Limb and tail lengths in relation to substrate usage in Tropidurus lizards.
A close relationship between morphology and habitat is well documented for anoline lizards. To test the generality of this relationship in lizards, snout-vent, tail, and limb lengths of 18 species of Tropidurus (Tropiduridae) were measured and comparisons made between body proportions and substrate usage. Phylogenetic analysis of covariance by computer simulation suggests that the three species inhabiting sandy soils have relatively longer feet than do other species. Phylogenetic ANCOVA also demonstrates that the three species inhabiting tree canopies and locomoting on small branches have short tails and hind limbs. These three species constitute a single subclade within the overall Tropidurus phylogeny and analyses with independent contrasts indicate that divergence in relative tail and hind limb length has been rapid since they split from their sister clade. Being restricted to a single subclade, the difference in body proportions could logically be interpreted as either an adaptation to the clade's lifestyle or simply a nonadaptive synapomorphy for this lineage. Nevertheless, previous comparative studies of another clade of lizards (Anolis) as well as experimental studies of Sceloporus lizards sprinting on rods of different diameters support the adaptive interpretation.


Qigong massage treatment for sensory and self-regulation problems in young children with autism: a randomized controlled trial.
Autism is commonly associated with sensory and self-regulatory disturbances. This article presents a randomized controlled study evaluating the effect of a 5-month intervention directed toward improving sensory impairment, digestion, and sleep in 46 children with autism < age 6. The intervention, Qigong Sensory Training (QST), is a qigong massage intervention based in Chinese medicine. It is two-pronged: Trainers work with children directly 20 times over 5 months, and parents give the massage daily to their children. Improvement was evaluated in two settings--preschool and home--by teachers (blind to group) and parents. Teacher evaluations showed that treated children had significant classroom improvement of social and language skills and reduction in autistic behavior compared with wait-list control participants. These findings were confirmed by parent data, indicating that the gains had generalized across contexts. A model and supporting data for understanding and treating sensory and self-regulation problems in autism is presented.


[Implementation of medical specialists brigades in the areas of Universal Health coverage: the Peruvian Ministry of Health experience, 2009-2010].
Peru has a high degree of inequity reflected in the distribution of morbidity and mortality, consistent with the inaccessibility to health care and human resource gap, especially in remote areas of the capital. The Peruvian Ministry of Health, recognizing the right of all people to quality health care, initiated the Universal Health Insurance (AUS), and in this context, increased access to specialized care in pilot AUS areas by brigades of specialist doctors. This article offers an approach to this strategy presents the management and implementation processes, a quantitative analysis with indicators of output / efficiency, and provides a qualitative look from the perspective of the members of the brigades. Its main findings reflect the lack of effective and efficient management, translated in the absence of: production goals, work plans, working partnerships with local stakeholders, monitoring and effective supervision, recurrent shortages of human and technological resources, and high costs.


Mesothelioma in patients with nonoccupational asbestos exposure. An evidence-based approach to causation assessment.
The specific parameters of nonoccupational asbestos exposures (NOAE) that can distinguish an idiopathic from an asbestos-caused malignant mesothelioma (MM) are controversial. A systematic literature review yielded 1028 cases with this putative association. Only 287 of those reports had a defined single exposure to a household, building occupant, or neighborhood/community asbestos source. The available "evidence" was used to develop semiarbitrary evidence-based causation guideline rules for the assessment of putative associations between MM and NOAE. The rules are classified into class A (tissue burden analysis shows asbestos body counts or fiber counts in lung tissues comparable to MM caused by occupational exposure to asbestos) and classes B to D based on whether certain combinations of NOAE features and MM (evidence) have been described in over 15% (class B), 5% to 15% (class C), and less than 5% (class D) of the patients reviewed. The proposed 4 classes of evidence-based causation guidelines provide a semiarbitrary framework to evaluate the causation of individual MM patients by NOAE based on decreasing levels of currently available evidence. The neoplasms in classes A to C patients are probably caused by NOAE, with decreasing weight of evidence in the 3 groups. There is minimal evidence to support the causation of MM by NOAE in class D patients. There is no evidence or only anecdotal evidence to support a causal association between MM and NOAE in individuals who cannot be classified into any of the 4 classes. Future studies are needed to provide more comprehensive data regarding the association between MM and NOAE.


Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD.
Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of β-oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16-C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain-to-intermediate-chain acylcarnitine ratio, a marker of efficiency of β-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (P<0.001). Additionally, multiple linear regression revealed that the long-chain-to-intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16-C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16-C20 FFAs coupled with impaired β-oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.


Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.
Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 x 10-10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals.


A mathematical model of compartmentalized neurotransmitter metabolism in the human brain.
After administration of enriched [1-13C]glucose, the rate of 13C label incorporation into glutamate C4, C3, and C2, glutamine C4, C3, and C2, and aspartate C2 and C3 was simultaneously measured in six normal subjects by 13C NMR at 4 Tesla in 45-ml volumes encompassing the visual cortex. The resulting eight time courses were simultaneously fitted to a mathematical model. The rate of (neuronal) tricarboxylic acid cycle flux (V(PDH)), 0.57 +/- 0.06 micromol. g(-1). min(-1), was comparable to the exchange rate between (mitochondrial) 2-oxoglutarate and (cytosolic) glutamate (Vx), 0.57 +/- 0.19 micromol. g(-1). min(-1)), which may reflect to a large extent malate-aspartate shuttle activity. At rest, oxidative glucose consumption [CMR(Glc(ox))] was 0.41 +/- 0.03 miccromol. g(-1). min(-1), and (glial) pyruvate carboxylation (VPC) was 0.09 +/- 0.02 micromol. g(-1). min(-1). The flux through glutamine synthetase (Vsyn) was 0.26 +/- 0.06 micromol. g(-1). min(-1). A fraction of Vsyn was attributed to be from (neuronal) glutamate, and the corresponding rate of apparent glutamatergic neurotransmission (VNT) was 0.17 +/- 0.05 micromol. g(-1). min(-1). The ratio [VNT/CMR(Glcox)] was 0.41 +/- 0.14 and thus clearly different from a 1:1 stoichiometry, consistent with a significant fraction (approximately 90%) of ATP generated in astrocytes being oxidative. The study underlines the importance of assumptions made in modeling 13C labeling data in brain.


New dual ligands for the D2 and 5-HT1A receptors from the group of 1,8-naphthyl derivatives of LCAP.
More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT1AR and dopamine D2R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT1A/D2 receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT1A,5-HT2A,5-HT6,5-HT7) and dopamine (D2) receptors have been evaluated in vitro. Compounds 5.3a, 5.4, 5.1c, 5.3d, 5.2a are promising dual 5-HT1AR/D2R ligands. The SAR analysis were additionally supported with molecular docking studies.


Image continuity at different levels of zoom for fringe patterns.
Fringe patterns are raw output data from many measurement systems including laser interferometers and moiré systems. For instruments with a range of zoom levels to measure the object at different scales, a technique (algorithm) is needed to combine and/or compare data to obtain information at different levels of details. A technique to keep the continuity of output images both at different levels of zoom and within the same level of zoom is developed and demonstrated. Image registration is used to correlate images, find relative zoom values, and obtain shift between images in the lateral plane. Fringe patterns from a moiré system and a laser interferometer are used as images to be stitched and demonstrate the technique. Interferomteric fringes are used to find the required parameters to inter-relate locations and scale of the fringe patterns at different levels of zoom. The calculated parameters are scale and translation in both directions; these parameters make it possible to locate the coordinates of the region that the measurement system is zoomed in on, related to the area with lower magnification and relative locations of images within the same level of zoom. Results show that this technique is capable of finding the scale and shift parameters within the resolution of one pixel and therefore can restore continuity between images at different levels of zoom.


Quantitative real time polymerase chain reaction assays for the sensitive detection of Besnoitia besnoiti infection in cattle.
Bovine besnoitiosis, an economically important disease in cattle in some countries of Africa and Asia, is emerging in Europe. The definitive host of Besnoitia besnoiti, the causative agent of bovine besnoitiosis, is unknown and the transmission of the parasite is not completely understood. Sensitive and quantitative DNA detection methods are needed to determine whether serologically positive animals are infectious and to examine the role of vectors (e.g. haematophagous insects) in the transmission of the parasite. To this end, we established two different 5'-nuclease quantitative assays to detect B. besnoiti infection in cattle and to estimate the parasite load in samples (BbRT1 and BbRT2). These PCRs are based on the sequence of the internal transcribed spacer region 1 (ITS-1) of the ribosomal RNA gene. Tests with serial dilutions of B. besnoiti genomic DNA in a buffer containing 100 ng/μl bovine DNA revealed a detection limit of 0.01 pg genomic B. besnoiti DNA. Reliable quantification was possible in samples containing ≥1 pg B. besnoiti genomic DNA with a coefficient of variation of ≤ 2%. To estimate the diagnostic sensitivity of the tests, skin biopsies and scrapings from the mucous membrane of the vestibulum vaginae (vaginal scrapings) were taken from cattle with clinical signs of chronic besnoitiosis. Regardless of the real time PCR assay used, 90.7% (39/43) of these animals were positive in at least one of two samples (skin or vaginal scrapings). Antibody titers, as determined by an immunofluorescent antibody test, and the threshold cycle values of the real time PCR obtained for skin samples and vaginal scrapings, were significantly correlated. The specificity of the PCRs was confirmed using genomic DNA from related parasites, including genomic DNA of Besnoitia spp., Neospora caninum, Toxoplasma gondii, Hammondia hammondi, Hammondia heydorni, Isospora spp., Sarcocystis spp., Eimeria bovis, Cryptosporidium parvum, and Trypanosoma brucei brucei. Since the sequence of the ITS-1 region of B. besnoiti is identical with that of Besnoitia species isolated from donkeys (Besnoitia bennetti), and reindeer (Besnoitia tarandi), both real time PCRs detected also DNA of these parasites. One of the B. besnoiti real time PCRs, BbRT1, but not BbRT2, cross-reacted with Besnoitia darlingi, Besnoitia oryctofelisi, and Besnoitia neotomofelis when large amounts of genomic DNA (10 ng) were used. The other B. besnoiti real time PCR assay (BbRT2) was specific for B. besnoiti, B. bennetti and B. tarandi, but did not react when 10 ng DNA of other related parasite species from the genus Besnoitia or other genera were subjected to analysis.


