The effects of a pre-conception lifestyle intervention in women with obesity and infertility on perceived stress, mood symptoms, sleep and quality of life.
Obesity is an increasing problem worldwide and is associated with serious health risks. Obesity not only reduces physical health, but can also negatively affect levels of perceived stress, mood symptoms, sleep quality and quality of life (QoL), which may lead to further weight gain. We have previously shown that a pre-conception lifestyle intervention reduced weight and improved physical QoL in the short term. In the current study, we assessed the effects of this intervention in women with obesity and infertility on perceived stress, mood symptoms, sleep quality and QoL five years after randomization. We followed women who participated in the LIFEstyle study. This is a multi-center randomized controlled trial comparing a six-month lifestyle intervention to improve diet and increase physical activity followed by infertility treatment, versus prompt infertility treatment. Participants were 577 women with infertility between 18 and 39 years of age with a body mass index (BMI) ≥ 29 kg/m2. For the current study we measured perceived stress, mood symptoms, sleep quality and QoL in 178 women five years after randomization. T-tests and linear regression models were used to assess differences between the intervention and control groups. Five years after randomization, no differences were observed for perceived stress, mood symptoms, sleep quality and QoL between the intervention (n = 84) and control groups (n = 94). There was selective participation: women who did not participate in the follow-up had lower baseline mental QoL, and benefitted more from the intervention in terms of improved physical QoL during the original LIFEstyle intervention. We found no evidence that a pre-conception lifestyle intervention improved female well-being five years after randomization.


Executive functions in preschool children with externalizing behavior problems: a meta-analysis.
Deficits in executive functions (EF) have been found in school-age children and adolescents with externalizing behavior disorders. Present meta-analysis was carried out to determine whether these EF impairments can also be found in preschool children with externalizing behavior problems. Twenty-two studies were included with a total of 4021 children. Four separate meta-analyses were conducted, concerning overall EF, working memory, inhibition and cognitive flexibility. A medium correlation effect size was obtained for overall EF (ESzr = 0.22) and for inhibition (0.24), whereas a small effect size was found for working memory (0.17) and for cognitive flexibility (0.13). Moderator analyses revealed a stronger effect for older preschoolers compared to younger preschoolers, and for children from referred samples compared to community samples. These results show that EF, especially inhibition, is related to externalizing behavior problems already in preschool years.


Endomyocardial biopsy-related tricuspid regurgitation after orthotopic heart transplantation: single-center experience.
Damage of tricuspid valve (TV) with resultant tricuspid regurgitation (TR) induced by endomyocardial biopsy (EMB) following heart transplantation has been reported in several studies. This study tried to determine the prevalence of EMB-related iatrogenic damage over tricuspid apparatus following orthotopic heart transplantation and to evaluate its impact on the patients. Fifty patients received orthotopic heart transplantation between July 1987 and March 2005. Eleven patients were excluded from the study due to early postoperative mortality or inadequate follow-up. The medical records of the remaining 39 patients were reviewed retrospectively for basic characteristics as well as each attempted EMB. The iatrogenic damage of tricuspid apparatus and serial change of TR were accessed with 2-D and Doppler echocardiography. The obtained data were analyzed for their statistical significance with SPSS (version 12.0). A total of 373 biopsies were performed on the 39 patients between 1987 and 2005. The follow-up duration was 42.9+/-26.7 months. The prevalence of TR immediately following heart transplantation was 84.6%, with only 25.6% of patients having moderate or severe TR. At the end of the follow-up, the prevalence of TR increased to 92.3% and 61.5% of patients having moderate or severe TR, respectively. Eight patients (20.5%) had small chordae rupture (SCR) noted after 6.6+/-3.2 biopsies, and 10 patients (25.6%) had flail tricuspid valve (FTV) after 5.7+/-5.1 biopsies. Of patients with SCR, 62.5% had progression of TR, and 70% of patients with FTV showed significant TR change. The prevalence of iatrogenic tricuspid apparatus damage was high in this study. It contributed to the progression of TR significantly regardless of the damage severity. Measurements should be taken for prevention of iatrogenic tricuspid apparatus damage induced by EMB.


Integrating Subjective and Objective Dimensions of Resilience in Fire-Prone Landscapes.
Resilience has become a common goal for science-based natural resource management, particularly in the context of changing climate and disturbance regimes. Integrating varying perspectives and definitions of resilience is a complex and often unrecognized challenge to applying resilience concepts to social-ecological systems (SESs) management. Using wildfire as an example, we develop a framework to expose and separate two important dimensions of resilience: the inherent properties that maintain structure, function, or states of an SES and the human perceptions of desirable or valued components of an SES. In doing so, the framework distinguishes between value-free and human-derived, value-explicit dimensions of resilience. Four archetypal scenarios highlight that ecological resilience and human values do not always align and that recognizing and anticipating potential misalignment is critical for developing effective management goals. Our framework clarifies existing resilience theory, connects literature across disciplines, and facilitates use of the resilience concept in research and land-management applications.


Bridging the HIV-syphilis testing gap: dual testing among men who have sex with men living in China.
The WHO recommends dual testing for HIV and syphilis among key populations, including men who have sex with men (MSM). We assessed the proportion of men who had dual tested and reasons for not dual testing. In 2017, an online survey of MSM was conducted in eight cities from two provinces in China. Data on sociodemographics and sexual behaviours were collected. Descriptive analysis was used to examine the experience of dual testing. Multivariable logistic regression identified characteristics associated with men who had dual tested. Among 802 men who had ever tested for HIV, 297 dual tested (37%, 95% CI 34 to 40). Men dual tested in a variety of settings: public hospital (35%), voluntary counselling and testing sites (28%), self-testing at home (18%), community-based organisation (8%), community health centre (7%), other (3%) or private hospital (1%). Greater odds for dual testing was found in men who had disclosed their sexuality to a healthcare provider (adjusted OR (AOR) 1.81, 95% CI 1.27 to 2.59, p=0.001), and who had substantial (AOR 2.71, 95% CI 1.67 to 4.41, p<0.001) or moderate community engagement in sexual health (AOR 2.30, 95% CI 1.49 to 3.57, p<0.001), compared with those with no community engagement. The most common reasons for not dual testing were no knowledge that they could be dual tested (34%), did not ask the doctor to be dual tested (25%) and did not believe they were at risk for syphilis (19%). Chinese MSM are dual testing through a variety of test sites, including home self-testing. However, the overall dual testing rate remains low despite recent efforts to integrate HIV and syphilis testing.


