 29.05 % decrease in Fe in untreated state of the KA patients. In the same group, Cu has been increased by 16.73 %. Cu/Zn ratio has been altered in diseased state. The association of bromine with the disease is reported for the first time and altered levels of trace elements (Br, Cu, Fe and Zn) may come back to normal after completion of the treatment regimen with Amphotericin B.


Albumin messenger RNA as a marker of circulating hepatocytes in hepatocellular carcinoma.
Hepatocellular carcinoma is one of the most frequent malignancies. Liver transplantation is theoretically the treatment of choice because it eliminates both the hepatocellular carcinoma and the cirrhosis. High frequency of relapse observed after liver transplantation may be explained by the existence of undetectable metastasis before transplantation. The aim of this study was to determine whether albumin messenger RNA (mRNA), a specifically hepatocyte-expressed gene, could be a marker of metastasis in hepatocellular carcinoma. Albumin mRNA from circulating malignant hepatocytes was detected in the blood by reverse transcription followed by enzymatic amplification. Albumin mRNA was found in the blood of 3 patients with histologically proven metastatic hepatocellular carcinoma and in 9 of 21 patients with hepatocellular carcinoma and undetectable metastases, giving a percentage rate of 43, similar to the relapse rate following liver transplantation for hepatocellular carcinoma. None of the 8 patients with secondary liver cancer had detectable albumin mRNA. These results suggest that patients with hepatocellular carcinoma and no detectable albumin mRNA in the blood may be a subgroup with a low risk of relapse following liver transplantation.


Noviherbaspirillum humi sp. nov., isolated from soil.
Two novel Gram-stain negative, motile, non-spore forming, facultative aerobic and short rod shaped bacterial strains, designated U15(T) and U32, were isolated from soil obtained from Ukraine. The sequence similarity of the 16S rRNA gene between strains U15(T) and U32 was found to be 99.5 %. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that new bacteria belong to the genus Noviherbaspirillum. The closest member of the genus was found to be Noviherbaspirillum malthae (97.0 %) followed by Noviherbaspirillum suwonensis (96.3 %). The novel isolates was observed to grow optimally at 30 °C and pH 7.0. The major fatty acids present in the two strains were identified as summed feature 3 (C16:1 ω7c/C16:1 ω6c), C16:0, and summed feature 8 (C18:1 ω7c/C18:1 ω6c). Ubiquinone 8 was identified as the respiratory quinone component for both the strains. The polar lipid (L) profile contained phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, unidentified aminolipid and unidentified Ls, and putrescine and 2-hydroxyputrescine as major polyamines. The G+C content of the DNA for the strain U15(T) was found to be 61.2 mol%. The DNA-DNA relatedness between U15(T) and U32 and closely related species was less than 40 %. Based on the polyphasic taxonomic analysis, a new species, Noviherbaspirillum humi sp. nov., is proposed. The type strain is strain U15(T) = JCM 19873(T) = KEMB 7305-102(T).


Effects of long-term postoperative dienogest use for treatment of endometriosis on bone mineral density.
This study was conducted to evaluate the effects of long-term postoperative dienogest (DNG) use for the treatment of endometriosis on bone mineral density (BMD). Sixty reproductive-aged women who underwent conservative surgery for endometriomas and received postoperative DNG (2mg/day) for at least 12 months to prevent recurrence were analyzed. BMD was measured before and after DNG treatment by using dual energy X-ray absorptiometry, and changes in BMD were evaluated. Mean patient age was 30.5 years, and mean duration of DNG treatment was 18.6 months. BMD at the lumbar spine significantly decreased after the first 6 months (-2.2%), and 1year (-2.7%) of DNG treatment, compared to baseline. The proportion of women who had significantly decreased BMD at the lumbar spine after 1year was 75% (45/60). In addition, BMD at the femur neck also decreased significantly after 1year (-2.8%). BMDs after 2 years were not different from those after 1year at both sites in 24 women who received DNG for ≥2years. In addition, there were no differences in baseline characteristics between women who had significantly reduced BMD at the lumbar spine after 1year (N=45) and women who did not (N=15). This study suggests that long-term postoperative DNG treatment might have an adverse effect on BMD in reproductive-aged women. Bone loss mostly occurs during the first 6 months of treatment with DNG. A clinical trial is warranted to establish the effects of long-term DNG treatment on bone mass.


New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection.
Epidemiological studies suggest diabetes mellitus (DM) may be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Since diabetes and HCV are common in liver transplant recipients, we sought to examine the unique contribution of HCV infection to risk of de novo diabetes posttransplantation. Using a cohort of 555 liver transplant recipients (median age 49 years, 54% males, 82% Caucasian) without preexisting diabetes from 3 U.S. centers enrolled between 1990 and 1994 and followed for a median duration of 5 years, we determined the incidence of de novo diabetes and the independent predictors of the development of diabetes. De novo diabetes was defined by the use of antidiabetic medications. De novo diabetes developed in 209/555 (37.7%) patients of whom 157 (28.3%) had transient-DM (T-DM) and 52 (9.4%) had persistent-DM (P-DM). Among HCV-infected transplant recipients, de novo T-DM and P-DM developed in 26% and 14%, respectively. HCV was predictive of P-DM (P =.02) but not T-DM. Older age (P =.03) and tacrolimus use (P =.02) were also independent predictors of P-DM. In conclusion, de novo diabetes is common in transplant recipients, but is typically transient in nature. However, among those developing de novo persistent diabetes, HCV is one of the most important risk factors. This adds further support to the epidemiological data linking HCV and diabetes.


[Prophage induction in lysogenic cultures of bacteria as a test of the biological indication of relatively low doses of gamma radiation].
Induction of prophage in lysogenic cultures, Pseudomonas aeruginosa (strain PA01 (PM63)) and Escherichia coli K-12 (strain AB1157 (lambda) pKM101), was proposed as a test for biological indication of gamma-irradiation with relatively low doses. Sufficient resolving power (the sensitivity threshold of the method was 0.25 to 0.5 Gy) and relative simplicity of the practical use of the method were demonstrated. Within the dose range from 0.25 to 10 Gy, the relationship between the value of the prophage induction and radiation dose was linear.


Combined central retinal artery occlusion and anterior ischemic optic neuropathy as presenting signs of systemic lupus erythematosus.
Systemic Lupus Erythematosus (SLE) is a chronic auto-immune condition with systemic and ocular involvement. Ophthalmological findings are diverse and can involve all layers of the globe. Posterior segment manifestations can include lupus retinopathy, retinal vascular occlusions and lupus choroidopathy. We report here a rare case of central retinal artery occlusion (CRAO) associated with anterior ischemic optic neuropathy (AION) in a young female patient as presenting signs of SLE. In this case report, we highlight a very uncommon initial presentation of this severe systemic vasculitis. A multidisciplinary approach is required in order to prevent life-threatening vaso-occlusive complications.


Adaptive Restart of the Optimized Gradient Method for Convex Optimization.
First-order methods with momentum such as Nesterov's fast gradient method are very useful for convex optimization problems, but can exhibit undesirable oscillations yielding slow convergence for some applications. An adaptive restarting scheme can improve the convergence rate of the fast gradient methd, when the parameter of a strongly convex cost function is unknown or when the iterates of the algorithm enter a locally well-conditioned region. Recently, we introduced an optimized gradient method, a first-order algorithm that has an inexpensive per-iteration computational cost similar to that of the fast gradient method, yet has a worst-case cost function convergence bound that is twice smaller than that of the fast gradient method and that is optimal for large-dimensional smooth convex problems. Building upon the success of accelerating the fast gradient method using adaptive restart, this paper investigates similar heuristic acceleration of the optimized gradient method. We first derive new step coefficients of the optimized gradient method for a strongly convex quadratic problem with known function parameters, yielding a convergence rate that is faster than that of the analogous version of the fast gradient method. We then provide a heuristic analysis and numerical experiments that illustrate that adaptive restart can accelerate the convergence of the optimized gradient method. Numerical results also illustrate that adaptive restart is helpful for a proximal version of the optimized gradient method for nonsmooth composite convex functions.