Inhibition of macrophage tumoricidal activity by immune complexes and altered erythrocytes.
Engagement of the macrophage membrane by biologic particles including insoluble immune complexes inhibited the development of lymphokine-mediated nonspecific tumoricidal activity by murine macrophages. The degree of inhibition was dependent on the dose of particles and the lymphokine concentration. Inhibition was not due to macrophage cell death or to diminution of cell adherence after ingestion of the immune complexes. Soluble immune complexes were not inhibitory, although approximately 10% of the complexes became cell-associated. Monomeric or heat-aggregated IgG was also not inhibitory. IgG-opsonized erythrocytes (EA) were inhibitory and inhibition was dependent on the degree of opsonization. In contrast, nonopsonized erythrocytes (E), which did not bind to macrophages, were not inhibitory. Phagocytosis of glutaraldehyde-treated E or E carrying IgM antibody and complement (EAC) also led to a reduction of tumorilytic activity. Insoluble immune complexes were inhibitory when added either before or after lymphokine. Phagocytosis was neither sufficient nor necessary to cause inhibition because 1) ingestion of polystyrene latex beads did not diminish tumoricidal activity, and 2) macrophages plated on IgG-coated surfaces were inhibited with respect to the tumoricidal function. Inhibition was not affected when indomethacin (10(-6) M) was included in the assay, which indicated that prostaglandins were not involved in the process. Thus, macrophage tumoricidal responsiveness may be compromised by interaction of biologic substances with macrophage plasma membranes. This process may thereby inactivate an important host defense mechanism against neoplastic cells.


Hemolytic disease of the newborn due to anti-U.
Anti-U is a rare red blood cell alloantibody that has been found exclusively in blacks. It can cause hemolytic disease of the newborn and hemolytic transfusion reactions. We describe the case of a female newborn presenting a strongly positive direct antiglobulin test due to an IgG antibody in cord blood. Anti-U was recovered from cord blood using acid eluate technique. Her mother presented positive screening of antibodies with anti-U identified at delivery. It was of IgG1 and IgG3 subclasses and showed a titer of 32. Monocyte monolayer assay showed moderate interaction of Fc receptors with maternal serum with a positive result (3.1%). The newborn was treated only with 48 hours of phototherapy for mild hemolytic disease. She recovered well and was discharged on the 4th day of life. We conclude that whenever an antibody against a high frequency erythrocyte antigen is identified in brown and black pregnant women, anti-U must be investigated.


Chromatin immunoprecipitation improvements for the processing of small frozen pieces of adipose tissue.
Chromatin immunoprecipitation (ChIP) has gained importance to identify links between the genome and the proteome. Adipose tissue has emerged as an active tissue, which secretes a wide range of molecules that have been related to metabolic and obesity-related disorders, such as diabetes, cardiovascular failure, metabolic syndrome, or cancer. In turn, epigenetics has raised the importance in discerning the possible relationship between metabolic disorders, lifestyle and environment. However, ChIP application in human adipose tissue is limited by several factors, such as sample size, frozen sample availability, high lipid content and cellular composition of the tissue. Here, we optimize the standard protocol of ChIP for small pieces of frozen human adipose tissue. In addition, we test ChIP for the histone mark H3K4m3, which is related to active promoters, and validate the performance of the ChIP by analyzing gene promoters for factors usually studied in adipose tissue using qPCR. Our improvements result in a higher performance in chromatin shearing and DNA recovery of adipocytes from the tissue, which may be useful for ChIP-qPCR or ChIP-seq analysis.


Looking different, feeling different: women's reactions to risk-reducing breast and ovarian surgery.
Most studies of quality of life following risk-reducing bilateral salpingo-oophorectomy (RRSO) and mastectomy (RRM) for inherited breast and ovarian cancer susceptibility were conducted before counseling protocols were established and included women at varying times since surgery. This study aimed to overcome these deficiencies and to provide current data on outcomes for this growing group of women. Semi-structured interviews were used to explore the experiences of an Australian cohort of 40 high-risk women 3 years after they underwent RRM and/or RRSO. Data were analyzed using the method of constant comparison. 19/40 women underwent RRSO, 8/40 RRM and 13/40 both procedures. Two themes-looking different and feeling different-captured the psychosocial impact of surgery upon interviewees. All regarded RR surgery as a positive experience and were relieved at having their risks of cancer substantially reduced; however, reducing risk by removing these body parts is not without costs. In addition to relief interviewees also reported experiencing a range of negative emotions and a range of unexpected bodily sensations following surgery and reflected upon both positive and negative changes in their appearance. Women said they had been unprepared for the lack of sensation in reconstructed breasts and/or the severity of menopausal symptoms, which often had a negative impact upon sexuality. At-risk women regard RR surgery as a positive way to manage cancer risk. However, although women who currently undergo RR surgery are informed about its sequelae, few are entirely prepared for the reality of undergoing this procedure. We recommend that women who undergo these procedures should be provided with information supported by psychosocial input before and after RR surgery.


Age-related changes in attentional control across adolescence: how does this impact emotion regulation capacities?
This study set out to establish the novel use of the go/no-go Overlap task for investigating the role of attentional control capacities in the processing of emotional expressions across different age-groups within adolescence: at the onset of adolescence (11-12 year-olds) and toward the end of adolescence (17-18 year-olds). We also looked at how attentional control in the processing of fearful, happy, and neutral expressions relates to individual differences in trait anxiety in these adolescent groups. We were able to show that younger adolescents, but not older adolescents had more difficulties with attention control in the presence of all faces, but particularly in the presence of fearful faces. Moreover, we found that across all groups, adolescents with higher trait anxiety exhibited attentional avoidance of all faces, which facilitated relatively better performance on the primary task. These differences in reaction time emerged in the context of comparable accuracy level in the primary task across age-groups. Our results contribute to our understanding of how attentional control abilities to faces but in particular fearful expressions may mature across adolescence. This may affect learning about the environment and the acquisition of behavioral response patterns in the social world.


Optimum dose of ursodeoxycholic acid in primary biliary cirrhosis.
Ursodeoxycholic acid (UDCA) improves liver function tests and prolongs survival in primary biliary cirrhosis (PBC). The dose of 10- 15 mg/kg/day used in the large trials has largely been based on that used for gallstone dissolution. The only dose-response study of UDCA in PBC suggested that a dose of 8 mg/kg/day was the most efficacious. However, disease stage of the patients was not known, higher doses of UDCA were not tried and there was no 'washout period' between the different doses. The aim of this study was to determine the optimum dose of UDCA in early-stage PBC (stage 1 and 2). Twenty-four biopsy-proven early-stage PBC patients (one male, 23 female) received five doses of UDCA (0, 300, 600, 900, 1200 mg/day) each for 8 weeks with 4-week washout periods between doses. Symptoms (pruritus, fatigue, diarrhoea) were assessed on a four-point scale (none, mild, moderate, severe). Liver function tests (LFTs) were performed using conventional methods, and serum bile acids were measured using gas liquid chromatography. The dose of 900 mg/day produced the greatest enrichment of UDCA in serum bile acids; although there was no difference in the enrichment of UDCA between the different doses. There was a trend towards normalization of the abnormal LFTs in a dose-dependent manner (for y-glutamyl transferase (yGT), alkaline phosphatase (ALP), alanine transaminase (ALT) and IgM). Multi-factorial analysis showed that UDCA treatment, irrespective of dose, was significantly better than placebo for all the variables. The 900 and 1200 mg doses were better than both 300 and 600 mg using yGT and total bilirubin as variables, better than 300 mg using ALP and IgM as variables, and better than 600 mg using albumin as a variable. No variables showed a significant difference between 900 and 1200 mg. The optimum dose of UDCA is 900 mg/day (equivalent to 13.5 mg/kg/day).