The energy expenditure benefits of reallocating sedentary time with physical activity: a systematic review and meta-analysis.
We compared direct and daily cumulative energy expenditure (EE) differences associated with reallocating sedentary time to physical activity in adults for meaningful EE changes. Peer-reviewed studies in PubMed, Medline, EMBASE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched from inception to March 2017. Randomized and non-randomized interventions with sedentary time and EE outcomes in adults were included. Study quality was assessed by the National Heart Lung and Blood Institute tool, and summarized using random-effects meta-analysis and meta-regression. In total, 26 studies were reviewed, and 24 studies examined by meta-analysis. Reallocating 6-9 h of sedentary time to light-intensity physical activity (LIPA) (standardized mean difference [SMD], 2.501 [CI: 1.204-5.363]) had lower cumulative EE than 6-9 h of combined LIPA and moderate-vigorous intensity physical activity (LIPA and moderate-vigorous physical activity [MVPA]) (SMD, 5.218 [CI: 3.822-6.613]). Reallocating 1 h of MVPA resulted in greater cumulative EE than 3-5 h of LIPA and MVPA, but <6-9 h of LIPA and MVPA. Comparable EE can be achieved by different strategies, and promoting MVPA might be effective for those individuals where a combination of MVPA and LIPA is challenging.


Combined use of a videolaryngoscope and a flexible bronchoscope for awake tracheal intubation when front-of-neck airway is not an option.
We report a case of successful tracheal intubation with the combined use of a videolaryngoscope and flexible bronchoscope in a patient with difficult airway when both techniques had individually failed. A 35-year-old man presented with airway obstruction due to massive neck swelling causing hypoxia, stridor and respiratory distress. He had a history of oral cancer which had been resected with bilateral neck dissection and free flap reconstruction 2 months previously. Due to extensive anterior neck swelling, we judged that front-of-neck airway would not be a suitable approach. After unsuccessful attempts at awake tracheal intubation with videolaryngoscopy and flexible bronchoscopy separately, we combined both techniques with a successful outcome. By using a combined technique to address the specific problems presented by this case, a life-threatening emergency was resolved. This case highlights why it is useful for anaesthetists to be familiar with multiple techniques to awake tracheal intubation, both individually and in combination.


The Combination of Probiotic Complex, Rosavin, and Zinc Improves Pain and Cartilage Destruction in an Osteoarthritis Rat Model.
Osteoarthritis (OA), a degenerative disorder, induces pain, joint inflammation, and destruction of the articular cartilage matrix. Probiotic complex, rosavin, and zinc have been used as dietary supplements that exhibit anti-inflammatory and antioxidant properties. However, there is no evidence demonstrating a synergic effect in OA. This study aims to determine whether combination with probiotic complex, rosavin, and zinc decreases progression of monosodium iodoacetate (MIA)-induced OA rat model. The combination improved pain levels by preventing cartilage damage. The expression of proinflammatory cytokines and catabolic factors was reduced by the combination within the joint tissue. However, the combination increased anti-inflammatory cytokines as well as the anabolic factor production. The gene level of catabolic factors was decreased with treatment of the combination in chondrocytes isolated from OA patients. These results suggest that the combination can improve MIA development through the inhibition of proinflammatory cytokines and cartilage destruction, thus playing a key role as a therapeutic candidate for OA treatment.


CD8(+) T cells mediate CD40-independent maturation of dendritic cells in vivo.
Induction of cytotoxic T lymphocyte (CTL) responses against minor histocompatibility antigens is dependent upon the presence of T cell help and requires the interaction of CD40 on dendritic cells (DCs) with CD40 ligand on activated T helper cells (Th). This study demonstrates that CD40 is neither involved in Th-dependent nor Th-independent antiviral CTL responses. Moreover, the data show that DC maturation occurs in vivo after viral infection in the absence of CD40 and Th. This maturation did not require viral infection of DCs but was mediated by peptide-specific CD8(+) T cells. Surprisingly, naive CD8(+) T cells were able to trigger DC maturation within 24 h after activation in vivo and in vitro. Moreover, peptide-activated CD8(+) T cells were able to induce maturation in trans, as DCs that failed to present the relevant antigen in vivo also underwent maturation. Upon isolation, the in vivo-stimulated DCs were able to convert a classically Th-dependent CTL response (anti-HY) into a Th-independent response in vitro. Thus, antiviral CD8(+) T cells are sufficient for the maturation of DCs in the absence of CD40.


Electronystagmographic and gaschromatographic studies in rabbits.
Complaints of vertigo from people who are exposed to industrial solvents have focused interest on their toxic effect on the nervous system. In order to evaluate the influence of an organic solvent, xylene, on the mammalian vestibular system, a series of rabbit experiments were performed. To achieve a constant concentration, the xylene was infused as a lipid emulsion. Blood concentrations were estimated by gas chromatography. Electronystagmography in darkness revealed that at blood xylene concentrations of 30 ppm all rabbits had a positional nystagmus. The beat direction was the opposite of positional alcohol nystagmus. Another difference between the alcohol and the xylene reaction was that rotatory nystagmus responses were exaggerated. The relations between the present findings and the reactions and blood concentrations in people exposed to industrial solvents are discussed.


Oral contraceptives as related to cancer and benign lesions of the breast.
We conducted a case-control study to search for any relationship between use of oral contraceptives and development of breast cancer or benign breast disease. Women less than 50 years old with these diseases were matched with 2 controls by age, race, religion, and hospital. Home interviews elicited information on oral contraceptive use and other host and environmental factors. The study population comprised 1,770 women, including 452 with breast cancer and 446 with benign breast disease. The relative risk of developing cancer or benign disease was measured by matched set and summary chi-square analyses. Although the relative risk of developing breast cancer among "ever-users" of oral contraceptives was 1.1, the risk among women using oral contraceptives for 2-4 years was 1.9 (significantly increased). This risk estimate reached 2.5 for the 2- to 4-year users if they were still taking oral contraceptives when entered into study. Moreover, prior biopsy for benign breast disease increased the cancer risk among long-term users by as much as 11-fold. The relative risk of breast cancer did not vary by age, interval since first use, earliest year of use, or interval since last use. These results could be interpreted to indicate that oral contraceptives did not induce breast cancer but may have accelerated the growth rate of preexisting breast cancer. The relative risk of developing benign breast disease among ever-users of oral contraceptives was 0.8 (significantly reduced); it decreased with longer duration of use until it reached 0.2 for women who took these hormones 8 years or more. The relative risk of benign breast was not affected by earliest year of use or interval since last use. We concluded that oral contraceptives reduced the incidence of benign breast disease, but that use of steroid hormones is ill-advised for women with already established benign breast disease.