Platelet involvement in cutaneous small vessel vasculitis.
Secretory products of platelets serve important functions in inflammation and thrombosis. Participation of platelets in the tissue reaction associated with cutaneous small vessel vasculitis has not yet been evaluated, so we systematically investigated the presence of platelet aggregates in inflamed microvessels. Thirty-six biopsies containing vasculitis and 18 biopsies with perivascular or interface type dermatitis were reviewed and adjacent sections were immunohistochemically stained with anti-CD61 antibody recognizing GPIIbIIIa receptors on platelets and with anti-von Willebrand factor (anti-vWF) antibody. Platelet aggregates were observed in 27 (75%) of the vasculitis biopsies and three (16.7%) of the perivascular dermatitis biopsies, of which two (11%) had traumatic vessel damage. In all vasculitis cases, platelet clumps were associated with diffuse immunostaining of the perivascular stroma with the initiator of platelet aggregation anti-vWF. In the non-vasculitis type of dermatitis anti-vWF staining remained strictly limited to the cytoplasm of endothelial cells in 10 cases, and in eight cases there was also slight diffuse perivascular staining, albeit less extensively than in vasculitis cases. Formation of platelet aggregates appears to play a thus far unrecognized role in cutaneous small vasculitis. Secretory products of platelets will likely contribute to the inflammatory response and tissue damage in vasculitis. Moreover, platelet immunohistochemistry may be helpful in the diagnosis of microvascular damage in paraffin sections.


Uveal metastasis in 1111 patients: Interval to metastasis and overall survival based on timing of primary cancer diagnosis.
To evaluate interval between primary cancer diagnosis and uveal metastasis and assess survival outcomes based on whether the primary cancer was diagnosed before or after uveal metastasis. In this retrospective analysis, all patients with uveal metastasis evaluated on the Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA, USA between February 1, 1974 and June 1, 2017 were included. Features and outcomes based on timing of primary cancer diagnosis, whether before or after diagnosis of uveal metastasis, were assessed. A total of 2214 uveal metastases were diagnosed in 1310 eyes of 1111 consecutive patients. Primary cancer was known prior to uveal metastasis in 742 patients (67%) and not known in 369 (33%). Of those not known, the primary cancer was later found in 192 patients (17%) and never found in 177 patients (16%). For those with known primary cancer, mean interval from primary cancer diagnosis to uveal metastasis was 5.2 years with differences in primary sites of gastrointestinal (2.1 years, p = 0.003), lung (2.2 years, p < 0.001), breast (6.5 years, p < 0.001), and thyroid (13 years, p < 0.001). By Kaplan-Meier analysis, the 5-year overall survival showed no difference between patients with primary cancer found before (28%) vs after (20%) vs never found (33%), relative to uveal metastasis. Of 1111 patients with uveal metastasis, early-onset uveal metastases were found with lung and gastrointestinal tract cancers, whereas late-onset metastases were found with breast and thyroid cancers. Overall survival did not vary on whether the primary tumor was diagnosed before, after, or never found, relative to uveal metastasis.


Amniotic band syndrome in monozygotic twins: prenatal diagnosis and pathogenesis.
Amniotic band syndrome is a well-described disorder lacking a precise definition or a scientifically validated hypothesis of pathogenesis. The widely accepted "exogenous" theory suggests that early amniotic rupture leads to the formation of pathologic amniotic strands, which then induce nonanatomic fetal abnormalities. This paradigm appears to be challenged by observations that amniotic band syndrome occurs in monozygotic twin gestations. The exclusive development of amniotic band syndrome in monozygotic versus dizygotic twin gestations, the description of early amniotic rupture in one sac of a dizygotic twin gestation without subsequent fetal abnormalities, and the paradoxical observations of discordance in monoamniotic and concordance in diamniotic twin gestations, fail to support an "exogenous" etiology for amniotic band syndrome.


Comparison of dose distributions between transverse magnetic fields of 0.35 T and 1.5 T for radiotherapy in lung tumor using Monte Carlo calculation.
We investigated the impact of the transverse magnetic fields of 0.35 T and 1.5 T on the dose distributions for a 6 MV beam, by using a thorax phantom with a lung tumor. First, the dose distributions in the magnetic flux densities of 0 T, 0.35 T, and 1.5 T were compared by increasing the number of irradiation fields. Next, the dose distributions for stereotactic body radiotherapy (SBRT) with 5-fields for an isolated lung tumor was compared in transverse magnetic fields. All dose distributions were calculated by the Monte Carlo method. The prescription doses for SBRT with 5-fields was 48 Gy for D95 (dose covering 95% volume) in the planning target volume (PTV). The dose distributions were analyzed by the dose difference map (DD map), dose volume histogram (DVH), and dose indices. For the 1-field, the dose distributions were more affected at 1.5 T rather than 0.35 T. The DVHs for PTV at 1.5 T almost agreed with those at 0 T for more than 5-fields. In contrast, the D98 in the PTV at 0.35 T reduced constantly by 6.0% with more than 5-fields. The D95 in PTV for SBRT with 5-fields was 9.0% lower at 0.35 T and 2.5% higher at 1.5 T, in comparison with that at 0 T. For dispersed irradiation angles of more than 5-fields, it is more desirable to use the magnetic flux density of 1.5 T than 0.35 T for the radiotherapy in the lung tumor.


The structure and function of yeast ARS elements.
The past year has seen significant advances in our understanding of the structure and function of yeast ARS elements. These elements, some of which function as chromosomal origins of DNA replication, are modular in structure. An essential domain, the ARS consensus sequence, binds a multiprotein complex that might be the long-sought initiator protein. The flanking domain contains a DNA unwinding element and a binding site for a multifunctional protein that acts as a replication enhancer.


Histopathology of renal osteodystrophy with particular reference to the effects of 1alpha-hydroxyvitamin D3 in patients treated by long-term haemodialysis.
(1) The bone histology of 233 non-dialysed and 276 haemodialysed patients with chronic renal failure is reviewed. In non-dialysed patients osteitis fibrosa occurred in 83.7% and osteomalacia in 23.6% of patients. Osteomalacia was not found in the absence of osteitis fibrosa. In haemodialysed patients there was a more variable bone histology, sometimes resembling non-dialysed bone disease, but in general with a greater incidence of osteomalacia, especially with increasing time on dialysis. In some patients there was a predominance of osteomalacia accompanied by no or only mild osteitis fibrosa and the serum alkaline phosphatase was normal. (2) The results of treating twenty-six haemodialysed patients with 1alpha-hydroxyvitamin D3 (1alpha-OHD3) are described. Patients with osteomalacia and minimal or no osteitis fibrosa and a normal serum alkaline phosphatase (Group I) in general failed to respond and it is suggested that 1,25-dihydroxyvitamin D3 deficiency is not the sole factor responsible for the osteomalacia in these patients. In contrast, 1alpha-OHD3 therapy was effective in improving osteitis fibrosa and osteomalacia in some patients with moderate to severe degrees of osteitis fibrosa and osteomalacia (Group IIa) and in improving osteitis fibrosa where this occurred alone (Group IIb).


Agonist-independent regulation of constitutively active G-protein-coupled receptors.
G-protein-coupled receptors constitute one of the largest protein super-families in mammals. Since the cloning of the encoding genes, these important drug targets have been subjected to thorough biochemical and pharmacological studies. It has become clear that G-protein-coupled receptors not only transmit signals after stimulation by agonists but can also spontaneously couple to signal-transduction pathways. Recent findings show that constitutively active G-protein-coupled receptors can also be regulated in an agonist-independent manner, which has important implications for the interpretation of the actions of (inverse) agonists and the results of site-directed-mutagenesis studies.


Short and long-term efficacy of massage for functional constipation: A protocol for systematic review and meta analysis.
Functional constipation (FC) is one of the most common diseases throughout the world, which brings a bad influence on life quality as well as mental health. Massage has been widely used in the treatment of functional constipation in china. In several randomized controlled trials indicate that massage has a positive effect on FC. However, there remain exist controversy towards its effectiveness and safety. What's more, how about the short and long-term efficacy? We, therefore, design this systematic review to assess the short and long-term effects of massage for FC. The following electronic databases will be searched from their inception to May 2020, including PubMed, Cochrane Library, EMBASE, Web of Science, WHO International Clinical Trials Registry Platform, Chinese National Knowledge Infrastructure (CNKI), WanFang Database, Chinese Biomedical Literature Database (CBM), the Chongqing VIP Chinese Science, and Technology Periodical Database (VIP). This systematic review will assess the short and long-term effects of massage in the treatment of FC. This study will provide high-quality current evidence of short and long-term effects of massage for FC. Ethical approval is not required, for this review will not involve individuals' information. The results will be published in a peer-reviewed publication or disseminated in relevant conferences.INPLASY Registration number: INPLASY202050001.