Rapid encoding of musical tones discovered in whole-brain connectivity.
Information encoding has received a wide neuroscientific attention, but the underlying rapid spatiotemporal brain dynamics remain largely unknown. Here, we investigated the rapid brain mechanisms for encoding of sounds forming a complex temporal sequence. Specifically, we used magnetoencephalography (MEG) to record the brain activity of 68 participants while they listened to a highly structured musical prelude. Functional connectivity analyses performed using phase synchronisation and graph theoretical measures showed a large network of brain areas recruited during encoding of sounds, comprising primary and secondary auditory cortices, frontal operculum, insula, hippocampus and basal ganglia. Moreover, our results highlighted the rapid transition of brain activity from primary auditory cortex to higher order association areas including insula and superior temporal pole within a whole-brain network, occurring during the first 220 ms of the encoding process. Further, we discovered that individual differences along cognitive abilities and musicianship modulated the degree centrality of the brain areas implicated in the encoding process. Indeed, participants with higher musical expertise presented a stronger centrality of superior temporal gyrus and insula, while individuals with high working memory abilities showed a stronger centrality of frontal operculum. In conclusion, our study revealed the rapid unfolding of brain network dynamics responsible for the encoding of sounds and their relationship with individual differences, showing a complex picture which extends beyond the well-known involvement of auditory areas. Indeed, our results expanded our understanding of the general mechanisms underlying auditory pattern encoding in the human brain.


A comparative effectiveness review of parenting and trauma-focused interventions for children exposed to maltreatment.
To systematically review the comparative effectiveness evidence for interventions to ameliorate the negative sequelae of maltreatment exposure in children ages birth to 14 years. We assessed the research on pharmacological and psychosocial interventions (parent-mediated approaches or trauma-focused treatments) reporting mental and behavioral health, caregiver-child relationship, and developmental and/or school functioning outcomes. We conducted focused searches of MEDLINE (through PubMed), Social Sciences Citation Index, PsycINFO, and the Cochrane Library (1990-2012). Reviewer pairs independently evaluated the studies for eligibility using predetermined inclusion/exclusion criteria, evaluated studies for risk of bias, extracted data, and graded the strength of evidence (SOE) for each comparison and each outcome based on predetermined criteria. Based on our review of 6282 unduplicated citations, we found 17 trials eligible for inclusion. Although several interventions show promising comparative benefit for child well-being outcomes, the SOE for all but one of these interventions was low. The results highlight numerous substantive and methodological gaps to address in the future research. It is too early to make strong treatment recommendations, as comparative research remains relatively nascent in the child maltreatment arena. These gaps reflect, in large part, the Herculean demands on researchers involved in conducting high-quality clinical studies with this highly vulnerable population. The National Child Traumatic Stress Network and the Developmental-Behavioral Pediatrics Research Network (DBPNet) are two potentially powerful platforms to conduct large rigorous trials needed to move the field forward. More broadly, a paradigm shift among researchers and funders alike is needed to galvanize the commitment and resources necessary for conducting collaborative clinical trials with this highly vulnerable population.


AAPM/RSNA tutorial on equipment selection: PACS equipment overview: general guidelines for purchasing and acceptance testing of PACS equipment.
A picture archiving and communication system (PACS) is a comprehensive computer system that is responsible for the electronic storage and distribution of medical images in the medical enterprise. The system is highly integrated with digital acquisition and display devices and is often related closely to other medical information systems, such as the radiology information system or hospital information system. In the past few years, there has been continuous growth in clinical implementation of PACS to reduce costs and improve patient care, a trend that is expected to continue. However, a PACS is complex and costly to acquire, replace, maintain, and repair. To select a system that best meets their requirements, purchasers of PACS equipment need to be aware of the key characteristics and differing features of the various products. After the PACS has been installed, the user should perform technical and clinical acceptance testing to ensure that the system meets expectations.


VDAC1 and SERCA3 Mediate Progesterone-Triggered Ca2+ Signaling in Breast Cancer Cells.
Progesterone is a biphasic hormone whose confounding role in breast cancer cells involves an initial proliferative surge, followed by sustained growth arrest. Recently we reported that progesterone induces a time- and concentration-dependent release of reactive oxygen species and thus regulates the antiproliferative activity in the breast cancer cell line. Furthermore, the expression of p27, a crucial cell cycle control protein, was regulated by binding of progesterone on progesterone receptor B, thus leading to antiproliferative signaling via multiple signaling pathways including p53, PTEN, and antioxidant systems. Here, we performed an LC-MS/MS analysis of three different breast cancer cell lines. Bioinformatics data analysis and functional classification of proteins revealed a role of progesterone in calcium signaling in MCF-7 cells, and the major differentially expressed calcium regulators were S100A11, S100A10, calreticulin, VDAC1, SERCA3, and SERCA1. Later on we confirmed it by a cell-line-based system having a calcium cameleon sensor targeted at endoplasmic reticulum and found moderate calcium efflux from endoplasmic reticulum upon progesterone treatment. Real-time PCR, Western blot, and TMRM staining confirmed the role of calcium signaling regulators VDAC1 and SERCA3 in progesterone response. Taking together all of these results with our previous studies, we suggest that progesterone, by regulating important proteins involved in calcium signaling and transport, can modulate cell proliferation and cell death. Furthermore, our research may open new avenues for the hypothesis that surgery conducted during the luteal phase of the menstrual cycle might facilitate improved patient survival.


Chabazite-Type Zeolite Membranes for Effective CO2 Separation: The Role of Hydrophobicity and Defect Structure.
Chabazite (CHA)-type zeolites are promising for the separation of CO2 from larger molecules, such as N2 (relevant to postcombustion carbon capture) and CH4 (relevant to natural gas/biogas upgrading). In particular, the pore size of CHA zeolites (0.37 × 0.42 nm2) can recognize slight molecular size differences between CO2 (0.33 nm) and the larger N2 (0.364 nm) or CH4 (0.38 nm) molecules, thus allowing separation in favor of CO2 through CHA membranes. Furthermore, the siliceous constituents in the CHA zeolite can reduce the adsorption capacity toward the smaller H2O molecule (0.265 nm) and, thus, the H2O permeation rate. This is highly desirable for securing good molecular sieving ability with CO2 permselectivity in the presence of H2O vapor. Indeed, a siliceous CHA film obtained with a nominal Si/Al ratio of 100 (CHA_100) showed high CO2/N2 and CO2/CH4 separation performance, especially in the presence of H2O vapor; ∼13.4 CO2/N2 and ∼37 CO2/CH4 separation factors (SFs) at 30 °C. These SFs were higher than the corresponding values (∼5.2 CO2/CH4 SFs and ∼31 CO2/CH4 SFs) under dry conditions; such improvement could be ascribed to defect blocking by physisorbed water molecules. Finally, the contribution of molecular transport through zeolitic and nonzeolitic parts was quantitatively analyzed by combining information extracted from image processing of fluorescence confocal optical microscopy images with a one-dimensional permeation model. It appears that ∼19 and ∼20% of the total CO2 permeance for CHA_100 were reduced due to transport inhibition by the physisorbed water molecules on the membrane surface and defect, respectively.


The utility of routine surveillance blood cultures in asymptomatic hematopoietic stem cell transplant patients.
Surveillance blood cultures (BCs) are often obtained in hematopoietic stem cell transplant (HSCT) patients for earlier detection of blood stream infections (BSI). The major aim of this study was to determine the utility of the current practice of obtaining surveillance blood cultures from asymptomatic transplant patients upon admission for the preparative regimen. We conducted an 8-year retrospective study of all patients consecutively admitted to the hospital for a HSCT from 2000 to 2008. In this retrospective analysis, surveillance BCs from 191 eligible patients were analyzed. The incidence of definitive BSIs was 0.52% (1/191) with 6 BCs from other HSCT patients growing probable contaminants. The overall incidence of positive surveillance BCs was 2.9% (7/238) for the BCs taken and 3.7% (7/191) for patients cultured with coagulase negative staphylococcus being isolated from 6 of the 7 patients. The probability of increased BSI after transplantation in patients with initial positive surveillance BCs compared with those having negative BCs, was not significant (P=0.675). No infection-related mortality was observed during the first 60 days posttransplantation in these patients. The frequency of positive surveillance BCs in asymptomatic HSCT patients at the time of hospital admission for transplant seems to be extremely low. These results, if confirmed by larger studies, show the reduced utility of obtaining surveillance BC in asymptomatic patients before administration of the conditioning regimen and the need for re-evaluation of this practice.


Glucosylsphingosine Causes Hematological and Visceral Changes in Mice-Evidence for a Pathophysiological Role in Gaucher Disease.
Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg-1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD.


Dissociative experience in hypothetically psychosis-prone college students.
The relationship between dissociative experiences and psychosis proneness was investigated in a sample of 523 college undergraduates. Participants were administered the Dissociative Experiences Scale (DES), the Perceptual Aberration Scale, the Magical Ideation Scale, the Social Anhedonia Scale, and the Physical Anhedonia Scale. As hypothesized, the Perceptual Aberration and Magical Ideation Scales were positively correlated with the DES. The Social Anhedonia Scale had a modest correlation with the DES, but this relationship was largely mediated by the Perceptual Aberration and Magical Ideation Scales. The Physical Anhedonia Scale was uncorrelated with the DES. Exploratory factor analysis of the psychosis-proneness scales and the DES subscales resulted in a three-factor solution: dissociative experiences, positive schizotypy, and negative schizotypy. The DES depersonalization subscale loaded on both the dissociation and positive schizotypy factors.