A De Novo Germline APC Mutation (3927del5) in a Patient with Familial Adenomatous Polyposis: Case Report and Literature Review.
Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype.6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations.7 A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition.


Proliferation capacity of the renal proximal tubule involves the bulk of differentiated epithelial cells.
We investigated the proliferative capacity of renal proximal tubular cells in healthy rats. Previously, we observed that tubular cells originate from differentiated cells. We now found 1) by application of bromo-deoxyuridine (BrdU) for 14 days and costaining for BrdU, and the G(1)-phase marker cyclin D1 that the bulk of cells in the S3 segment of juvenile rats were involved in proliferation; 2) that although the proliferation rate was about 10-fold higher in juvenile rats compared with adult rats, roughly 40% of S3 cells were in G(1) in both groups; 3) that after a strong mitotic stimulus (lead acetate), proliferation was similar in juveniles and adults; 4) that there was a high incidence of cyclin D1-positive cells also in the healthy human kidney; and 5) by labeling dividing cells with BrdU for 2 days before the application of lead acetate and subsequent costaining for BrdU and cell cycle markers, that, although a strong mitotic stimulus does not abolish the period of quiescence following division, it shortens it markedly. Thus the capacity of the proximal tubule to rapidly recruit cells into division relies on a large reserve pool of cells in G(1) and on the shortening of the obligatory period of quiescence that follows division.


Human 7SL RNA consists of a 140 nucleotide middle-repetitive sequence inserted in an alu sequence.
We have cloned and sequenced a cDNA copy of in vitro-polyadenylated 7SL RNA of HeLa cells. The cloned fragment is 303 bp long and has a composite structure. A central block of 140 bp is homologous to a new set of human middle-repetitive sequences. This block appears to be inserted in an Alu consensus sequence, 100 bp from the 5' end and 40 bp from the 3' end of the Alu monomer. Two 6 bp direct repeats are found at the junction between the Alu flanking sequences and the central element. The analysis of several clones shows the existence of sequence microheterogeneity in the 5' portion of the molecule. The 7L DNA probably represents a subset of the Alu family of DNA, highly conserved in evolution.


Speckle tracking echocardiography in acute lupus myocarditis: comparison to conventional echocardiography.
Lupus myocarditis occurs in 5-10% of patients with systemic lupus erythematosus (SLE). No single feature is diagnostic of lupus myocarditis. Speckle tracking echocardiography (STE) can detect subclinical left ventricular dysfunction in SLE patients, with limited research on its utility in clinical lupus myocarditis. We report on STE in comparison to conventional echocardiography in patients with clinical lupus myocarditis. A retrospective study was done at a tertiary referral hospital in South Africa. SLE patients with lupus myocarditis were included and compared to healthy controls. Echocardiographic images were reanalyzed, including global longitudinal strain through STE. A poor echocardiographic outcome was defined as final left ventricular ejection fraction (LVEF) <40%. 28 SLE patients fulfilled the criteria. Global longitudinal strain correlated with global (LVEF: r = -0.808; P = 0.001) and regional (wall motion score: r = 0.715; P < 0.001) function. In patients presenting with a LVEF ≥50%, global longitudinal strain (P = 0.023), wall motion score (P = 0.005) and diastolic function (P = 0.004) were significantly impaired vs controls. Following treatment, LVEF (35-47% (P = 0.023)) and wall motion score (1.88-1.5 (P = 0.017)) improved but not global longitudinal strain. Initial LVEF (34%; P = 0.046) and global longitudinal strain (-9.5%; P = 0.095) were lower in patients with a final LVEF <40%. This is the first known report on STE in a series of patients with clinical lupus myocarditis. Global longitudinal strain correlated with regional and global left ventricular function. Global longitudinal strain, wall motion score and diastolic parameters may be more sensitive markers of lupus myocarditis in patients presenting with a preserved LVEF ≥50%. A poor initial LVEF and global longitudinal strain were associated with a persistent LVEF <40%. Echocardiography is a non-invasive tool with diagnostic and prognostic value in lupus myocarditis.


In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice.
In an attempt to examine the in vivo proinflammatory properties of IL-1, the effects of rIL-1 beta on the development of collagen-induced arthritis in mice were investigated. The results presented in this paper demonstrated that the administration of rIL-1 beta via mini-osmotic pumps into DBA/1 mice which were suboptimally immunized with native chick type II collagen (NcII) markedly accelerated the onset as well as the progression of the arthritic disease. When IL-1-containing osmotic pumps were s.c. implanted onto mice 18 days post-collagen immunization, clinical signs of arthritis appeared within 3 to 4 days after the implant with the pumps. Maximal incidence of arthritis which was usually 80 to 100% occurred between the 6th and 7th day after the administration of rIL-1 beta. Histologic analyses revealed that the knee and ankle joints from mice which were treated with rIL-1 beta for 7 days were most severely and consistently affected. Furthermore, these IL-1-treated mice exhibited granulocytic hyperplasia within the marrow as well as marked peripheral blood neutrophilia. By contrast, arthritis was not observed during the 7-day course of the IL-1 study in the following control groups: 1) mice that were only immunized with NcII, and 2) collagen-immunized mice which received osmotic pumps containing PBS. A substantial number of these collagen-immunized mice which were not treated with IL-1 eventually developed arthritis but at later times after the incidence of arthritis had peaked in the IL-1-treated group. In addition, unimmunized mice failed to develop arthritis upon treatments with IL-1 beta. Moreover, the humoral responses to NcII were not altered in the IL-1-treated mice. Thus, these in vivo studies suggest that IL-1 is potentially capable of triggering the various inflammatory events of collagen-induced arthritis, and thereby, contribute to the pathogenesis of murine arthritis.