Acute effects of resveratrol to enhance cocaine-induced dopamine neurotransmission in the striatum.
Resveratrol is known as an activator of SIRT1, which leads to the deacetylation of histone and non-histone protein substrates, but also has other pharmacological profiles such as the inhibition of monoamine oxidase (MAO)-A and MAO-B. Resveratrol was previously demonstrated to potentiate the rewarding effects of chronic cocaine via activation of SIRT1. However, the role of resveratrol in cocaine responses in the acute phase remains unexplored. Therefore, we investigated the acute effects of resveratrol on cocaine-stimulated dopamine neurotransmission by analyzing protein phosphorylation in neostriatal slices. Treatment with resveratrol (50μM for 30min) enhanced cocaine-induced increases in the phosphorylation of DARPP-32 at Thr34 and GluA1 at Ser845, postsynaptic substrates for dopamine/D1 receptor/PKA signaling, and a cocaine-induced decrease in the phosphorylation of tyrosine hydroxylase at Ser40, a presynaptic substrate for dopamine/D2 receptor signaling. The inhibition of both MAO-A and MAO-B by clorgyline and pargyline, respectively, enhanced the effects of cocaine on DARPP-32 phosphorylation. The acute effect of resveratrol on cocaine-induced DARPP-32 phosphorylation was occluded with inhibition of MAO-A and MAO-B. In behavioral studies, resveratrol (40mg/kg, s.c.) enhanced the increase in locomotor activity induced by acute cocaine administration (10mg/kg, i.p.). Thus, this study provides pharmacological evidence that acute resveratrol enhances cocaine-induced dopamine neurotransmission and behavioral responses, presumably via mechanisms involving the inhibition of dopamine catabolism by MAO-A and MAO-B. Resveratrol may be useful to treat dysregulated dopamine neurotransmission, but it may enhance the risk of developing drug addiction.


Shortened REM latency as a psychobiological marker for psychotic depression? An age-, gender-, and polarity-controlled study.
Previous reports suggest that the clinical dichotomy separating psychotic and nonpsychotic depression corresponds to different neurobiological profiles. The aim of the present study is to further investigate the psychobiological correlates of these two particular depressive subtypes. Thyroid-stimulating hormone response to thyrotropin-releasing hormone postdexamethasone cortisol levels, and electroencephalgraphic sleep characteristics of 44 psychotic major depressive patients were compared to those of 44 nonpsychotic depressives matched for age, gender, and polarity. Some biological disturbances usually associated with depression (increased wakefulness, diminished rapid eye movement latency, hypercortisolism, blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone stimulation) seemed to be significantly more pronounced in the psychotic depressed group as a reflection of greater illness severity; however, shortened REM latency was not influenced by severity and seemed to be more specifically related to the co-occurrence of psychotic and depressive symptoms. Our data provide further support for the validity of the clinical dichotomy separating psychotic and nonpsychotic major depression independently of severity.


Bovine Brucellosis in Gauteng, South Africa: Seroprevalence amongst Cattle Handlers and Variables Associated with Seropositive Cattle Herds, 2014-2016.
In South Africa, the prevalence of cattle handler exposure to Brucella on cattle farms is unknown and risk factors and cattle symptoms associated with infected cattle herds are unavailable. To address this gap, a case-control study of cattle herds was conducted in Gauteng province and farm workers and veterinary officials were tested for exposure to Brucella. Seroprevalence amongst farm workers exposed to case herds ranged from 4.0% (BrucellaCapt®) to 16.7% (IgG ELISA®), compared to those exposed to control herds, where seroprevalence ranged from 1.9% (BrucellaCapt®) to 5.7% (IgG ELISA®). Seroprevalence amongst veterinary officials was significantly greater compared to farm workers exposed to case herds for the outcome RBT+ IgM- IgG+ (OR = 11.1, 95% CI: 2.5-49.9, p = 0.002) and RBT- IgM- IgG+ (OR = 6.3, 95% CI: 2.3-17.3, p < 0.001). Risk factors associated with being an infected herd were: being a government-sponsored farm vs. private farm (OR 4.0; 95% CI: 1.4-11.3; p = 0.009), beef vs. dairy herd (OR 7.9; 95% CI: 1.4-44.9; p = 0.020), open vs. closed herd (OR 3.3; 95% CI: 1.1-10.4; p = 0.038) and the presence of antelope on the farm (OR 29.4; 95% CI: 4.0-218.2; p = 0.001). Abortions (OR = 5.1; 95% CI: 2.0-13.3; p < 0.001), weak calves in the herd (OR = 8.0; 95% CI: 2.6-24.4; p < 0.001), reduction in number of calves born (OR = 9.0; 95% CI: 2.1-43.6; p < 0.001), reduction in conception rate (OR = 3.9; 95% CI: 0.8-18.3; p = 0.046), hygromas in cattle (p = 0.011) and farmers reporting brucellosis-like symptoms in their farm workers or in him/herself (OR = 3.4; 95% CI: 1.3-8.7; p = 0.006) were more likely to be associated with Brucella infected herds than control herds. This evidence can be used in strategic planning to protect both human and herd health.


Effect of new antioxidant cysteinyl-flavanol conjugates on skin cancer cells.
Novel catechin derivatives obtained from grape procyanidins and l-cysteine scavenge free radicals by hydrogen atom donation, rather than electron transfer, and reduce cell viability in A375 and M21 melanoma cells. In particular, 4beta-(S-cysteinyl)epicatechin 3-O-gallate has a free radical scavenging capacity as strong as that of tea (-)-epigallocatechin gallate and causes a significant S-phase cell-cycle arrest in both cell lines at doses higher than 100 microM. The other cysteinyl compounds do not affect normal cell cycle distribution. The gallate derivative also induces apoptosis in melanoma cells more strongly than the other derivatives and the parent (-)-epicatechin do. The gallate compound seems to trigger nuclear condensation and fragmentation, which is confirmed by DNA laddering. Interestingly, they do not induce apoptosis in keratinocytes (HaCaT).


Molecular characterization of Myxoboluscatmrigalae (Myxosporea: Myxobolidae) infecting the gill lamellae of carp Cirrhinusmrigala (Hamilton).
The present study attempted sequencing the 18S rRNA gene of Myxoboluscatmrigalae infecting the gill lamellae of carp, Cirrhinusmrigala and compared its genetic homology and phylogenetic characteristics with 18S rRNA genes of other Myxobolus spp. The infected fish had up to 3 small, creamy white plasmodia per gill filament with 30-50 spores each. The spore size was 17.90 ± 0.70 × 7.40 ± 0.40 μm. The sporoplasm contained two large nuclei of size 0.57 ± 0.09 μm and no iodinophilous vacuole. The DNA sequence of M.catmrigalae was clustered phylogenetically with other Myxobolus spp. infecting the gills of cyprinids available in GenBank, which showed 77-87 % homogeneity. On the phylogenetic tree, M.catmrigalae (KC933944) was clustered with M.pavlovskii (HM991164) infecting the gill lamellae of silver carp, Hypophthalmichthysmolitrix. The species most closely related to M.catmrigalae in GenBank was M.pavlovskii (AF507973) infecting the gill lamellae of big head carp, Aristichthysnobilis with 87 % homogeneity. This is the first report on molecular characterization of gill lamellae infecting M. catmrigalae.


A new method for semi-automated quantitation of E-rosettes using a particle size analyser (Coulter Channelyzer).
Visual counts of the number of SRBC attached to individual lymphocytes in E-rosette preparations from 3 healthy young adults were made by 3 experienced observers: from these data the size distribution profile of particles in each E-rosette preparation was calculated. In parallel experiments the size distribution profile was measured directly with a particle size analyser (Coulter Counter and Channelyzer): in every case the observed profile lay within the 95% confidence band around the reconstructed profiles. It was concluded that the Coulter Channelyzer profile is an accurate measurement of the E-rosette size distribution and that particle sizing could provide a reasonable basis for semi-automated tests for E-rosettes. A mathematical model has been developed by which the percentage of lymphocytes forming E-rosettes, the distribution of number of attached SRBC and the average avidity of the lymphocyte receptor for SRBC could be deduced from the size-distribution profiles. The method has a high degree of precision, and a good correlation (P less than 0.01) was obtained when the percentage of E-rosettes (defined for this purpose as having three or more attached SRBC) obtained from the new method was compared with results from standard light microscopy.