Impact of the demographic and aetiological factors and intraoperative findings on postoperative outcomes in chronic otitis media surgery
Surgical success is related with many factors belonging to both the patient and the disease. This study aims to analyse the preoperative and intraoperative characteristics, the postoperative results, and the factors affecting the surgical success in different types of chronic otitis media (COM). A total of 1510 ears of 1398 patients who underwent COM surgery were included in the study. Postoperative results were obtained from 376 ears of 356 patients who had been followed after surgery. The demographic characteristics of the patients, such as age and sex, operative findings, preoperative audiological examination results, and final audiometric and otoscopic examination findings, were retrospectively obtained from the archives of the department. The most frequent diagnosis was simple COM (39.9%), and the most frequently performed surgery was tympanoplasty without mastoidectomy (46.6%). The overall hearing success rate was found to be 75.8%. Postoperative hearing success was significantly associated with the chronic otitis subgroup, ossicular pathologies, and the condition of the middle ear mucosa. Postoperative graft take rate was found to be 78.6%. Graft success was statistically significantly higher in patients with normal middle ear mucosa. Performing mastoidectomy, the presence of patency in aditus ad antrum, and being a paediatric case had no impact on graft success. Factors affecting the success of COM surgery include age, chronic otitis subgroup, location and size of perforation, the condition of the middle ear mucosa, and the level of the ossicular disease. These factors should be known and an appropriate treatment plan should be prepared.


Transcriptome screen for fast evolving genes by Inter-Specific Selective Hybridization (ISSH).
Fast evolving genes are targets of an increasing panel of biological studies, from cancer research to population genetics and species specific adaptations. Yet, their identification and isolation are still laborious, particularly for non-model organisms. We developed a method, named the Inter-Specific Selective Hybridization (ISSH) method, for generating cDNA libraries enriched in fast evolving genes. It utilizes transcripts of homologous tissues of distinct yet related species. Experimental hybridization conditions are monitored in order to discard transcripts that do not find their homologous counterparts in the two species sets as well as transcripts that display a strong complementarity between the two species. Only heteroduplexes that disanneal at low stringency are used for constructing the resulting cDNA library. We demonstrate the efficiency of the ISSH method by generating a brain cDNA library enriched in fast evolving transcripts of a non-model catfish species as well as a control, non-enriched library. Our results indicate that the enriched library contains effectively more fast evolving sequences than the control library. Gene annotation analyses also indicate enrichment in genes with low expression levels and non-ubiquitously expressed genes, both categories encompassing the majority of fast evolving genes. Furthermore, most of the identified transcripts show higher sequence divergence between two closely related catfish species as compared to recognized fast evolving DNA markers. The ISSH method offers a simple, inexpensive and efficient way to screen the transcriptome for isolating fast evolving genes. This method opens new opportunities in the investigation of biological mechanisms that include fast evolving genes, such as the evolution of lineage specific processes and traits responsible for species adaptation to their environment.


Normal, benign, preneoplastic, and malignant prostate cells have distinct protein expression profiles resolved by surface enhanced laser desorption/ionization mass spectrometry.
The objective of this study was to discover protein biomarkers that differentiate malignant from nonmalignant cell populations, especially early protein alterations that signal the initiation of a developing cancer. We hypothesized that Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry-assisted protein profiling could detect these protein alterations. Epithelial cell populations [benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN), and prostate cancer (PCA)] were procured from nine prostatectomy specimens using laser capture microdissection. Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry analysis was performed on cell lysates, and the relative intensity levels of each protein or peptide in the mass spectra was calculated and compared for each cell type. Several small molecular mass peptides or proteins (3000-5000 Da) were found in greater abundance in PIN and PCA cell lysates. Another peak, with an average mass of 5666 Da, was observed to be up-regulated in 86% of the BPH cell lysates. Higher levels of this same peak were found in only 22% of the PIN lysates and none of the PCA lysates. Expression differences were also found for intracellular levels of prostate-specific antigen, which were reduced in PIN and PCA cells when compared with matched normals. Although no single protein alteration was observed in all PIN/PCA samples, combining two or more of the markers was effective in distinguishing the benign cell types (normal/BPH) from diseased cell types (PIN/PCA). Logistic regression analysis using seven differentially expressed proteins resulted in a predictive equation that correctly distinguished the diseased lysates with a sensitivity and specificity of 93.3 and 93.8%, respectively. We have shown that the protein profiles from prostate cells with different disease states have discriminating differences. These differentially regulated proteins are potential markers for early detection and/or risk factors for development of prostate cancer. Studies are under way to identify these protein/peptides, with the goal of developing a diagnostic test for the early detection of prostate cancer.


Cardiorespiratory Fitness and Bone Turnover Markers in Adults With Metabolic Syndrome: The Mediator Role of Inflammation.
The relationship between inflammatory markers and bone turnover in adults is well known, and a negative association between cardiorespiratory fitness (CRF) and inflammatory markers has also been described. Hence, we tested whether the association between CRF and bone turnover markers is mediated by inflammatory markers in adults with metabolic syndrome. A total of 81 adults (58.5 ± 5.0 years, 62.7% women) were included in the analysis. CRF was measured by the 6-min walking test. Serum interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor alpha, high-sensitivity c-reactive protein (hsCRP) and vascular endothelial growth factor, collagen type I cross-linked C-telopeptide, procollagen type I N-terminal propeptide (P1NP), and total osteocalcin were assessed using a sensitive ELISA kit. Body composition was assessed by dual-energy X-ray absorptiometry. Partial correlation was used to test the relationship between CRF, inflammatory markers, and bone turnover markers, controlling for sex, lean mass, and fat mass. Boot-strapped mediation procedures were performed, and indirect effects with confidence intervals not including zero were interpreted as statistically significant. CRF was positively correlated with P1NP levels (r = .228, p = .044) and osteocalcin levels (r = .296, p = .009). Furthermore, CRF was positively correlated with IL-1β levels (r = .340, p = .002) and negatively correlated with hsCRP levels (r = -.335, p = .003), whereas IL-1β levels were positively correlated with P1NP levels (r = .245, p = .030), and hsCRP levels were negatively correlated with P1NP levels (r = -.319, p = .004). Finally, the association between CRF and P1NP levels was totally mediated by hsCRP (percentage of mediation = 39.9). Therefore, CRF benefits on bone formation could be dependent on hsCRP concentrations in this population.


Role of dopamine D1 receptor in 3-fluoromethamphetamine-induced neurotoxicity in mice.
3-Fluoromethamphetamine (3-FMA) is an illegal designer drug of methamphetamine (MA) derivative. Up to date, little is known about the neurotoxic potential of 3-FMA. In the present study, we investigated the role of dopamine receptors in neurotoxicity induced by 3-FMA in comparison with MA (35 mg/kg, i.p.) as a control drug. Here we found that 3-FMA (40, 60 or 80 mg/kg, i.p.) produced mortality in a dose-dependent manner in mice. Treatment with 3-FMA (40 mg/kg, i.p.) resulted in significant hyperthermia, oxidative stress and microgliosis (microglial differentiation into M1 phenotype) followed by pro-apoptotic changes and the induction of terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL)-positive cells. Moreover, 3-FMA significantly produced dopaminergic impairments [i.e., increase in dopamine (DA) turnover rate and decreases in DA level, and in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2)] with behavioral impairments. These dopaminergic neurotoxic effects of 3-FMA were comparable to those of MA. SCH23390, a dopamine D1 receptor antagonist, but not sulpiride, a dopamine D2 receptor antagonist significantly attenuated 3-FMA-induced neurotoxicity. Although both SCH23390 and sulpiride attenuated MA-induced dopaminergic neurotoxicity, sulpiride is more effective than SCH23390 on the dopaminergic neurotoxicity. Interestingly, SCH23390 treatment positively modulated 3-FMA-induced microglial activation (i.e., SCH23390 inhibited M1 phenotype from 3-FMA insult, but activated M2 phenotype). Therefore, our results suggest that the activation of dopamine D1 receptor is critical to 3-FMA-induced neurotoxicity, while both dopamine D1 and D2 receptors (dopamine D2 receptor > dopamine D1 receptor) mediate MA-induced dopaminergic neurotoxicity.


Morphologic organization of pulmonary granulomas in mice infected with Paracoccidioides brasiliensis.
A morphologic study of the lungs was carried out in Swiss mice infected with yeast isolated from Paracoccidioides brasiliensis (Pb18). The lung was processed 1, 2, 4, and 8 weeks after inoculation for histologic staining with hematoxylin and eosin (H&E), methenamine silver nitrate (Gomori-Grocott), and picrosirius to qualitative and quantitative analyses of the granulomas and the presence of fungal lesions. The numbers of CFUs/g counted in the lungs were 189.8 +/- 20.64, 353.6 +/- 46.21, 547.2 +/- 108.1, and 295.2 +/- 89.17 in the first, second, fourth, and eighth weeks, respectively. One week after infection, inflammatory cells and reticular and collagens fibers, the latest typical of fibrosis, were detected. After 2 and 4 weeks, a progressive intensification of the infection and fibrosis was observed, but in week 8 a more organized granuloma was evident, with macrophages, epithelioid cells, and yeasts in the central portion, and intense peripheral basophilia. Pycnotic structures typical of apoptotic bodies were observed in weeks 1 and 8. The different histologic staining used acted as a fundamental tool for the study of the morphologic organization of granuloma formation.