Metal-metal multiple bonding in C3-symmetric bimetallic complexes of the first row transition metals.
Metal-metal multiple bonds have been an intense area of focus in inorganic chemistry for many decades as a result of their fundamentally interesting bonding properties, as well as their potential applications in multielectron transfer and small molecule activation processes. Much of what is known in this field revolves around 2nd and 3rd row transition metals, with fundamental knowledge lacking in the area of bonds between elements of the first transition series. The smaller size and tendency of first row ions to adopt high-spin electron configurations weaken metal-metal interactions and serve to complicate the interpretation of the electronic structure and bonding in bimetallic species containing first row transition metals. Furthermore, traditional tetragonal "paddlewheel" complexes dominate the metal-metal multiple bond literature, and only recently have researchers begun to take advantage of the weaker ligand field in three-fold symmetric bimetallic complexes to encourage more favourable metal-metal bonding interactions. In the past 5 years, several research groups have exploited three-fold symmetric frameworks to investigate new trends in metal-metal bonding involving the first row transition metals. This feature article serves to highlight recent achievements in this area and to use C3-symmetric systems as a model to better understand the fundamental aspects of multiple bonds featuring first row transition metals.


A qualitative investigation of Foundation Year 2 doctors' views on the European Working Time Directive.
PURPOSE - The purpose of this paper is to examine the personal views and experiences of Foundation Year 2 doctors operating under the European Working Time Directive (EWTD). DESIGN/METHODOLOGY/APPROACH - In total, 36 Foundation Year 2 doctors from a single UK-based Deanery participated in this semistructured interview study. FINDINGS - Findings indicated that Foundation doctors typically welcomed a regulation of working hours, but reported frustration at the manner in which the Directive had been implemented. Participants reported concerns at reducing hours by removing out-of-hours working in order to meet EWTD requirements. Out-of-hours shifts were highly valued owing to their increased opportunities for autonomous clinical decision making. By contrast, day-shifts were regarded as heavily administrative in nature and were perceived as service provision. Foundation doctors discussed the unique nature of the out-of-hours working period which appeared to provide specific learning opportunities as doctors draw on time management and prioritisation skills. ORIGINALITY/VALUE - Given the challenges the EWTD presents, careful rota planning is essential. First, the authors would encourage the restructuring of day-shift work to provide a greater emphasis on hands-on skills experience in a supportive, supervised environment. Second, where possible, Foundation doctors might benefit from the opportunity to engage in some out-of-hours working, such as with multi-professional "Hospital at Night" teams. Third, the authors would encourage junior doctor involvement in rota design and planning which may increase their perceived autonomy and therefore buy-in of working practices.


Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards.
Prior studies suggest that fructose compared with glucose may be a weaker suppressor of appetite, and neuroimaging research shows that food cues trigger greater brain reward responses in a fasted relative to a fed state. We sought to determine the effects of ingesting fructose versus glucose on brain, hormone, and appetitive responses to food cues and food-approach behavior. Twenty-four healthy volunteers underwent two functional magnetic resonance imaging (fMRI) sessions with ingestion of either fructose or glucose in a double-blinded, random-order cross-over design. fMRI was performed while participants viewed images of high-calorie foods and nonfood items using a block design. After each block, participants rated hunger and desire for food. Participants also performed a decision task in which they chose between immediate food rewards and delayed monetary bonuses. Hormones were measured at baseline and 30 and 60 min after drink ingestion. Ingestion of fructose relative to glucose resulted in smaller increases in plasma insulin levels and greater brain reactivity to food cues in the visual cortex (in whole-brain analysis) and left orbital frontal cortex (in region-of-interest analysis). Parallel to the neuroimaging findings, fructose versus glucose led to greater hunger and desire for food and a greater willingness to give up long-term monetary rewards to obtain immediate high-calorie foods. These findings suggest that ingestion of fructose relative to glucose results in greater activation of brain regions involved in attention and reward processing and may promote feeding behavior.


Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells.
Estrogen receptor α (ERα) is a ligand-dependent transcription factor that plays an important role in breast cancer. Estrogen-dependent gene regulation by ERα can be mediated by interaction with other DNA-binding proteins, such as activator protein-1 (AP-1). The nature of such interactions in mediating the estrogen response in breast cancer cells remains unclear. Here we show that knockdown of c-Fos, a component of the transcription factor AP-1, attenuates the expression of 37% of all estrogen-regulated genes, suggesting that c-Fos is a fundamental factor for ERα-mediated transcription. Additionally, knockdown of c-Fos affected the expression of a number of genes that were not regulated by estrogen. Pathway analysis reveals that silencing of c-Fos downregulates an E2F1-dependent proproliferative gene network. Thus, modulation of the E2F1 pathway by c-Fos represents a novel mechanism by which c-Fos enhances breast cancer cell proliferation. Furthermore, we show that c-Fos and ERα can cooperate in regulating E2F1 gene expression by binding to regulatory elements in the E2F1 promoter. To start to dissect the molecular details of the cross talk between AP-1 and estrogen signaling, we identify a novel ERα/AP-1 target, PKIB (cAMP-dependent protein kinase inhibitor-β), which is overexpressed in ERα-positive breast cancer tissues. Knockdown of PKIB results in robust growth suppression of breast cancer cells. Collectively, our findings support c-Fos as a critical factor that governs estrogen-dependent gene expression and breast cancer proliferation programs.


Dietary carbohydrates and amino acids influence oocyte quality in dairy heifers.
The objective of the present experiment was to determine whether increasing plasma insulin by different nutritional regimes affects oocyte quality. Holstein dairy heifers (eight per treatment) were assigned, using a two times two factorial design, to diets containing either low or high dietary leucine and either low or high dietary starch. Each heifer underwent six sessions of ovum pick-up beginning 25 days after introduction of the diets. Oocyte quality was assessed by development to the blastocyst stage in synthetic oviducal fluid following in vitro fertilisation. Feeding diets containing high leucine resulted in significantly higher plasma free leucine and tyrosine concentrations. The high-starch diet significantly increased plasma insulin but not glucagon concentration, whereas high dietary leucine increased plasma glucagon but not insulin. Oocyte cleavage was not influenced by diet. The high-starch diet, which was associated with a high plasma insulin : glucagon ratio, had adverse effects on oocyte quality that were avoided when leucine intake was increased. There was an association between total plasma free amino acid concentration and oocyte cleavage. Therefore, in dairy heifers dietary amino acids and carbohydrates during antral follicle development appear to mediate effects on oocyte quality by different mechanisms. These findings have implications for both diet formulation and feeding regimes.