Non-motor connections of the pedunculopontine nucleus of the rat and human brain.
The connections of the pedunculopontine nucleus (PPN) with motor areas of the central nervous system (CNS) are well described in the literature, in contrast relations with non-motor areas are lacking. Thus, the aim of the present study is to define the non-motor connections of the PPN in rats using the fluoro-gold (FG) tracer and compare the presence of these connections in healthy human adults using diffusion tensor tractography (DTI). We injected FG into the PPN of 12 rats. The non-motor connections of the PPN with cortical, subcortical, and brainstem structures were documented. The non-motor connections of the rats were compared with the DTI obtained from 35 healthy adults. The results of the tract-tracing study in the rat showed that the PPN was connected to non-motor cortical (cingulate, somatosensory, visual, auditory, medial frontal cortices), subcortical (amygdala, hypothalamus, thalamus, habenular, and bed nucleus of stria terminalis), and brainstem (medullary reticular, trigeminal spinal, external cuneate, pontine reticular, vestibular, superior and inferior colliculus, locus ceruleus, periaqueductal gray, parabrachial, dorsal raphe, pretectal, lateral lemniscus nuclei, and the contralateral PPN) structures. The DTI obtained from healthy adults showed similar PPN non-motor connections as in rats. Understanding the connections of the PPN with non-motor cortical, subcortical, and brainstem areas of the CNS will enrich our knowledge of its contribution in various circuits and the areas that PPN activity can influence. Further, it will provide insight into the role of Parkinson's disease and related disorders and explain the non-motor complications which occur subsequent to deep brain stimulation (DBS) of the PPN.


Primates and mouse NumtS in the UCSC Genome Browser.
NumtS (Nuclear MiTochondrial Sequences) are mitochondrial DNA sequences that, after stress events involving the mitochondrion, colonized the nuclear genome. Accurate mapping of NumtS avoids contamination during mtDNA PCR amplification, thus supplying reliable bases for detecting false heteroplasmies. In addition, since they commonly populate mammalian genomes (especially primates) and are polymorphic, in terms of presence/absence and content of SNPs, they may be used as evolutionary markers in intra- and inter-species population analyses. The need for an exhaustive NumtS annotation led us to produce the Reference Human NumtS compilation, followed, as reported in this paper, by those for chimpanzee, rhesus macaque and mouse ones. Identification of NumtS inside the UCSC Genome Browser and their inter-species comparison required the design and the implementation of NumtS tracks, starting from the compilation data. NumtS retrieval through the UCSC Genome Browser, in the species examined, is now feasible at a glance. Analyses involving NumtS tracks, together with other genome element tracks publicly available at the UCSC Genome Browser, can provide deep insight into genome evolution and comparative genomics, thus improving studies dealing with the mechanisms that drove the generation of NumtS. In addition, the NumtS tracks constitute a useful tool in the design of mitochondrial DNA primers.


Blink reflex and discomplete facial nerve palsy.
Electrophysiologic findings of the blink reflex in patients with Bell's palsy are usually said to be either prolonged latencies and/or absent early and middle responses of it. Facial nerve conduction and blink reflex studies were performed on a 42-year-old male patient with right-side Bell's palsy. Studies were done using protocols previously validated and published elsewhere. The right compound muscle action potential was not found after stimulation of the right facial nerve as expected. Absence of the short (R1) and middle (R2) responses of the blink reflex were also noted after right and left supraorbital nerve stimulation. Further, the late (R3) response of the blink reflex was displayed on the abnormal side when electrical stimuli were applied to the right supraorbital nerve while the patient attempted to perform voluntary movement of the paralyzed facial muscles including eye closing. The recording of R3-a late response following fibers and using motoneurons other than those employed by R1 and R2-on the paralyzed side after performing some reinforcement maneuvers allows us to suggest that, in some facial nerve palsies, there are some structures remaining alive that may be useful for carrying out a more timely and accurate diagnosis and follow-up.


Fundamental frequency and perturbation measures of sustained vowels in Malaysian Malay children between 7 and 12 years old.
The study is going to investigate the fundamental frequency (F(0)) and perturbation measures of sustained vowels in 360 native Malaysian Malay children aged between 7 and 12 years using acoustical analysis. Praat software (Boersma and Weenink, University of Amsterdam, The Netherlands) was used to analyze the F(0) and perturbation measures of the sustained vowels. Statistical analyses were conducted to determine the significant differences in F(0) and perturbation measures across the vowels, sex, and age groups. The mean F(0) of Malaysian Malay male and female children were reported at 240±34.88 and 254.48±23.35Hz, respectively. The jitter (Jitt), relative average perturbation (RAP), five-point period perturbation quotient (PPQ5), shimmer (Shim), and 11-point amplitude perturbation quotient (APQ11) of Malaysian male children were reported at 0.43±0.26%, 0.25±0.16%, 0.26±0.15%, 2.48±1.61%, and 1.75±1.04%, respectively. As for female children, the Jitt, RAP, PPQ5, Shim, and APQ11 were reported at 0.42±0.22%, 0.25±0.14%, 0.25±0.13%, 2.47±1.53%, and 1.75±1.10%, respectively. No significant differences in F(0) were reported across the Malay vowels for both males and females. Malay females had significantly higher F(0) than that in Malay males at the age of 8, 10, and 12 years. Malaysian Malay children underwent the nonsystematic decrement in F(0) across the age groups. Significant differences in F(0) were found across the age groups. Significant differences in perturbation measures were observed across the vowels in certain age groups of Malay males and females. Generally, no significant differences in perturbation measures between the sex were observed in all the age groups and vowels. No significant differences in all the perturbation measures across the age groups were reported in both Malaysian Malay male and female children.


Costimulatory function of CD28 in avian gammadelta T cells is evolutionarily conserved.
CD28 costimulatory signals are required for T-cell proliferation and lymphokine production. In this work, the functional conservation of CD28 was studied in avian gammadelta T cells. The avian CD28 molecule is expressed on all alphabeta T cells and is capable of giving a costimulatory signal. Most peripheral gammadelta T cells are CD28 negative; however, we identified a CD28-positive gammadelta T-cell subset from peripheral blood comprising about 12% of gammadelta T cells. The peripheral CD28+ gammadelta T-cell subset included all CD8+ gammadelta T cells known to be a responding subset during activation. After polyclonal activation, the frequency of CD28+ gammadelta T cells was increased and the activation also up-regulated CD5, CD25 and major histocompatibility complex (MHC) class II molecules. These changes were detected after both polyclonal and antigen-specific T-cell activation. In addition, we also showed that CD28 can give a costimulatory signal to gammadelta T cells and that this signal leads to up-regulation of IL-2 and bcl-x transcripts. These results indicate that the function of CD28 is evolutionarily conserved and can already be detected in avian gammadelta T cells.


Human skin neural crest progenitor cells are susceptible to BRAF(V600E)-induced transformation.
Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAF(V600E) in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCs(V600E)) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo. Unlike in human melanocytes, BRAF(V600E) expression in hNCPCs did not induce p16(INK4a) expression. BRAF(V600E) induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCs(V600E) dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAF(V600E)-induced transformation, and MITF potentiates the oncogenic effect of BRAF(V600E) in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAF(V600E)-induced melanocytic tumor formation.


Utility of Urine Biomarkers and Electrolytes for the Management of Heart Failure.
To provide insight into the role of urine biomarkers and electrolytes for the management of heart failure. The age-dependent decrease in glomerular filtration rate due to loss of functional nephrons occurs at a faster pace in heart failure, potentially exacerbated by episodes of acute kidney injury. Urine biomarkers have not convincingly demonstrated to improve detection of irreversible renal damage and predict long-term renal trajectories, compared with serial creatinine measurements. Recent data show that natriuresis and diuretic response track poorly with glomerular filtration, but strongly with prognosis. Urine sodium concentration > 50-70 mmol/L was recently put forward through expert consensus as an adequate diuretic response. The value of urine biomarkers to detect structural renal damage in heart failure remains unsure and the latter is probably uncommon, especially over short-term follow-up. Urine electrolytes on the other hand predict diuretic response accurately and may allow better diuretic titration.