C-peptide secretion during the remission phase of juvenile diabetes.
C-peptide secretion was studied in eight juvenile diabetics during the remission phase of the disease. The release of C-peptide was measured after a (1) normal intravenous glucose tolerance test, (2) a double glucose tolerance test, (3) an arginine infusion, and (4) after an intravenous glucose tolerance test followed by an arginine infusion. Under all conditions the intravenous glucose load had only a minimal effect on the secretion of C-peptide, while arginine alone or after the intravenous glucose tolerance test stimulated the release of the peptide in all patients. Pretreatment with glucose did not augment the effect of arginine on C-peptide release. The results indicate that during the remission phase of juvenile-onset diabetes the endocrine pancreas does not recognize glucose as and appropriate signal for C-peptide release and cannot transform the amplifying effect of glucose into a higher hormonal secretion rate.


Chasing central nervous system plasticity: the brainstem's contribution to locomotor recovery in rats with spinal cord injury.
Anatomical plasticity such as fibre growth and the formation of new connections in the cortex and spinal cord is one known mechanism mediating functional recovery after damage to the central nervous system. Little is known about anatomical plasticity in the brainstem, which contains key locomotor regions. We compared changes of the spinal projection pattern of the major descending systems following a cervical unilateral spinal cord hemisection in adult rats. As in humans (Brown-Séquard syndrome), this type of injury resulted in a permanent loss of fine motor control of the ipsilesional fore- and hindlimb, but for basic locomotor functions substantial recovery was observed. Antero- and retrograde tracings revealed spontaneous changes in spinal projections originating from the reticular formation, in particular from the contralesional gigantocellular reticular nucleus: more reticulospinal fibres from the intact hemicord crossed the spinal midline at cervical and lumbar levels. The intact-side rubrospinal tract showed a statistically not significant tendency towards an increased number of midline crossings after injury. In contrast, the corticospinal and the vestibulospinal tract, as well as serotonergic projections, showed little or no side-switching in this lesion paradigm. Spinal adaptations were accompanied by modifications at higher levels of control including side-switching of the input to the gigantocellular reticular nuclei from the mesencephalic locomotor region. Electrolytic microlesioning of one or both gigantocellular reticular nuclei in behaviourally recovered rats led to the reappearance of the impairments observed acutely after the initial injury showing that anatomical plasticity in defined brainstem motor networks contributes significantly to functional recovery after injury of the central nervous system.


Mössbauer characterization of the iron-sulfur clusters in Desulfovibrio vulgaris hydrogenase.
The periplasmic hydrogenase of Desulfovibrio vulgaris (Hildenbourough) is an all Fe-containing hydrogenase. It contains two ferredoxin type [4Fe-4S] clusters, termed the F clusters, and a catalytic H cluster. Recent X-ray crystallographic studies on two Fe hydrogenases revealed that the H cluster is composed of two sub-clusters, a [4Fe-4S] cluster ([4Fe-4S](H)) and a binuclear Fe cluster ([2Fe](H)), bridged by a cysteine sulfur. The aerobically purified D. vulgaris hydrogenase is stable in air. It is inactive and requires reductive activation. Upon reduction, the enzyme becomes sensitive to O(2), indicating that the reductive activation process is irreversible. Previous EPR investigations showed that upon reoxidation (under argon) the H cluster exhibits a rhombic EPR signal that is not seen in the as-purified enzyme, suggesting a conformational change in association with the reductive activation. For the purpose of gaining more information on the electronic properties of this unique H cluster and to understand further the reductive activation process, variable-temperature and variable-field Mössbauer spectroscopy has been used to characterize the Fe-S clusters in D. vulgaris hydrogenase poised at different redox states generated during a reductive titration, and in the CO-reacted enzyme. The data were successfully decomposed into spectral components corresponding to the F and H clusters, and characteristic parameters describing the electronic and magnetic properties of the F and H clusters were obtained. Consistent with the X-ray crystallographic results, the spectra of the H cluster can be understood as originating from an exchange coupled [4Fe-4S]-[2Fe] system. In particular, detailed analysis of the data reveals that the reductive activation begins with reduction of the [4Fe-4S](H) cluster from the 2+ to the 1+ state, followed by transfer of the reducing equivalent from the [4Fe-4S](H) subcluster to the binuclear [2Fe](H) subcluster. The results also reveal that binding of exogenous CO to the H cluster affects significantly the exchange coupling between the [4Fe-4S](H) and the [2Fe](H) subclusters. Implication of such a CO binding effect is discussed.


A human circulating immune cell landscape in aging and COVID-19.
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Ultrahigh resolution drug design. II. Atomic resolution structures of human aldose reductase holoenzyme complexed with Fidarestat and Minalrestat: implications for the binding of cyclic imide inhibitors.
The X-ray structures of human aldose reductase holoenzyme in complex with the inhibitors Fidarestat (SNK-860) and Minalrestat (WAY-509) were determined at atomic resolutions of 0.92 A and 1.1 A, respectively. The hydantoin and succinimide moieties of the inhibitors interacted with the conserved anion-binding site located between the nicotinamide ring of the coenzyme and active site residues Tyr48, His110, and Trp111. Minalrestat's hydrophobic isoquinoline ring was bound in an adjacent pocket lined by residues Trp20, Phe122, and Trp219, with the bromo-fluorobenzyl group inside the "specificity" pocket. The interactions between Minalrestat's bromo-fluorobenzyl group and the enzyme include the stacking against the side-chain of Trp111 as well as hydrogen bonding distances with residues Leu300 and Thr113. The carbamoyl group in Fidarestat formed a hydrogen bond with the main-chain nitrogen atom of Leu300. The atomic resolution refinement allowed the positioning of hydrogen atoms and accurate determination of bond lengths of the inhibitors, coenzyme NADP+ and active-site residue His110. The 1'-position nitrogen atom in the hydantoin and succinimide moieties of Fidarestat and Minalrestat, respectively, form a hydrogen bond with the Nepsilon2 atom of His 110. For Fidarestat, the electron density indicated two possible positions for the H-atom in this bond. Furthermore, both native and anomalous difference maps indicated the replacement of a water molecule linked to His110 by a Cl-ion. These observations suggest a mechanism in which Fidarestat is bound protonated and becomes negatively charged by donating the proton to His110, which may have important implications on drug design.


Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes explosive outbreaks of febrile illness associated with rash, and painful arthralgia. The CHIK vaccine strain 181/clone25 (181/25) developed by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) was shown to be well-tolerated and highly immunogenic in phase I and II clinical trials although it induced transient arthralgia in some healthy adult volunteers. In an attempt to better understand the host factors that are involved in the attenuating phenotype of CHIK 181/25 vaccine virus we conducted studies in interferon (IFN)-compromised mice and also evaluated its immunogenic potential and protective capacity. Infection of AG129 mice (defective in IFN-α/β and IFN-γ receptor signaling) with CHIK 181/25 resulted in rapid mortality within 3-4 days. In contrast, all infected A129 mice (defective in IFN-α/β receptor signaling) survived with temporary morbidity characterized by ruffled appearance and body weight loss. A129 heterozygote mice that retain partial IFN-α/β receptor signaling activity remained healthy. Infection of A129 mice with CHIK 181/25 induced significant levels of IFN-γ and IL-12 while the inflammatory cytokines, TNFα and IL-6 remained low. A single administration of the CHIK 181/25 vaccine provided both short-term and long-term protection (38 days and 247 days post-prime, respectively) against challenge with wt CHIKV-La Reunion (CHIKV-LR). This protection was at least partially mediated by antibodies since passively transferred immune serum protected both A129 and AG129 mice from wt CHIKV-LR and 181/25 virus challenge. Overall, these data highlight the importance of IFNs in controlling CHIK 181/25 vaccine and demonstrate the ability of this vaccine to elicit neutralizing antibody responses that confer short-and long-term protection against wt CHIKV-LR challenge.


Phase I Trial of Triapine-Cisplatin-Paclitaxel Chemotherapy for Advanced Stage or Metastatic Solid Tumor Cancers.
Ribonucleotide reductase (RNR) is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine is a small-molecule RNR inhibitor. A phase I trial studied the safety of triapine in combination with cisplatin-paclitaxel in patients with advanced stage or metastatic solid tumor cancers in an effort to capitalize on disrupted DNA damage repair. A total of 13 patients with various previously treated cancers were given a 96-h continuous intravenous (i.v.) infusion of triapine (40-120 mg/m2) on day 1, and then 3-h i.v. paclitaxel (80 mg/m2) followed by 1-h i.v. cisplatin (50-75 mg/m2) on day 3. This combination regimen was repeated every 21 days. The maximum tolerated dose (MTD) for each agent was identified to be triapine (80 mg/m2), cisplatin (50 mg/m2), and paclitaxel (80 mg/m2). Common grade 3 or 4 toxicities included reversible anemia, leukopenia, thrombocytopenia, or electrolyte abnormalities. The combination regimen of triapine-cisplatin-paclitaxel resulted in no objective responses; however, five (83%) of six patients treated at the MTD had stable disease between 1 and 8 months duration. This phase I study showed that the combination regimen of triapine-cisplatin-paclitaxel was safe and provides a rational basis for a follow-up phase II trial to evaluate efficacy and progression-free survival in women with metastatic or recurrent uterine cervix cancer.