Medical record review of transition to lanreotide following octreotide for neuroendocrine tumors.
Octreotide has been used for decades in the United States (US) and Europe to treat patients with advanced neuroendocrine tumors (NETs). Lanreotide was approved in 2014 to improve progression-free survival (PFS) in patients with unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic NETs. Therefore, clinicians and patients may consider sequencing therapy from octreotide to lanreotide. However, current real-world outcomes data on patients who have made this transition is limited. We conducted a multicenter, noninterventional, retrospective medical record review of patients with locally advanced or metastatic gastroenteropancreatic NETs (NCT03112694). Included patients had been treated with long-acting octreotide monotherapy for ≥90 days before transitioning to lanreotide monotherapy and continued on lanreotide for ≥90 days. Abstractors entered patient demographic and clinical data into a customized, web-based case report form. We assessed clinically defined PFS and other tumor-related outcomes while patients were treated with lanreotide. Outcomes were analyzed according to level of response at the time of transition from octreotide to lanreotide: progressive disease, nonprogressive disease, or unknown. Statistical analyses were descriptive. Clinically defined PFS and duration of treatment with lanreotide were estimated using the Kaplan-Meier method. Data were abstracted for 91 patients with gastroenteropancreatic NETs who received long-acting octreotide followed by lanreotide at six US based sites. At initial diagnosis, 71.4% of patients had stage IV disease. Small intestine (63.7%) and pancreas (14.3%) were the most common primary tumor sites. Mean [standard deviation (SD)] duration of follow-up from diagnosis was 70.6 (41.3) months. Patients received long-acting octreotide for a mean (SD) of 38.4 (32.8) months. When patients transitioned to lanreotide, 57.1% had nonprogressive disease on octreotide, 30.8% had progressive disease, and the remainder had unknown disease status. The most common reasons for switching from octreotide to lanreotide were progressive disease (22.0%), formulary change (15.4%), and patient preference (9.9%). Patients received lanreotide for a median (95% CI) duration of 24.7 (16.7-59.9) months. At the end of follow-up, 74% of patients remained on lanreotide monotherapy. Progression occurred in 24.2% of patients during lanreotide treatment. Overall median (95% CI) clinician-defined PFS following the transition to lanreotide was estimated to be 23.7 months [20.2 months-NE (not estimable)]. Patients with nonprogressive disease when they transitioned to lanreotide experienced a median clinician-defined PFS of 24.7 (17.0-NE) months. Among patients reported to have progressive disease when they transitioned to lanreotide, median (95% CI) clinician-defined PFS was estimated to be 15.2 (11.4-NE) months. There were no material differences in adverse events recorded during the long-acting octreotide and lanreotide treatment periods. Our study suggests that lanreotide monotherapy is well tolerated and may contribute to stabilization of disease in a subset of patients with locally advanced or metastatic gastroenteropancreatic NETs previously treated with long-acting octreotide.


Mathematical models for somite formation.
Somitogenesis is the process of division of the anterior-posterior vertebrate embryonic axis into similar morphological units known as somites. These segments generate the prepattern which guides formation of the vertebrae, ribs and other associated features of the body trunk. In this work, we review and discuss a series of mathematical models which account for different stages of somite formation. We begin by presenting current experimental information and mechanisms explaining somite formation, highlighting features which will be included in the models. For each model we outline the mathematical basis, show results of numerical simulations, discuss their successes and shortcomings and avenues for future exploration. We conclude with a brief discussion of the state of modeling in the field and current challenges which need to be overcome in order to further our understanding in this area.


Discovery of the fossil otter Enhydritherium terraenovae (Carnivora, Mammalia) in Mexico reconciles a palaeozoogeographic mystery.
The North American fossil otter Enhydritherium terraenovae is thought to be partially convergent in ecological niche with the living sea otter Enhydra lutris, both having low-crowned crushing teeth and a close association with marine environments. Fossil records of Enhydritherium are found in mostly marginal marine deposits in California and Florida; despite presence of very rich records of fossil terrestrial mammals in contemporaneous localities inland, no Enhydritherium fossils are hitherto known in interior North America. Here we report the first occurrence of Enhydritherium outside of Florida and California, in a land-locked terrestrial mammal fauna of the upper Miocene deposits of Juchipila Basin, Zacatecas State, Mexico. This new occurrence of Enhydritherium is at least 200 km from the modern Pacific coastline, and nearly 600 km from the Gulf of Mexico. Besides providing further evidence that Enhydritherium was not dependent on coastal marine environments as originally interpreted, this discovery leads us to propose a new east-to-west dispersal route between the Florida and California Enhydritherium populations through central Mexico. The proximity of the fossil locality to nearby populations of modern neotropical otters Lontra longicaudis suggests that trans-Mexican freshwater corridors for vertebrate species in riparian habitats may have persisted for a prolonged period of time, pre-dating the Great American Biotic Interchange.