The role lipid aldehydes and ALEs in the pathogenesis of diabetic retinopathy.
Diabetic retinopathy is one of the most common causes of blindness in people of working age in developed countries. The retinal vasculature is central to the development of diabetic retinopathy, but there is accumulating evidence that neuroretinal dysfunction and degeneration also contributes to the aetiology and progression of this disease. The precise mechanisms through which diabetes causes neuroretinal dysfunction and degeneration remain to be fully established, but recent evidence from our own group has suggested that lipid aldehyde generation and the formation of advanced lipoxidation end-products (ALEs) plays a key contributory role. In the present talk, I will outline our recent data suggesting that the progressive and selective accumulation of the acrolein-derived ALE, FDP-lysine, in retinal Müller glial cells during diabetes is involved in the pathogenesis of neuroretinal dysfunction during diabetic retinopathy. More recent unpublished data will also be presented suggesting that FDP-lysine accumulation in the diabetic retina may occur primarily through a mechanism involving the downregulation of aldehyde detoxification enzymes. Current studies examining potential therapeutic strategies for preventing ALE accumulation in the diabetic retina will also be briefly discussed.


Survival in acidic and alcoholic medium of Shiga toxin-producing Escherichia coli O157:H7 and non-O157:H7 isolated in Argentina.
In spite of Argentina having one of the highest frequencies of haemolytic uraemic syndrome (HUS), the incidence of Escherichia coli O157:H7 is low in comparison to rates registered in the US. Isolation of several non-O157 shiga toxin-producing Escherichia coli (STEC) strains from cattle and foods suggests that E. coli O157:H7 is an uncommon serotype in Argentina. The present study was undertaken to compare the survival rates of selected non-O157 STEC strains under acidic and alcoholic stress conditions, using an E. coli O157:H7 strain as reference. Growth at 37 degrees C of E. coli O26:H11, O88:H21, O91:H21, O111:H-, O113:H21, O116:H21, O117:H7, O157:H7, O171:H2 and OX3:H21, was found to occur at pH higher than 4.0. When the strains were challenged to acid tolerance at pH as low as 2.5, viability extended beyond 8 h, but none of the bacteria, except E. coli O91:H21, could survive longer than 24 h, the autochthonous E. coli O91:H21 being the more resistant serotype. No survival was found after 24 h in Luria Bertani broth supplemented with 12% ethanol, but all these serotypes were shown to be very resistant to 6% ethanol. E. coli O91:H21 showed the highest resistance among serotypes tested. This information is relevant in food industry, which strongly relies on the acid or alcoholic conditions to inactivate pathogens. This study revealed that stress resistance of some STEC serotypes isolated in Argentina is higher than that for E. coli O157:H7.


Restoring microcirculatory perfusion in a preclinical model of severe hemorrhagic shock: The role of microcirculatory function.
No reflow in capillaries (no reflow) is the lack of tissue perfusion that occurs once central hemodynamics are restored. This prevents oxygen transfer and debt repayment to vital tissues after shock resuscitation. Since metabolic swelling of cells and tissues can cause no reflow, it is a target for study in shock. We hypothesize no reflow secondary to metabolic cell swelling causes the problem not addressed by current strategies that increase central hemodynamics alone. Anesthetized swine were bled until plasma lactate reached 7.5 mM to 9 mM. Intravenous low volume resuscitation solutions were administered (6.8 mL/kg over 5 minutes) consisting of; (1) lactated Ringer (LR), (2) autologous whole blood, (3) high-dose vitamin C (200 mg/kg), or (4) 10% PEG-20k, a polymer-based cell impermeant that corrects metabolic cell swelling. Outcomes were macrohemodynamics (MAP), plasma lactate, capillary flow in the gut and tongue mucosa using orthogonal polarization spectral imaging (OPSI), and survival to 4 hours. All PEG-20k resuscitated swine survived 240 minutes with MAP above 60 mm Hg compared with 50% and 0% of the whole blood and LR groups, respectively. The vitamin C group died at just over 2 hours with MAPs below 40 and high lactate. The LR swine only survived 30 minutes and died with low MAP and high lactate. Capillary flow positively correlated ( p < 0.05) with survival and MAP. Sublingual OPSI correlated with intestinal OPSI and OPSI was validated with a histological technique. Targeting micro-hemodynamics in resuscitation may be more important than macrohemodynamics. Fixing both is optimal. Sublingual OPSI is clinically achievable to assess micro-hemodynamic status. Targeting tissue cell swelling that occurs during ATP depletion in shock using optimized osmotically active cell impermeants in crystalloid low volume resuscitation solutions improves perfusion in shocked tissues, which leverages a primary mechanism of injury.


CK1δ activity is modulated by CDK2/E- and CDK5/p35-mediated phosphorylation.
CK1 protein kinases form a family of serine/threonine kinases which are highly conserved through different species and ubiquitously expressed. CK1 family members can phosphorylate numerous substrates thereby regulating different biological processes including membrane trafficking, cell cycle regulation, circadian rhythm, apoptosis, and signal transduction. Deregulation of CK1 activity and/or expression contributes to the development of neurological diseases and cancer. Therefore, CK1 became an interesting target for drug development and it is relevant to further understand the mechanisms of its regulation. In the present study, Cyclin-dependent kinase 2/Cyclin E (CDK2/E) and Cyclin-dependent kinase 5/p35 (CDK5/p35) were identified as cellular kinases able to modulate CK1δ activity through site-specific phosphorylation of its C-terminal domain. Furthermore, pre-incubation of CK1δ with CDK2/E or CDK5/p35 reduces CK1δ activity in vitro, indicating a functional impact of the interaction between CK1δ and CDK/cyclin complexes. Interestingly, inhibition of Cyclin-dependent kinases by Dinaciclib increases CK1δ activity in pancreatic cancer cells. In summary, these results suggest that CK1δ activity can be modulated by the interplay between CK1δ and CDK2/E or CDK5/p35. These findings extend our knowledge about CK1δ regulation and may be of use for future development of CK1-related therapeutic strategies in the treatment of neurological diseases or cancer.


Premature mortality and chronic alcoholism: medical examiner cases, New Jersey.
To obtain estimates of premature mortality from nonviolent causes associated with chronic alcoholism, median ages at death were calculated for 994 Essex County, New Jersey Medical Examiner cases aged 25 or older classified as (1) 'nonabusers' or (2) alcoholics whose underlying cause of death was natural disease and (3) those who died of chronic alcoholism. Alcohol-associated mortality accounts for considerable years of potential life lost. Differences in its life-shortening effects according to sex, race, and natural disease versus chronic alcoholism as underlying and/or contributing cause(s) of death are analyzed. Criteria for classifying cases as alcoholics were: (1) autopsy findings attributable to alcoholism; (2) case information that the decedent was a 'known alcoholic', or ever had any health or other related problems because of drinking; or, (3) alcohol-specific disease or condition attributable to alcoholism as underlying or contributing cause of death. Nonabusers were cases not classified as alcoholics and/or other drug abusers. Nonabusers had the oldest median age at death, followed by alcoholics who died of (1) natural disease and (2) chronic alcoholism. Female nonabusers were older than their male counterparts, whereas female alcoholics whose underlying cause of death was natural diseases or chronic alcoholism were younger than male alcoholics with the same underlying cause. Median age at death was considerably lower for blacks than whites in all subgroups, with consistently greater race than sex differences. Evidence is presented which supports the accelerated development of alcoholism symptoms and associated illness among women. Aspects of increased mortality risk among alcoholics with natural disease and/or chronic alcoholism as underlying or contributing cause(s) of death are discussed.


[Chloroquine enantiomers. Activity against P. vinckei and binding on DNA (author's transl)].
(+)-Chloroquine is more active against P. vinckei than (-)-chloroquine. No correlation has been observed between antiplasmodial activity and DNA-binding of the chloroquine enantiomers.


Detection of occult nasopharyngeal primary tumours by means of in situ hybridization.
Detection of nasopharyngeal carcinoma primaries in patients presenting with neck node metastases may sometimes demand considerable efforts. By using the 'in situ hybridization' technique, we manage to identify the Epstein-Barr virus in neck metastases secondary to nasopharyngeal carcinomas. We propose that such identification in neck node metastases where the primary lesion is unknown indicates a nasopharyngeal primary.