Quantifying the hydrological impact of simulated changes in land use on peak discharge in a small catchment.
A physically-based, distributed hydrological model (MIKE SHE) was used to quantify overland runoff in response to four extreme rain events and four types of simulated land use measure in a catchment in Norway. The current land use in the catchment comprises arable lands, forest, urban areas and a stream that passes under a motorway at the catchment outlet. This model simulation study demonstrates how the composition and configuration of land use measures affect discharge at the catchment outlet differently in response to storms of different sizes. For example, clear-cutting on 30% of the catchment area produced a 60% increase in peak discharge and a 10% increase in total runoff resulting from a 50-year storm event in summer, but the effects on peak discharge were less pronounced during smaller storms. Reforestation of 60% of the catchment area was the most effective measure in reducing peak flows for smaller (2-, 5- and 10-year) storms. Introducing grassed waterways reduced water velocity in the stream and resulted in a 28% reduction in peak flow at the catchment outlet for the 50-year storm event. Overall, the results indicate that the specific effect of land use measures on catchment discharge depends on their spatial distribution and on the size and timing of storm events.


Endoscopically assisted reconstruction of orbital medial wall fractures.
Traditional surgical approaches to orbital medial wall fractures are either direct extraocular skin incisions or indirect bicoronal flap. However, these methods can leave remarkable orbital scars or scalp alopecia with the possible associated complications. A minimally invasive endoscopic technique with the assistance of a 2.7-mm, 30-degree telescope through a medial transconjunctival incision has been successfully used to reconstruct the orbital medial wall fractures. This technique was applied to four patients who had orbital medial wall fractures. Three patients also had concomitant orbital floor fractures. The other had associated superior orbital fissure syndrome. All patients were presented with limited eye movement, positive forced duction test, horizontal diplopia, and enophthalmos (3 mm to 6 mm) preoperatively. The entrapped periorbital tissues in the ethmoid sinus were completely reduced endoscopically. The bone defect of orbital medial wall was reconstructed with autogenous rib bone grafts under endoscopic control. The patients were followed up for 8 to 16 months with an average of 11 months. Three patients recovered completely without any residual eye symptoms after intervention. Clinically significant residual enophthalmos of 3 mm occurred in the patient with the superior orbital fissure syndrome. His eye movement limitation caused by entrapment of medial rectus muscle was relieved postoperatively. There was no donor-site morbidity or any complications related to the endoscopically assisted procedure. Endoscopically assisted medial transconjunctival approach to the orbital medial wall fractures is an excellent adjunct for the exposure and complete reduction of herniated periorbital tissue and bony reconstruction of the medial orbital wall.


High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology.
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) is a newly defined entity in the latest World Health Organization Classification. Accurate diagnosis would appear to mandate fluorescence in situ hybridization (FISH) for all tumors with diffuse large B-cell lymphoma (DLBCL) morphology. We present the results of FISH, cell-of-origin, and immunohistochemistry (IHC) testing from 1228 DLBCL biopsies from 3 clinical trials and a population-based registry. HGBL-DH/TH made up 7.9% of the DLBCL, confined primarily to the germinal center B-cell-like (GCB; 13.3%) compared with activated B-cell-like (ABC; 1.7%) subtype (P < .001). HGBL-DH/TH with BCL2 rearrangement is a GCB phenomenon with no cases observed in 415 ABC DLBCL. A screening strategy restricting FISH testing to tumors of GCB subtype (by Lymph2Cx or Hans IHC) plus dual protein expression of MYC and BCL2 by IHC could limit testing to 11% to 14% of tumors, with a positive predictive value of 30% to 37%; however, this strategy would miss approximately one-quarter of tumors with HBGL-DH/TH with BCL2 rearrangement and one-third of all HGBL-DH/TH. These results provide accurate estimation of the proportion of HGBL-DH/TH among tumors with DLBCL morphology and allow determination of the impact of various methods available to screen DLBCL tumors for FISH testing.


Potato cyst nematodes Globodera rostochiensis and G. pallida.
Phylum Nematoda; class Chromadorea; order Rhabditida; suborder Tylenchina; infraorder Tylenchomorpha; superfamily Tylenchoidea; family Heteroderidae; subfamily Heteroderinae; Genus Globodera. Potato cyst nematodes (PCN) are biotrophic, sedentary endoparasitic nematodes. Invasive (second) stage juveniles (J2) hatch from eggs in response to the presence of host root exudates and subsequently locate and invade the host. The nematodes induce the formation of a large, multinucleate syncytium in host roots, formed by fusion of up to 300 root cell protoplasts. The nematodes rely on this single syncytium for the nutrients required to develop through a further three moults to the adult male or female stage. This extended period of biotrophy-between 4 and 6 weeks in total-is almost unparalleled in plant-pathogen interactions. Females remain at the root while adult males revert to the vermiform body plan of the J2 and leave the root to locate and fertilize the female nematodes. The female body forms a cyst that contains the next generation of eggs. The host range of PCN is limited to plants of the Solanaceae family. While the most economically important hosts are potato (Solanum tuberosum), tomato (Solanum lycopersicum), and aubergine (Solanum melongena), over 170 species of Solanaceae are thought to be potential hosts for PCN (Sullivan et al., 2007). Symptoms are similar to those associated with nutrient deficiency, such as stunted growth, yellowing of leaves and reduced yields. This absence of specific symptoms reduces awareness of the disease among growers. Resistance genes (where available in suitable cultivars), application of nematicides, crop rotation. Great effort is put into reducing the spread of PCN through quarantine measures and use of certified seed stocks. Genomic information for PCN is accessible through WormBase ParaSite.


A biomonitoring study assessing the exposure of young German adults to butylated hydroxytoluene (BHT).
The antioxidant 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene, BHT) is used ubiquitously in food, cosmetics, pharmaceuticals, fuels, plastics, rubbers and many other products. Therefore, exposure of the general population to this substance is likely. We analyzed the BHT metabolite 3,5-di-tert-butyl-4-hydroxybenzoic acid ("BHT acid") in 24-h urine samples from the German Environmental Specimen Bank with the aim of gaining a better understanding of the internal burden of BHT in young nonspecifically exposed adults. The study population consisted of students between 20 and 29 years of age at the time of sampling, all from Halle/Saale in Central Germany. In total, 329 samples collected in the years 2000, 2004, 2008, 2012, 2015, and 2018 were measured by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). BHT acid was detected above the limit of quantification (0.2 μg/L) in 98% of the samples. The median of the measured concentrations was 1.06 μg/L and 1.24 μg/g creatinine respectively, the median of the daily excretion was 1.76 μg/24 h and - additionally normalized for body weight - 26.8 ng/24 h × kg bw respectively. The corresponding 90th percentiles were 3.28 μg/L, 3.91 μg/g creatinine, 5.05 μg/24 h, and 81.9 ng/24 h × kg bw. Medians of creatinine-corrected values were slightly higher in women than in men, while the opposite situation was observed for the volume concentrations and the 24-h excretion values (not corrected for body weight). Values simultaneously normalized both for 24-h excretion and body weight did not exhibit any significant differences between males and females, probably indicating a virtually identical magnitude of exposure for both genders. The background exposure of the investigated population was found to be largely constant since the year 2000, with only weak temporal trends at most. Daily intakes were estimated from excretion values and found to be largely below the acceptable daily intake (ADI) of BHT at 0.25 mg/kg bw: our worst-case estimate is a daily BHT intake of approximately 0.1 mg/kg bw at the 95th percentile level. However, these intake assessments rely on very limited quantitative data regarding human metabolism of BHT.


Developing a data infrastructure for a learning health system: the PORTAL network.
The Kaiser Permanente & Strategic Partners Patient Outcomes Research To Advance Learning (PORTAL) network engages four healthcare delivery systems (Kaiser Permanente, Group Health Cooperative, HealthPartners, and Denver Health) and their affiliated research centers to create a new national network infrastructure that builds on existing relationships among these institutions. PORTAL is enhancing its current capabilities by expanding the scope of the common data model, paying particular attention to incorporating patient-reported data more systematically, implementing new multi-site data governance procedures, and integrating the PCORnet PopMedNet platform across our research centers. PORTAL is partnering with clinical research and patient experts to create cohorts of patients with a common diagnosis (colorectal cancer), a rare diagnosis (adolescents and adults with severe congenital heart disease), and adults who are overweight or obese, including those with pre-diabetes or diabetes, to conduct large-scale observational comparative effectiveness research and pragmatic clinical trials across diverse clinical care settings.


Cavopulmonary anastomosis induces pulmonary expression of the angiotensin II receptor family.
Cavopulmonary anastomosis is used for palliation of cyanotic cardiac lesions. Postoperative development of pulmonary arteriovenous malformations can be significant in 10% to 25% of patients. To study the basis for formation of arteriovenous malformations, we developed an ovine model that reliably induces their development 8 weeks after cavopulmonary anastomosis. Previously, we found that cavopulmonary anastomosis inhibits the expression of pulmonary angiotensin-converting enzyme and suppresses angiotensin II production. This study examines the role of the angiotensin II receptors, type 1 and type 2, in this setting of pulmonary vascular remodeling. Lambs, aged 40 to 50 days, underwent cavopulmonary anastomosis. In age-matched control animals, a sham operation was performed. Messenger RNA and protein expression in lung specimens was measured at successive time points after cavopulmonary anastomosis or sham operations (n = 3 at each time point). Angiotensin type 1 mRNA was maximally upregulated 2-fold at 5 weeks after cavopulmonary anastomosis (P =.006). Expression of angiotensin type 1 protein was increased at least 2-fold at 2, 5, and 15 weeks after cavopulmonary anastomosis (P =.005). Cavopulmonary anastomosis also increased angiotensin type 2 mRNA and protein expression at least 2-fold at 2 and 5 weeks (P =.02) after surgical intervention. At 15 weeks, expression of angiotensin type 2 mRNA and protein was unchanged from that seen in control animals. Immunolocalization in pulmonary tissue sections 2 weeks after cavopulmonary anastomosis revealed markedly enhanced staining of angiotensin II receptor type 1 in vascular smooth muscle and angiotensin II receptor type 2 in the endothelium of pulmonary arteries. Rapid elevation in the expression of the type 1 and 2 angiotensin II receptors in the affected pulmonary vasculature after cavopulmonary anastomosis suggests their involvement in the pathologic vascular remodeling that occurs after cavopulmonary anastomosis.