A web-based program improves physical activity outcomes in a primary care angina population: randomized controlled trial.
Angina affects more than 50 million people worldwide. Secondary prevention interventions such as cardiac rehabilitation are not widely available for this population. An Internet-based version could offer a feasible alternative. Our aim was to examine the effectiveness of a Web-based cardiac rehabilitation program for those with angina. We conducted a randomized controlled trial, recruiting those diagnosed with angina from general practitioners (GPs) in primary care to an intervention or control group. Intervention group participants were offered a 6-week Web-based rehabilitation program ("ActivateYourHeart"). The program was introduced during a face-to-face appointment and then delivered via the Internet (no further face-to-face contact). The program contained information about the secondary prevention of coronary heart disease (CHD) and set each user goals around physical activity, diet, managing emotions, and smoking. Performance against goals was reviewed throughout the program and goals were then reset/modified. Participants completed an online exercise diary and communicated with rehabilitation specialists through an email link/synchronized chat room. Participants in the control group continued with GP treatment as usual, which consisted of being placed on a CHD register and attending an annual review. Outcomes were measured at 6-week and 6-month follow-ups during face-to-face assessments. The primary outcome measure was change in daily steps at 6 weeks, measured using an accelerometer. Secondary outcome measures were energy expenditure (EE), duration of sedentary activity (DSA), duration of moderate activity (DMA), weight, diastolic/systolic blood pressure, and body fat percentage. Self-assessed questionnaire outcomes included fat/fiber intake, anxiety/depression, self-efficacy, and quality of life (QOL). A total of 94 participants were recruited and randomized to the intervention (n=48) or the usual care (n=46) group; 84 and 73 participants completed the 6-week and 6-month follow-ups, respectively. The mean number of log-ins to the program was 18.68 (SD 13.13, range 1-51), an average of 3 log-ins per week per participant. Change in daily steps walked at the 6-week follow-up was +497 (SD 2171) in the intervention group and -861 (SD 2534) in the control group (95% CI 263-2451, P=.02). Significant intervention effects were observed at the 6-week follow-up in EE (+43.94 kcal, 95% CI 43.93-309.98, P=.01), DSA (-7.79 minutes, 95% CI -55.01 to -7.01, P=.01), DMA (+6.31 minutes, 95% CI 6.01-51.20, P=.01), weight (-0.56 kg, 95% CI -1.78 to -0.15, P=.02), self-efficacy (95% CI 0.30-4.79, P=.03), emotional QOL score (95% CI 0.01-0.54, P=.04), and angina frequency (95% CI 8.57-35.05, P=.002). Significant benefits in angina frequency (95% CI 1.89-29.41, P=.02) and social QOL score (95% CI 0.05-0.54, P=.02) were also observed at the 6-month follow-up. An Internet-based secondary prevention intervention could be offered to those with angina. A larger pragmatic trial is required to provide definitive evidence of effectiveness and cost-effectiveness. International Standard Randomized Controlled Trial Number (ISRCTN): 90110503; http://www.controlled-trials.com/ISRCTN90110503/ISRCTN90110503 (Archived by WebCite at http://www.webcitation.org/6RYVOQFKM).


Hepatitis B virus subgenotypes D1 and D3 are prevalent in Pakistan.
As the hepatitis B genotyping is important for assessing its clinical implications and geographical distribution, the sub-genotypes have been found useful for determination of specific genomic markers related to hepatocarcinogenesis. In Pakistan, there is no reported data on molecular evolutionary analysis of HBV. A study was, therefore, much needed to evaluate the spectra of mutations present in the strains prevalent here. to confirm specificity of PCR typing, phylogenetic analysis of the pre-S1 region and the divergence was studied through 13 sequences of 362 bp (accession number EF432765 - EF432777). A total of 315 serum samples, selected from HBsAg positive patients representing the major ethnic groups, residing in Karachi, Sindh were tested for genotyping. Genotype D (219/315) was found to be the most prevalent (70%) amongst our patients. The rest of the genotypes A and a mixture of A and D (AD) were distributed as 20%, and 10% respectively. Phylogenetic tree demonstrated clustering of 11 samples with subgenotype D1 sequences and the remaining two strains on a branch within D3 samples. All samples intermixed with strains from other countries and were found to be closely related to Indian, Iranian and Egyptian HBV strains with 98.7 - 99.0% homology. This study confirms the predominance of genotype D in southeastern Asia and presence of subgenotypes DI and D3 in the Pakistani infected patients. More studies are required to investigate the reason for fewer inclusions of D3 compared to the D1 in Pakistani HBV strains.


Teleneuropsychology: evidence for video teleconference-based neuropsychological assessment.
The use of videoconference technology to deliver health care diagnostics and treatment continues to grow at a rapid pace. Telepsychiatry and telepsychology applications are well-accepted by patients and providers, and both diagnostic and treatment outcomes have generally been similar to traditional face-to-face interactions. Preliminary applications of videoconference-based neuropsychological assessment (teleneuropsychology) have yielded promising results in the feasibility and reliability of several standard tests, although large-scale studies are lacking. This investigation was conducted to determine the reliability of video teleconference (VTC) - based neuropsychological assessment using a brief battery of standard neuropsychological tests commonly used in the evaluation of known or suspected dementia. Tests included the Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test-Revised, Digit Span forward and backward, short form Boston Naming Test, Letter and Category Fluency, and Clock Drawing. Tests were administered via VTC and in-person to subjects, counterbalanced using alternate test forms and standard instructions. Two hundred two adult subjects were tested in both rural and urban settings, including 83 with cognitive impairment and 119 healthy controls. We found highly similar results across VTC and in-person conditions, with significant intraclass correlations (mean=.74; range: 0.55-0.91) between test scores. Findings remained consistent in subjects with or without cognitive impairment and in persons with MMSE scores as low as 15. VTC-based neuropsychological testing is a valid and reliable alternative to traditional face-to-face assessment using selected measures. More VTC-based studies using additional tests in different populations are needed to fully explore the utility of this new testing medium.


Syntaxin modulation of slow inactivation of N-type calcium channels.
Syntaxin, a membrane protein vital in triggering vesicle fusion, interacts with voltage-gated N- and P/Q-type Ca(2+) channels. This biochemical association is proposed to colocalize Ca(2+) channels and presynaptic release sites, thus supporting rapid and efficient initiation of neurotransmitter release. The syntaxin channel interaction may also support a novel signaling function, to modulate Ca(2+) channels according to the state of the associated release machinery (Bezprozvanny et al., 1995; Wiser et al., 1996; see also Mastrogiacomo et al., 1994). Here we report that syntaxin 1A (syn1A) coexpressed with N-type channels in Xenopus oocytes greatly promoted slow inactivation gating, but had little or no effect on the onset of and recovery from fast inactivation. Accordingly, the effectiveness of syntaxin depended strongly on voltage protocol. Slow inactivation was found for N-type channels even in the absence of syntaxin and could be distinguished from fast inactivation on the basis of its slow kinetics, distinct voltage dependence (voltage-independent at potentials higher than the level of half-inactivation), and temperature independence (Q(10), approximately 0.8). Trains of action potential-like stimuli were more effective than steady depolarizations in stabilizing the slowly inactivated condition. Agents that stimulate protein kinase C decreased the inhibitory effect of syntaxin on N-type channels. Application of BoNtC1 to cleave syntaxin sharply attenuated the modulatory effects on Ca(2+) channel gating, consistent with structural analysis of syntaxin modulation, supporting use of this toxin to test for the impact of syntaxin on Ca(2+) influx in nerve terminals.