Exosomal MicroRNA-9-3p Secreted from BMSCs Downregulates ESM1 to Suppress the Development of Bladder Cancer.
Exosomes, carriers to transfer endogenous molecules, derived from bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to play a role in the progression of bladder cancer. Here we aimed to test the functional mechanism of microRNA-9-3p (miR-9-3p)-containing exosomes derived from BMSCs in bladder cancer. BMSCs were cocultured with bladder cancer cells, and exosomes secreted from BMSCs were identified. Next, the expression of miR-9-3p and endothelial cell-specific molecule 1 (ESM1) in bladder cancer tissues and cells was determined. Then effects of miR-9-3p and ESM1 via BMSC-derived exosomes on bladder cancer cell viability, migration, invasion, and apoptosis were determined by loss- and gain-of-function experiments and on in vivo tumor growth, and metastasis was assessed in nude mice. miR-9-3p expression was decreased and ESM1 was increased in bladder cancer. BMSCs inhibited bladder cancer cell viability, migration, and invasion, and induced apoptosis, whereas the addition of exosome secretion inhibitor GW4869 achieved the opposite effects. Moreover, exosomal miR-9-3p upregulation or ESM1 silencing suppressed bladder cancer cell viability, migration, and invasion; induced cell apoptosis; and inhibited in vivo tumor growth and metastasis. Taken together, BMSC-derived exosomal miR-9-3p suppressed the progression of bladder cancer through ESM1 downregulation, offering a potential novel therapeutic target for bladder cancer therapy.


Comparison of eligible randomized patients with two groups of ineligible patients: can the results of the VA Total Parenteral Nutrition clinical trial be generalized?
The recently reported VA Cooperative Study "A Randomized Clinical Trial of Total Parenteral Nutrition (TPN) in Malnourished Surgical Patients" randomized 395 pre-operative patients to TPN treatment or control. The study concluded that the use of perioperative TPN should be limited to the most severely malnourished patients. The study also followed 233 patients eligible for the study who refused to give informed consent for randomization (Eligible Refusers) as well as 1220 patients who were ineligible because they were not sufficiently malnourished (Index Group). Patients in the Index Group were determined to be significantly healthier than those in the two eligible groups of patients. Those in the Eligible Refuser group were shown to be slightly less malnourished than the Randomized Patients. The 395 patients randomized to the study (Randomized Patients) showed the highest rate of septic complications at 30 days and at 90 days (10% and 13% respectively) with rates for the Eligible Refusers slightly lower (8% and 9%) and Index Group rates still lower (4% and 4%). Nonseptic complication rates showed the same pattern (19% and 22% for the Randomized group, 12% and 12% for Eligible Refusers, and 10% and 10% for the Index Group). Because (a) the beneficial effect of TPN is attained only in severely malnourished patients, (b) there is increased risk of septic complications with TPN use in patients not severely malnourished, (c) Index Group patients, and presumably the population of patients from which they are drawn, are not severely malnourished, it follows that unless specifically indicated, TPN should not be used in nonseverely malnourished patients.


Balanced performance measurement in research hospitals: the participative case study of a haematology department.
The paper aims to review, design and implement a multidimensional performance measurement system for a public research hospital in order to address the complexity of its multifaceted stakeholder requirements and its double institutional aim of care and research. The methodology relies on a participative case study performed by external researchers in close collaboration with the staff of an Italian research hospital. The paper develops and applies a customized version of balanced scorecard based on a new set of performance measures. Our findings suggest that it can be considered an effective framework for measuring the research hospital performance, thanks to a combination of generalizable and context-specific factors. By showing how the balanced scorecard framework can be customized to research hospitals, the paper is especially of interest for complex healthcare organizations that are implementing management accounting practices. The paper contributes to the body of literature on the application of the balanced scorecard in healthcare through an examination of the challenges in designing and implementing this multidimensional performance tool. This is one of the first papers that show how the balanced scorecard model can be adapted to fit the specific requirements of public research hospitals.


Putting the diet back into diet-induced obesity: diet-induced hypothalamic gene expression.
A wealth of detailed mechanistic information relating to obesity and body weight regulation has emerged from study of single gene mutation models, and continues to be generated by engineered rodent models targeting specific genes. However, as an early step in translational research, many researchers are turning to models of diet-induced obesity. Interpretation of data generated from such models is not aided by the variety of diets and rodent strains employed in these studies and a strong case could be made for rationalisation. Differences in experimental protocol, which may deploy a single obligatory solid diet, a choice of solid diets, or liquid/solid combinations, and which may or may not allow a preferred macronutrient composition to be selected, mean that different models of diet-induced obesity achieve that obesity by different routes. The priority should be to mimic the palatability- and choice-driven over-consumption that probably underlies the majority of human obesity. Some of the hypothalamic energy balance genes apparently 'recognise' developing diet-induced obesity as indicated by counter-regulatory changes in expression levels. However, substantial changes in gene expression on long-term exposure to obesogenic diets are not able to prevent weight gain. Forebrain reward systems are widely assumed to be overriding hypothalamic homeostatic energy balance systems under these circumstances. More mechanism-based research at the homeostatic/reward/diet interface may enable diets to be manipulated with therapeutic benefit, or define the contribution of these interactions to susceptibility to diet-induced obesity.


Linear growth and bone maturation are unaffected by 1 year of therapy with inhaled flunisolide hydrofluoroalkane in prepubescent children with mild persistent asthma: a randomized, double-blind, placebo-controlled trial.
Inhaled corticosteroids (ICS) are the preferred long-term therapy for subjects with persistent asthma. However, concerns remain about potential effects of long-term ICS use on growth in children. To determine the effect of 1 year of inhalation therapy with flunisolide hydrofluoroalkane (HFA) on growth velocity and bone maturation in children with mild persistent asthma. In this double-blind, placebo-controlled study, 218 prepubescent (Tanner Stage 1) children with mild persistent asthma ranging in age from 4 to 10 years were evaluated. After a 2-week run-in period, subjects were randomized (1:1) to 2 puffs flunisolide HFA twice daily (85 μg/puff) or placebo for 52 weeks. Height was assessed by stadiometry at each visit. Growth velocity (cm/52 weeks) was estimated by the slope of the linear regression of height over time. An independent assessor scored hand and wrist radiographs for bone development pretreatment and at week 52. Analysis of covariance was used for all efficacy endpoints. The 2 treatment groups were similar at baseline for sex, race, age, weight, and height. At the end of double-blind treatment, mean growth velocity was 6.01 ± 1.84 cm/52 weeks for flunisolide HFA (n = 106) and 6.19 ± 1.30 cm/52 weeks for placebo (n = 112) (P = .425). Mean advancement in bone age during the 1-year study was similar for the 2 groups: 0.93 ± 0.46 years for flunisolide HFA (n = 70) and 1.01 ± 0.41 years for placebo (n = 75) (P = .128). In this study, flunisolide HFA did not suppress growth or bone maturation at the highest approved dose for children with persistent asthma.


Parent mental health and neurodevelopmental outcomes of children hospitalized in the neonatal intensive care unit.
High-risk infants hospitalized in the Neonatal Intensive Care Unit (NICU) often receive life-saving interventions during a critical period of development, when their brain is highly sensitive to both positive and negative environmental factors. It is no surprise that this time is particularly challenging for families. In fact, parents of hospitalized newborns are likely to experience clinically-significant symptoms of stress, anxiety, and depression. These symptoms have the potential to impact the nature and quality of the early parent-infant relationship and can lead to long-term problematic consequences for the infant and the family. As such, perinatal parent mental health represents a key factor that impacts outcomes of high-risk children. We discuss future practices to optimize the wellbeing of NICU infants and their families in the long-term, including increasing awareness and screening for parent mental health in the NICU, as well as building systems for support and early intervention.


Prediction of mild and severe preeclampsia with blood pressure measurements in first and second trimester of pregnancy.
The study was designed to determine the accuracy of using systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), and increase of blood pressure (BP) to predict Preeclampsia (PE). We examined 300 normotensive and 100 PE pregnancies divided in two subgroups: mild (n = 67) and severe (n = 33) PE. The patients had a BP check in first and second trimester (SBFP DBP and MAP). We found out significant difference between the groups, but what is more important is that the difference in BP values (especially diastolic and MAP) existed before the pathological increase of the BP above the normal values. This was happening most often after 31 wg (at 92.5%) and less often after 26 wg (at 7.5%) at the pregnancies with mild PE while at the pregnancies with severe PE, 18,2% had increased tension after 21 wg; 24% in the period of 26-30 wg and 57.58% after 31 wg. Based on the results we could conclude that when BP is measured in the first or second trimester of pregnancy the MAP is a better predictor for PE than SBP and DBPR.