Emotional reasoning and anxiety sensitivity: associations with social anxiety disorder in childhood.
Two specific cognitive constructs that have been implicated in the development and maintenance of anxiety symptoms are anxiety sensitivity and emotional reasoning, both of which relate to the experience and meaning of physical symptoms of arousal or anxiety. The interpretation of physical symptoms has been particularly implicated in theories of social anxiety disorder, where internal physical symptoms are hypothesized to influence the individual's appraisals of the self as a social object. The current study compared 75 children on measures of anxiety sensitivity and emotional reasoning: 25 with social anxiety disorder, 25 with other anxiety disorders, and 25 nonanxious children (aged 7-12 years). Children with social anxiety disorder reported higher levels of anxiety sensitivity and were more likely than both other groups to view ambiguous situations as anxiety provoking, whether physical information was present or not. There were no group differences in the extent to which physical information altered children's interpretation of hypothetical scenarios. This study is the first to investigate emotional reasoning in clinically anxious children and therefore replication is needed. In addition, those in both anxious groups commonly had comorbid conditions and, consequently, specific conclusions about social anxiety disorder need to be treated with caution. The findings highlight cognitive characteristics that may be particularly pertinent in the context of social anxiety disorder in childhood and which may be potential targets for treatment. Furthermore, the findings suggest that strategies to modify these particular cognitive constructs may not be necessary in treatments of some other childhood anxiety disorders.


Mutation analysis of Leber's hereditary optic neuropathy using a multi-gene panel.
The present study investigates the spectrum and incidence of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in a Han population using a multi-gene panel with 46 LHON-associated mutations among 13 mitochondrial genes. A total of 23 mutations were observed in a cohort of 275 patients and 281 control subjects using multi-gene panel analysis. The causative mutations associated with LHON were identified to be m.11778G>A, m.14484T>C, m.3460 G>A, m.3635G>A, m.3866T>C and m.3733G>A, responsible for 70.55% cases in the patient cohort. The secondary mutations in the Chinese LHON population were m.12811T>C, m.11696 G>A, m.3316G>A, m.3394T>C, m.14502T>C, m.3497C>T, m.3571C>T, m.12338T>C, m.14693A>G, m.4216T>C and m.15951A>G, with incidences of 5.09, 4.36, 4.00, 4.00, 4.00, 2.55, 1.82, 1.82, 1.45, 1.09 and 1.09%, respectively. Besides three hotspot genes, MT-ND1, MT-ND4 and MT-ND6, MT-ND5 also had a high incidence of secondary mutations. Those mutations reported as rare causative mutations in a European LHON population, m.3376G>A, m.3700G>A and m.4171C>A, m.10663T>C, m.13051G>A, m.14482C>G/A, m.14495A>G and m.14568C>T were undetected in the present study. The primary and secondary mutations associated with LHON in the present multi-gene panel will advance the current understanding of the clinical phenotype of LHON, and provide useful information for early diagnosis.


Core principles in treating suicidal patients.
The treatment of suicidal individuals requires special attention to therapist interventions that promote a viable treatment alliance in the context of shared responsibilities for patient safety. Three core principles in the treatment process (alliance building, enhancing curiosity about the function of suicidal thoughts and urges, as well as enhancing experience and expression of intense emotions) are articulated and brief case vignettes are used to illuminate the principles. Results from open trails and randomized control trials involving suicidal patients are examined to support the evidence-based practice of these principles. The overarching principle undergirding the utility of the principles is a collaborative joining with the patient to decrease isolation and alienation when facing intense and overwhelming emotions.


What makes the patient-doctor relationship therapeutic? Exploring the connexional dimension of medical care.
Physicians do not receive from the medical model the same explicit guidance in relating to their patients as in making diagnoses and prescribing pharmacologic and other treatments. To meet this need, we offer a framework for expanding the model. Therapeutic contact takes place within a connexional, or transpersonal, dimension of human experience, within which basic human needs for connection and meaning are met. Although seldom explicitly recognized, connexional experience is basic to medical care. Awareness of this dimension of experience leads clinicians to appreciate that establishing a therapeutic relationship is one of the principal goals of medical practice. It also reframes the doctor's task to make clinical uncertainty more tolerable and situations in which there is no appropriate biomedical response (such as care of the terminally ill) less frustrating and more fulfilling.


Do post-migration perceptions of social mobility matter for Latino immigrant health?
Latino immigrants exhibit health declines with increasing duration in the United States, which some attribute to a loss in social status after migration or downward social mobility. Yet, research into the distribution of perceived social mobility and patterned associations to Latino health is sparse, despite extensive research to show that economic and social advancement is a key driver of voluntary migration. We investigated Latino immigrant sub-ethnic group variation in the distribution of perceived social mobility, defined as the difference between respondents' perceived social status of origin had they remained in their country of origin and their current social status in the U.S. We also examined the association between perceived social mobility and past-year major depressive episode (MDE) and self-rated fair/poor physical health, and whether Latino sub-ethnicity moderated these associations. We computed weighted logistic regression analyses using the Latino immigrant subsample (N=1561) of the National Latino and Asian American Study. Puerto Rican migrants were more likely to perceive downward social mobility relative to Mexican and Cuban immigrants who were more likely to perceive upward social mobility. Perceived downward social mobility was associated with increased odds of fair/poor physical health and MDE. Latino sub-ethnicity was a statistically significant moderator, such that perceived downward social mobility was associated with higher odds of MDE only among Puerto Rican and Other Latino immigrants. In contrast, perceived upward social mobility was not associated with self-rated fair/poor physical health. Our findings suggest that perceived downward social mobility might be an independent correlate of health among Latino immigrants, and might help explain Latino sub-ethnic group differences in mental health status. Future studies on Latino immigrant health should use prospective designs to examine the physiological and psychological costs associated with perceived changes in social status with integration into the U.S. mainland.


Onset of a hypotensive effect following ingestion of flavan 3-ols involved in the activation of adrenergic receptors.
A lot of epidemiological and intervention studies support the hypotensive action resulting from ingestion of foods rich in flavan 3-ols. However, the mechanisms of this action remain unclear. We have reported previously on the alteration of the micro- and systemic circulations after administration of a flavan 3-ol fraction (FL) derived from cocoa in mammals. We also confirmed that blood catecholamine levels increase significantly after administration of FL. In the present study, we examined whether adrenaline receptors are involved in the hemodynamic changes using several adrenaline receptor (AR) blockers. First, we confirmed that mean blood pressure (MBP) decreased significantly and aortic endothelial nitric oxide synthase (eNOS) levels increased significantly following oral treatment of 10mg/kg FL for 2 weeks in normal rats compared with vehicle administration. However, these changes were not observed with treatment of 1mg/kg (-)-epicatechin (EC), which contains nearly equivalent amount of 10mg/kg FL. Secondly, we observed that a single dose of FL produced different hemodynamic changes, such as a transient elevation in heart rate (HR) after ingestion of 1-100mg/kg FL, but not with 1mg/kg EC. Furthermore, although MBP rose transiently after 1 and 10mg/kg FL, this effect was not observed with 100mg/kg or 1mg/kg EC. The increases in HR, MBP, and aortic phosphorylated eNOS (p-eNOS) induced by 10mg/kg FL were prevented completely by pretreatment with the AR blocker, carvedilol. Combination treatment with 100mg/kg FL and an α1AR blocker, prazosin, significantly reduced MBP, whereas the elevation in HR was enhanced. In addition, after pretreatment with the β2AR blocker, butoxamine, we observed no significant hemodynamic changes with or without 100mg/kg FL. Moreover, the combination of 100mg/kg FL and the α2AR blocker, yohimbine, markedly increased MBP, HR and aortic p-eNOS level. These results suggested that the postprandial hemodynamic changes after a single oral dose of FL were induced by an adrenergic effect. This adrenomimetic activity suggested the involvement of a hypotensive effect of FL.


Transplant-Associated Thrombotic Microangiopathy Is a Multifactorial Disease Unresponsive to Immunosuppressant Withdrawal.
Transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic cell transplantation (HCT) has not been well characterized in large population studies with clinically adjudicated cases. We performed a retrospective cohort study of adults who underwent allogeneic HCT between 2006 and 2015 to determine the incidence of and risk factors for TA-TMA and to describe its natural history and response to immunosuppressant withdrawal management. Among 2145 patients in this study, 192 developed TA-TMA with a cumulative incidence of 7.6% by 100days post-transplant. Independent pretransplant risk factors included the receipt of a second (or third) allogeneic HCT, HLA-mismatched donor, and myeloablative conditioning with or without total body irradiation; post-transplant risk factors included the antecedent development of acute graft-versus-host disease, diffuse alveolar hemorrhage, bacteremia, invasive aspergillosis, BK viremia, and higher sirolimus trough level. Among TA-TMA patients 27% achieved hematologic resolution and 57% remained alive as of 90days after diagnosis. Antecedent risk factors stratified patients into different survival groups, and immunosuppressant withdrawal alone did not improve patient outcomes. In conclusion, TA-TMA is a heterogenous disease that occurs after allogeneic transplantation. Management with immunosuppressant withdrawal does not impact patient outcomes. Until further evidence becomes available, the management of TA-TMA should focus on the treatment of underlying diseases.