High-sensitivity troponin T and cardiovascular events in systolic blood pressure categories: atherosclerosis risk in communities study.
Based on observational studies, there is a linear increase in cardiovascular risk with higher systolic blood pressure (SBP), yet clinical trials have not shown benefit across all SBP categories. We assessed whether troponin T measured using high-sensitivity assay was associated with cardiovascular disease within SBP categories in 11 191 Atherosclerosis Risk in Communities study participants. Rested sitting SBP by 10-mm Hg increments and troponin categories were identified. Incident heart failure hospitalization, coronary heart disease, and stroke were ascertained for a median of 12 years after excluding individuals with corresponding disease. Approximately 53% of each type of cardiovascular event occurred in individuals with SBP<140 mm Hg and troponin T ≥3 ng/L. Higher troponin T was associated with increasing cardiovascular events across most SBP categories. The association was strongest for heart failure and least strong for stroke. There was no similar association of SBP with cardiovascular events across troponin T categories. Individuals with troponin T ≥3 ng/L and SBP <140 mm Hg had higher cardiovascular risk compared with those with troponin T <3 ng/L and SBP 140 to 159 mm Hg. Higher troponin T levels within narrow SBP categories portend increased cardiovascular risk, particularly for heart failure. Individuals with lower SBP but measurable troponin T had greater cardiovascular risk compared with those with suboptimal SBP but undetectable troponin T. Future trials of systolic hypertension may benefit by using high-sensitivity troponin T to target high-risk patients.


Implantation of vascular grafts lined with genetically modified endothelial cells.
The possibility of using the vascular endothelial cell as a target for gene replacement therapy was explored. Recombinant retroviruses were used to transduce the lacZ gene into endothelial cells harvested from mongrel dogs. Prosthetic vascular grafts seeded with the genetically modified cells were implanted as carotid interposition grafts into the dogs from which the original cells were harvested. Analysis of the graft 5 weeks after implantation revealed genetically modified endothelial cells lining the luminal surface of the graft. This technology could be used in the treatment of atherosclerosis disease and the design of new drug delivery systems.


Mental Health Interventions during the COVID-19 Pandemic: A Conceptual Framework by Early Career Psychiatrists.
The emergence of mental health (MH) problems during a pandemic is extremely common, though difficult to address due to the complexities of pandemics and the scarcity of evidence about the epidemiology of pandemic-related MH problems and the potential interventions to tackle them. Little attention has been devoted so far to this topic from policymakers, stakeholders and researchers, resulting in a lack of replicable, scalable and applicable frameworks to help plan, develop and deliver MH care during pandemics. As a response, we have attempted to develop a conceptual framework (CF) that could guide the development, implementation, and evaluation of MH interventions during the ongoing COVID-19 pandemic. This CF was developed by early career psychiatrists from 16 countries that cover all the WHO regions. Their opinions were elicited via a semi-structured questionnaire. They were asked to provide their views about the current MH situation in their countries and to elaborate on existing 'myths' and misinformation. They were also asked to name the resources available and to propose solutions and approaches to provide accessible and affordable care. The CF was prepared based on the extant literature and the views discussed in this group; it illustrates the epidemiology of MH problems, preparedness plans, stage-specific plans or innovative solutions, opportunities to integrate those plans and possible outcomes at policy level. This CF can serve as a technical guide for future research regarding pandemics. It can be used to monitor trends and to optimize efforts, and to develop evidence based MH interventions. Still, further research focusing on the individual components of this framework is needed.


Changes in Sexuality, Body Image and Health Related Quality of Life in Patients Treated for Hematologic Malignancies: A Longitudinal Study.
Longitudinal studies exploring sexuality, body image and health-related quality of life (HRQoL) are lacking in patients treated with chemo- or chemoimmuno-therapy for hematologic malignancies. The aim was to describe and explore changes in sexuality, body image and HRQoL in patients treated for hematologic malignancies, from baseline until 6 months after treatment. Twenty patients above 45 years (median age 62) treated for DLBCL, CLL or AML participated. Data were collected at baseline, 1- and 6-months after treatment by means of three instruments: SAQ-S, BIS and EORTC QLQ-C30. The results showed that patients' sexuality was negatively affected 1 month after treatment, but after 6 months the patient reported scores had returned almost entirely to baseline scores. Body image was slight negatively affected after 1 month and after 6 months, 50 % reported that body image was not affected at all. Regarding HRQoL, patients reported gradually improved scores during the study period. Regression analysis showed that changes in sexuality and body image seemed to influence changes in HRQoL. This study has shown changes in sexuality, body image and HRQoL over time in patients above age 45 treated for hematologic malignancies. One month after treatment all three areas becomes negatively affected, and thereafter the patients' scores recovered to a great extent regarding these issues within 6 months. Sexuality and body image seem to be important aspects of HRQoL for these patients and need to be integrated in the cancer rehabilitation during and after treatment.


Fine-grained semantic categorization across the abstract and concrete domains.
A consolidated approach to the study of the mental representation of word meanings has consisted in contrasting different domains of knowledge, broadly reflecting the abstract-concrete dichotomy. More fine-grained semantic distinctions have emerged in neuropsychological and cognitive neuroscience work, reflecting semantic category specificity, but almost exclusively within the concrete domain. Theoretical advances, particularly within the area of embodied cognition, have more recently put forward the idea that distributed neural representations tied to the kinds of experience maintained with the concepts' referents might distinguish conceptual meanings with a high degree of specificity, including those within the abstract domain. Here we report the results of two psycholinguistic rating studies incorporating such theoretical advances with two main objectives: first, to provide empirical evidence of fine-grained distinctions within both the abstract and the concrete semantic domains with respect to relevant psycholinguistic dimensions; second, to develop a carefully controlled linguistic stimulus set that may be used for auditory as well as visual neuroimaging studies focusing on the parametrization of the semantic space beyond the abstract-concrete dichotomy. Ninety-six participants rated a set of 210 sentences across pre-selected concrete (mouth, hand, or leg action-related) and abstract (mental state-, emotion-, mathematics-related) categories, with respect either to different semantic domain-related scales (rating study 1), or to concreteness, familiarity, and context availability (rating study 2). Inferential statistics and correspondence analyses highlighted distinguishing semantic and psycholinguistic traits for each of the pre-selected categories, indicating that a simple abstract-concrete dichotomy is not sufficient to account for the entire semantic variability within either domains.