Structure of the human Meckel-Gruber protein Meckelin.
Mutations in the Meckelin gene account for most cases of the Meckel-Gruber syndrome, the most severe ciliopathy with a 100% mortality rate. Here, we report a 3.3-Å cryo–electron microscopy structure of human Meckelin (also known as TMEM67 and MKS3). The structure reveals a unique protein fold consisting of an unusual cysteine-rich domain that folds as an arch bridge stabilized by 11 pairs of disulfide bonds, a previously uncharacterized domain named β sheet–rich domain, a previously unidentified seven-transmembrane fold wherein TM4 to TM6 are broken near the cytoplasmic surface of the membrane, and a coiled-coil domain placed below the transmembrane domain. Meckelin forms a stable homodimer with an extensive dimer interface. Our structure establishes a framework for dissecting the function and disease mechanisms of Meckelin.


Differential effects of Mandevilla velutina compounds on paw oedema induced by phospholipase A2 and phospholipase C.
This study compares the effect of Mandevilla velutina compounds with some anti-inflammatory drugs against phospholipase A2- and phospholipase C-induced rat hindpaw oedema. Injection of phospholipase A2 (Naja naja, 2.5-20 U/paw) and phospholipase C (Clostridium perfringens, 0.03-0.05 U/paw) caused a dose-and-time-related increase in paw oedema. Compounds MV 8608 (55 mumol/kg) and MV 8612 (32 mumol/kg, i.p.) inhibited phospholipase A2-induced paw oedema without interfering with phospholipase C-induced oedema. Local injection of both M. velutina compounds also partially attenuated the oedema evoked by phospholipases A2 and C. Dexamethasone (1.3 mumol/kg, p.o.) suppressed only phospholipase A2-induced paw oedema, while indomethacin (11 mumol/kg, p.o.) attenuated only the early phase of phospholipase C-induced oedema. By contrast, phenidone (616 mumol/kg, i.p.) inhibited only phospholipase C-induced oedema, while cyproheptadine (31 mumol/kg) and pyrilamine (100 mumol/kg, p.o.) inhibited only phospholipase A2 oedema. Treatment of animals with compound 48/80 markedly suppressed phospholipase A2-induced paw oedema and to a lesser degree the oedema caused by phospholipase C. Our results indicate that there are marked differences regarding the mechanisms underlying the paw oedema responses caused by phospholipase A2 and phospholipase C. In addition, our data show that M. velutina compounds cause potent and long-lasting inhibition of the pro-inflammatory action of phospholipase A2, an effect which may account for their reported anti-inflammatory activities.


Early treatment with recombinant factor VIIa results in greater efficacy with less product.
Early treatment of bleeding episodes in haemophilia patients offers advantages over later treatment, including minimizing the damage caused by the haemorrhage and reducing the amount of product needed to control it. Self-administration at home also offers greater convenience and time and cost savings for both patient and physician. We compared the amount of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) used in the treatment of peripheral intramuscular haemorrhages in people with haemophilia A and B with inhibitors and in those with acquired haemophilia, in the compassionate use, dose-finding and US home treatment studies. We also compared the response rates in each of the 3 studies. In the compassionate use setting, in which the mean time from onset of bleeding to initiation of treatment with rFVIIa was 5 d, the mean number of doses given per bleeding episode was 13.6, with 63.1% of episodes without compartment syndrome and 73% with tense muscle/compartment syndrome having an excellent or effective response. In the dose-finding study, average time from onset of bleeding to treatment with rFVIIa was 9 h. The average number of doses given was 3.55, and 72% in the high-dose arm were judged to have an excellent or effective response. In the US home treatment study in which bleeding episodes were treated earlier (mean 1.2 h from onset of bleeding), the mean number of doses given was 2.3, and 92% had an effective response to treatment. These findings indicate that early treatment with rFVIIa has a greater success rate, with fewer doses being required. Home treatment results in cost savings, greater convenience, and less morbidity.


The elongation factor 3 unique in higher fungi and essential for protein biosynthesis is an E site factor.
Two elongation factors drive the ribosomal elongation cycle; elongation factor 1 alpha (EF-1 alpha) mediates the binding of an aminoacyl-tRNA to the ribosomal A site, whereas elongation factor 2 (EF-2) catalyzes the translocation reaction. Ribosomes from yeast and other higher fungi require a third elongation factor (EF-3) which is essential for the elongation process, but the step affected by EF-3 has not yet been identified. Here we demonstrate that the first and the third tRNA binding site (A and E sites, respectively) of yeast ribosomes are reciprocally linked; if the A site is occupied the E site has lost its binding capability, and vice versa, if the E site is occupied the A site has a low affinity for tRNAs. EF-3 is essential for EF-1 alpha-dependent A site binding of amino-acyl-tRNA only when the E site is occupied with a deacylated tRNA. The ATP-dependent activity of EF-3 is required for the release of deacylated tRNA from the E site during A site occupation.


VOCs emission from a final landfill cover system induced by ground surface air temperature and barometric pressure fluctuation.
Volatile organic compounds (VOCs) emission flux and their concentration profiles were measured at a final municipal solid waste (MSW) landfill cover in Hangzhou, China. The influencing parameters, especially ground surface air temperature and pressure were monitored concomitantly. Furthermore, a numerical model incorporating coupled thermo-hydro-chemical interaction to assess VOCs emission from this final landfill cover (LFC) system was developed and validated with the field test results. The tested total VOC emission flux from the final cover is 0.0124 μg/m2/s, which indicates that the total amount of VOCs emitted into the atmosphere is 391 mg/m2 annually. Among these, dichloromethane (DCM) dominated VOCs emission flux during May, comprising 51.8% of the total emission flux. The numerical simulation results indicated that the diffusive emission flux of VOCs varied consistently with the fluctuation of atmospheric temperature. Whereas, the advective flux varied inversely with the fluctuation of barometric pressure. The highest difference in diffusive emission flux induced by temperature variation is 183 μg/m2/day and occurred in spring. Moreover, the results demonstrated that the impact of atmospheric temperature and pressure fluctuation on the emission of VOC from final covers is non-negligible when reasonably assessing the risks of landfill and landfill gas emission budget.


Intervention on malaria awareness among 'Bedia' tribal community in West Bengal, India.
Tribals have a vulnerable health status because of malarial morbidities, yet they ignore their illnesses and do not go to physicians during sickness for several reasons including poverty. This qualitative research project attempted to create awareness among 'Bedia' tribal to initiate preventive and other personal protective measures against malaria. Initially, efforts were made to create malaria awareness by literate 'Bedia' volunteers who were trained to do so; however, their tribal fellows were reluctant to receive awareness efforts from them. After thorough analysis and interaction, a novel "interprofessional team" of composer, vocalist, and instrumentalists approach was made to impart malaria awareness by composing songs in the language of the aborigine. Then health education was imparted to the 'Bedia' participants by the trained 'Bedia' through theme songs with their rustic music instruments and group dance performances in the intermingled media from the team. An evaluation was done to assess usefulness of the health education intervention by the researchers. Overall, 137 adult 'Bedias' in 42 families (M = 74; F = 63) participated in our study. In the informal feedback session, only 51 adult males and 46 adult females could furnish expected results. Out of the 42 families residing in the village, 11 houses consistently used mosquito bed nets before the awareness program; after the awareness program, it became 15 as was demonstrated by using social mapping. Our project activities on the Bedia tribes could unearth required interventions of awareness about malaria. However, it was possible to create awareness and confidence among them so that they could themselves take necessary preventive measures and positive approaches toward malaria.