Antibiotics for induction and maintenance of remission in ulcerative colitis: systematic review and meta-analysis.
Objectives: To ascertain the role of antibiotics in induction and maintenance of remission in ulcerative colitis (UC)Methods: We searched electronic databases for keywords ulcerative colitis or inflammatory bowel disease and antibiotics or antimicrobials. We performed a meta-analysis of randomized trials comparing antibiotics with control/placebo for clinical response, need for second line therapy, colectomy, and adverse effects. Subgroup analysis to clarify the mode of administration, number of antibiotics or the setting of use (acute severe UC or active non-severe UC) were also performed.Results: Thirteen trials with 785 patients were included. The pooled odds ratio of achieving clinical response with antibiotics was 1.74 (95% CI, 1.17-2.58). No differences were noted in relapse rates, need for second line therapy, colectomy or, adverse effects with the use of antibiotics. Subgroup analysis showed no differences with use of single or combination of antibiotics. Analysis of trials only in the setting of acute severe colitis did not demonstrate any benefit.Conclusion: The use of oral antibiotics in the setting of non-severe active UC could have some benefit in clinical response. The use of antibiotics is not of benefit in acute severe colitis, but oral antibiotics need to be evaluated in adult patients.


Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2.
Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.


The effect of caffeine ingestion on field hockey skill performance following physical fatigue.
This study examined the impact of caffeine ingestion on field hockey skill performance following high-intensity fatigue. Thirteen male hockey players (mean age = 21.1 ± 1.2 years) performed hockey sprint dribble and ball handling tests at rest and after a bout of total body fatigue (90% maximal capacity) following caffeine (5 mg kg(-1)) or placebo ingestion. Sprint dribble times were slower postfatigue compared with rest but were significantly faster postfatigue with caffeine compared with postfatigue with placebo ingestion (P < 0.01). Ball handling scores were higher at rest compared with postfatigue, but scores postfatigue were higher following caffeine than placebo ingestion (P < 0.01). Rating of perceived exhaustion (RPE) was lower (P < 0.01) and readiness to invest physical (P < 0.01) and mental effort (P = 0.01) were significantly higher in the caffeine condition. Caffeine ingestion may therefore be effective in offsetting decrements in skilled performance associated with fatigue.


EEG alpha phenotypes: linkage analyses and relation to alcohol dependence in an American Indian community study.
Evidence for a high degree of heritability of EEG alpha phenotypes has been demonstrated in twin and family studies in a number of populations. However, information on linkage of this phenotype to specific chromosome locations is still limited. This study's aims were to map loci linked to EEG alpha phenotypes and to determine if there was overlap with loci previously mapped for alcohol dependence in an American Indian community at high risk for substance dependence. Each participant gave a blood sample and completed a structured diagnostic interview using the Semi Structured Assessment for the Genetics of Alcoholism. Bipolar EEGs were collected and spectral power determined in the alpha (7.5-12.0 Hz) frequency band for two composite scalp locations previously identified by principal components analyses (bilateral fronto-central and bilateral centro-parietal-occipital). Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 410 members of multiplex families using SOLAR. Sixty percent of this study population had a lifetime diagnosis of alcohol dependence. Analyses of multipoint variance component LOD scores, for the EEG alpha power phenotype, revealed two loci that had a LOD score of 3.0 or above for the fronto-central scalp region on chromosomes 1 and 6. Additionally, 4 locations were identified with LOD scores above 2.0 on chromosomes 4, 11, 14, 16 for the fronto-central location and one on chromosome 2 for the centro-parietal-occipital location. These results corroborate the importance of regions on chromosome 4 and 6 highlighted in prior segregation studies in this and other populations for alcohol dependence-related phenotypes, as well as other areas that overlap with other substance dependence phenotypes identified in previous linkage studies in other populations. These studies additionally support the construct that EEG alpha recorded from fronto-central scalp areas may represent an important endophenotype associated with alcohol and other substance dependence.


Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology.
Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of (177)Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by (18)F-FDG and (68)gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and (68)Ga-somatostatin-receptor PET/CT in the management of MCC.


Herpes simplex virus 1 induces de novo phospholipid synthesis.
Herpes simplex virus type 1 capsids bud at nuclear membranes and Golgi membranes acquiring an envelope composed of phospholipids. Hence, we measured incorporation of phospholipid precursors into these membranes, and quantified changes in size of cellular compartments by morphometric analysis. Incorporation of [³H]-choline into both nuclear and cytoplasmic membranes was significantly enhanced upon infection. [³H]-choline was also part of isolated virions even grown in the presence of brefeldin A. Nuclei expanded early in infection. The Golgi complex and vacuoles increased substantially whereas the endoplasmic reticulum enlarged only temporarily. The data suggest that HSV-1 stimulates phospholipid synthesis, and that de novo synthesized phospholipids are inserted into nuclear and cytoplasmic membranes to i) maintain membrane integrity in the course of nuclear and cellular expansion, ii) to supply membrane constituents for envelopment of capsids by budding at nuclear membranes and Golgi membranes, and iii) to provide membranes for formation of transport vacuoles.


Pituitary Colloid Cyst.
Colloid cysts appear most commonly in the third ventricle, their occurrence in the sellar region is uncommon. The authors report a female patient with a pituitary colloid cyst. She was diagnosed incidentally with a sellar lesion by a routine paranasal computed tomography examination performed for planning of a dental implant surgery. Radiologic examinations revealed a pituitary lesion that was removed by transnasal transsphenoidal route. Her pathologic examination revealed that the lesion was a colloid cyst. Although rare, colloid cysts should be considered in the differential diagnosis of pituitary lesions.


Adipose tissue remodeling and obesity.
To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth.


Predicting dropout in dietary weight loss trials using demographic and early weight change characteristics: Implications for trial design.
Attrition causes analytical and efficacy issues in weight loss trials. Consistent predictors of attrition in weight loss trials have not been identified. Trial design could be improved if factors predicting attrition are accounted for. The aim of this study is to quantify the effect of easily measured pre study and early study variables to determine their relationship with attrition in dietary weight loss trials. Data was pooled from four previous dietary weight loss trials. Mixed effects logistic regression, Receiver Operator Curves and decision trees (classification and regression trees) were used to determine which of the variables (percent weight loss at 1 month, age, gender and baseline BMI) predicted dropout and to determine cutoffs useful for future trial design. The sample included 289 subjects, 73% female, with a mean age of 46.68±9.27years and average dropout of 25%. Percent weight loss at 1 month was the strongest predictor of dropout, those with a weight loss ≤2% were 4.99 times (95% CI 2.71, 9.18) more likely to drop out than those with a weight loss >2% in the first month (P<0.001). When considering only data available at the beginning of a trial those ≤50 years old were 2.07 times (95% CI 1.2, 3.5) more likely to drop out than those >50 (P=0.006). Early weight loss and age were identified as significant variables for predicting attrition in weight loss trials. Trial designs maybe improved by incorporating these variables and developing interventions targeting these factors may improve participant retention.


The effect of changes in referral behaviour following NICE guideline publication on agreement of examination findings between professionals in an established glaucoma referral refinement pathway: the Health Innovation & Education Cluster (HIEC) Glaucoma Pathways project.
To investigate whether the publication of the National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines had an effect on the agreement of examination findings between professionals involved in an established glaucoma referral refinement pathway. To report inter-professional agreement for the clinical examination findings of optometrists with a special interest in glaucoma (OSI), optometrists with no specialist interest in glaucoma (non-OSI) and a glaucoma consultant. Part 1 investigated agreement between an OSI and consultant and part 2 investigated agreement of clinical findings between the non-OSI and a specialist clinician (OSI or consultant). Part 1: Agreement between OSI and consultant in determining an abnormal intraocular pressure (IOP) (>21 mm Hg) expressed as a percentage positive predictive value (PPPV) was no different pre-NICE (60.6%) and post-NICE (61.4%, p=0.51) guidelines. PPPV for identification of an abnormal optic disc was better pre-NICE (60.6%) than post-NICE (42.7%, p=0.02). The appropriate referral rate for patients referred by an OSI was higher pre-NICE (69.6%) than post-NICE (61.2%) (p=0.07). Part 2: The PPPV between non-OSI and specialist clinician for an abnormal IOP was better pre-NICE (62.5%) than post-NICE (50.9%, p=0.12). This was also observed for abnormal optic discs, 70.0% pre-NICE and 52.9% post-NICE (p=0.04). The accuracy for detecting an abnormal IOP by the OSI has remained unchanged post-NICE, but there was a reduction in accuracy in detecting an abnormal optic disc as well as the appropriate referral rate. For the non-OSI, there was a decline in both IOP and optic disc assessment accuracy.