Clinical features and transmission risk analysis of dengue virus infections in Shenzhen, During 2014-2019.
Dengue fever (DF) and dengue hemorrhagic fever (DHF) are among the most common tropical diseases affecting humans. To analyze the risk of clinical and transmission of DF/DHF in Shenzhen, the surveillance on patients of all-age patients with dengue virus (DENV) infections was conducted. Our findings revealed that the majority of DENV-infected patients are young to middle-aged males, and the development of the disease is accompanied by abnormal changes in the percentages of neutrophils, lymphocytes, and basophils. Demographic analysis revealed that these patients is concentrated in areas such as Futian District, which may be due to the higher mosquito density and temperature than that in other area. Subsequent, mosquito infection experiments confirmed that the effect of temperature shift on DENV proliferation and transmission. Not only that, constant temperatures can enhance the spread of DENV, even increase the risk of epidemic. Thus, the role of innate immune response should be highlighted in the prediction of severe severity of DENV-infected patients, and temperature should be taken into account in the prevention and control of DENV. Dengue fever (DF) and dengue hemorrhagic fever (DHF) are among the most common tropical diseases affecting humans, and which caused by the four dengue virus serotypes (DENV 1-4). To analyze the risk of clinical and transmission of DF/DHF in Shenzhen. The surveillance on patients of all-age patients with dengue virus (DENV) infections was conducted. Our findings revealed that the majority of DENV-infected patients are young to middle-aged males, and the development of the disease is accompanied by abnormal changes in the percentages of neutrophils, lymphocytes, and basophils. Demographic analysis revealed that these patients is concentrated in areas such as Futian District, which may be due to the higher mosquito density and temperature than that in other area. Subsequent, mosquito infection experiments confirmed that the effect of temperature shift on DENV proliferation and transmission. Not only that, constant temperatures can enhance the spread of DENV, even increase the risk of epidemic. 1. Elevated levels of neutrophils, lymphocytes, basophils, and temperature are all significant risk factors for dengue transmission and pathogenesis; 2. Temperature increasing is associated with a higher risk of dengue transmission; 3. Fluctuations in temperature around 28 °C (28 ± 5 °C) would increase dengue transmission.


Transposition of human immunoglobulin V kappa genes within the same chromosome and the mechanism of their amplification.
The variable, joining and constant gene segments of the human immunoglobulin kappa locus (V kappa, J kappa and C kappa) are located on the short arm of chromosome 2 at 2p11-2p12. Here we describe a cluster of 11 V kappa genes on the long arm of chromosome 2 at 2cen-q11. By pulsed-field gel electrophoresis, cosmid cloning and DNA sequencing the cluster was shown to consist of four amplified units (amplicons). The amplicons, each 110-160 kb in size, are organized within 650 kb as an array of inverted repeats with short stretches of non-amplified DNA in between. Cloning and sequencing of three different joints between amplified and non-amplified DNA revealed the existence of parts of Alu repeats at each of the analysed joints. It is suggested that during evolution a group of five V kappa genes was transposed from the short to the long arm of chromosome 2 by a pericentric inversion. Three of the five V kappa genes were then amplified in two subsequent steps to yield the structure found in the majority of the present day population. The possible relation of this structure to a pericentric inversion of chromosome 2 that is seen cytogenetically in a small fraction of today's population is discussed.


Rheumatoid factor and anti-CCP autoantibodies in rheumatoid arthritis: a review.
For many years, laboratory diagnosis of rheumatoid arthritis has relied on the detection of rheumatoid factor. A new assay that detects antibodies to citrullinated peptides, called the anti-CCP assay, has demonstrated a comparable sensitivity but a much higher specificity than the RF test. This paper reviews RF and anti-CCP in rheumatoid arthritis and examines the usefulness of each autoantibody in RA testing.


Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases.
Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7-C12 and C9-C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7-C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: "nonreducing" ARO/CYCs, which act on nonreduced poly-β-ketones, and "reducing" ARO/CYCs, which act on cyclized C9 reduced poly-β-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.


Validation study of the modified HEART and HEAR scores in patients with chest pain who visit the emergency department.
To validate the efficacy of the history, electrocardiogram, age, risk factors, and troponin (HEART) and history, electrocardiogram, age, and risk factors (HEAR) scores in a Japanese cohort. We used the data of patients who visited our emergency department between 1 December, 2015 and 31 May, 2017. Patients aged ≥20 years who presented with non-traumatic and undifferentiated chest pain were eligible for the study. On the basis of the total score, the patients were stratified as low risk (HEART and HEAR scores of 0-3), intermediate risk (HEART and HEAR scores of 4-6), and high risk (HEART score of 7-10 and HEAR score of 7-8). The major adverse cardiac events (MACEs) that occurred within 6 weeks were investigated, and the diagnostic value and efficiency of both scores were analyzed. In total, 132 patients were included in the HEART score analysis and 220 patients in the HEAR score analysis. The incidence rates of MACEs in patients with low, intermediate, and high risks were 0%, 23.2%, and 63.6% in the HEART score analysis and 4.7%, 22.9%, and 62.5% in the HEAR score analysis (P < 0.001), respectively. The identification of MACEs in low-risk patients had a negative predictive value in the HEART score (1.00; 95% confidence interval, 0.90-1.00) and HEAR score (0.95; 95% confidence interval, 0.89-0.99) analyses. The modified HEART and HEAR scores were effective in identifying patients with chest pain who are at low risk of MACEs at an emergency department in Japan.


Antimicrobial activity of human beta-defensins and induction by Francisella.
The ability of human beta-defensins hBD-1, hBD-2, and hBD-3 to exert direct in vitro antimicrobial effects was evaluated using Francisella tularensis Live Vaccine Strain (LVS) and Francisella novicida. While hBD-2 showed some antimicrobial activity in these assays, only hBD-3 demonstrated significant potency against Francisella. Francisella tularensis LVS infection induced elevated levels of hBD-2 mRNA in human airway epithelial (A549) cells, while having no significant impact on the levels of hBD-3 and only a moderate effect on the level of hBD-1 mRNA. Francisella infection avoided stimulating the production of the most potent anti-Francisella host peptide, hBD-3, in A549 cells, although hBD-3 is stimulated by other treatments. The differential induction of beta-defensins in Francisella infected lung epithelial cells suggests a complex dynamic in the expression of antimicrobial peptides and the innate immune response.


A possible new approach to the management of brain abscesses.
A report is given of effective non-surgical treatment with antibiotics in a patient with a large brain abscess.Non-surgical treatment of brain abscesses may be possible if massive doses of specific bactericidal antibiotics are used and the patients are followed up with frequent brain scans and computerized tomography.


How does psilocybin therapy work? An exploration of experiential avoidance as a putative mechanism of change.
Psilocybin therapy is receiving attention as a mental health intervention with transdiagnostic potential. In line with psychotherapeutic research, qualitative research has highlighted the role of reductions in experiential avoidance (and increases in connectedness) within psilocybin therapy. However, no quantitative research has examined experiential avoidance as a mechanism underlying psilocybin therapy's therapeutic effects. Data was used from a double-blind randomized controlled trial that compared psilocybin therapy (two 25 mg psilocybin session plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among individuals with major depressive disorder (N = 59). All participants received psychological support. Experiential avoidance, connectedness, and treatment outcomes were measured at pre-treatment and at a 6 week primary endpoint. Acute psilocybin experiences and psychological insight were also measured. With psilocybin therapy, but not escitalopram, improvements in mental health outcomes (i.e., well-being, depression severity, suicidal ideation, and trait anxiety) occurred via reductions in experiential avoidance. Exploratory analyses suggested that improvements in mental health (except for suicidal ideation) via reduction in experiential avoidance were serially mediated through increases in connectedness. Additionally, experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance following psilocybin therapy. Difficulties inferring temporal causality, maintaining blindness to condition, and reliance upon self-report. These results provide support for the role of reduced experiential avoidance as a putative mechanism underlying psilocybin therapy's positive therapeutic outcomes. The present findings may help to tailor, refine, and optimize psilocybin therapy and its delivery.


Pair distribution functions of amorphous organic thin films from synchrotron X-ray scattering in transmission mode.
Using high-brilliance high-energy synchrotron X-ray radiation, for the first time the total scattering of a thin organic glass film deposited on a strongly scattering inorganic substrate has been measured in transmission mode. The organic thin film was composed of the weakly scattering pharmaceutical substance indomethacin in the amorphous state. The film was 130 µm thick atop a borosilicate glass substrate of equal thickness. The atomic pair distribution function derived from the thin-film measurement is in excellent agreement with that from bulk measurements. This ability to measure the total scattering of amorphous organic thin films in transmission will enable accurate in situ structural studies for a wide range of materials.