Comparison of methotrexate polyglutamylation in L1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor. Lack of evidence for influx route-specific effects.
We previously described a methotrexate-resistant L1210 cell line (MTXrA) that lacks a functional reduced folate carrier and does not appreciably express the folate receptor. In the present study, we utilized MTXrA cell lines stably transfected with cDNAs encoding either the folate receptor or the reduced folate carrier to investigate the influence of the route of folate influx on the rate and extent of methotrexate polyglutamylation. At an extracellular methotrexate concentration of 0.1 microM, influx in the folate receptor transfectant (MTXrA-TF1) and in the reduced folate carrier transfectant (MTXrA-R1) was equal and methotrexate polyglutamates accumulated at an identical rate, but the onset was delayed until dihydrofolate reductase was saturated with the monoglutamate (approxmately 3 hr). The onset of polyglutamate formation was immediate and identical among the lines in cells pretreated with the lipophilic dihydrofolate reductase inhibitor trimetrexate to block methotrexate binding to dihydrofolate reductase. The spectra of individual methotrexate polyglutamates that accumulated were similar, with the tetraglutamate present as the predominant form. A 100-fold higher methotrexate concentration was required to detect methotrexate uptake and polyglutamylation in the transport defective parent MTXrA line, demonstrating that diffusion or an unidentified low affinity route also supports polyglutamylation. Since the folate receptor and the reduced folate carrier achieve nearly identical rates of polyglutamylation despite very different mechanisms of methotrexate delivery, the data suggest that transport-mediated substrate channeling to folylpolyglutamate synthetase is unlikely to play a role in tetrahydrofolate metabolism. This study supports the notion that it is the intracellular concentration of methotrexate achieved within the cell that drives polyglutamylation irrespective of its route of entry.


'Just so you know, the patient is staff': healthcare professionals' perceptions of caring for healthcare professional-patients.
To explore healthcare professionals' conceptions of the care of patients who are also healthcare professionals. Explorative, with a qualitative, phenomenographic approach. 16 healthcare personnel within different professions (doctors, nurses, assistant nurses, physiotherapists, occupational therapists) were interviewed about the care of 32 patients who were themselves members of different healthcare professions, in one healthcare organisation in Sweden. The care of patients who are healthcare professionals was conceived in five different ways, as: usual, dutiful, prioritised and secure, insecure and responsive. An initial conception was that their care was usual, just as for any other patient, and also a perceived duty to treat them and to protect their right to be a patient--as any other patient. Exploring further, informants described that these patients did receive secure and prioritised care, as the informants experienced making a greater commitment, especially doctors giving privileges to doctor-patients. A conception of insecure care infused the informants' descriptions. This comprised of them feeling intimidated in their professional role, feeling affected by colleagues' stressful behaviour and ambiguity whether the healthcare professional-patient could be regarded as a competent professional. The deepest way of understanding care seemed to be responsive care, such as acknowledging and respecting the patient's identity and responding to their wishes of how treatment was to be met. Caring for healthcare professionals seems to trigger different ethical approaches, such as deontology and ethics of care. According to ethics of care, the findings may indeed suggest that these patients should be cared for just as any other patients would be, but only if this means that they are cared for as persons, that is, they are given 'person-centred care'. This would imply balancing between acknowledging the vulnerable patient in the colleague and acknowledging the identity of the colleague in the patient.


Versatile simulations of admixture and accurate local ancestry inference with mixnmatch and ancestryinfer.
It has become clear that hybridization between species is much more common than previously recognized. As a result, we now know that the genomes of many modern species, including our own, are a patchwork of regions derived from past hybridization events. Increasingly researchers are interested in disentangling which regions of the genome originated from each parental species using local ancestry inference methods. Due to the diverse effects of admixture, this interest is shared across disparate fields, from human genetics to research in ecology and evolutionary biology. However, local ancestry inference methods are sensitive to a range of biological and technical parameters which can impact accuracy. Here we present paired simulation and ancestry inference pipelines, mixnmatch and ancestryinfer, to help researchers plan and execute local ancestry inference studies. mixnmatch can simulate arbitrarily complex demographic histories in the parental and hybrid populations, selection on hybrids, and technical variables such as coverage and contamination. ancestryinfer takes as input sequencing reads from simulated or real individuals, and implements an efficient local ancestry inference pipeline. We perform a series of simulations with mixnmatch to pinpoint factors that influence accuracy in local ancestry inference and highlight useful features of the two pipelines. mixnmatch is a powerful tool for simulations of hybridization while ancestryinfer facilitates local ancestry inference on real or simulated data.


Polymorphic Spermatozoa in the Hymenopterous Wasp Dahlbominus.
Studies with the light and electron microscope reveal that at least five different types of spermatozoa are produced during spermatogenesis in the arrhenotokous hymenopteran. Dahlbominus fusciupennis (Zett. Eulophidae). Two of the types differ from the others in length, one type lacks a continuous spiral helix in the head piece, and two differ from the others in the direction of the helical coil. Few of the first three types reach the female sperm-storage organ. All the spermatozoa of the last two types that do reach the storage organ have heads with either dextral or sinistral helices extending from the apex of the head to the beginning of the tail piece. The mitochondrial filaments of the tail are also spirally coiled around the central axial filament, but only in a dextral direction. It is suggested that the coiling dimorphism may be related to fertilization of the egg and may thus affect the sex ratio.


Spirituality and practice. Stories, barriers and opportunities. Interview by Laurence A. Savett.
What are "spiritual matters?" Are "spiritual matters" the same as "religious matters?" What is spiritual inquiry? Are such questions appropriate for those of us in the caring professions, other than clergy, to consider? If we accept that role, how far should we go? When should we call for help? Whom should we call? We convened a gathering of a hospital chaplain, a social worker, a hospice nurse and a physician to discuss many of the dimensions of spirituality and then to apply their personal and professional paradigms of care to a discussion of an actual case. This article is a record of that conversation. It is actually several articles in one, for it deals with their own views of the meaning of spirituality, the degree to which their spirituality has impact on their practice, what they see as the merit of spiritual matters in the caring professions, barriers to collaboration among their professions and to addressing these issues with patients, and boundaries beyond which one should not go. One way to read this conversation is to include yourself; that is, to reflect on the points the participants make and the ways in which you might integrate their insights into your personal practice. We hope that you find this task worthwhile and that it provokes further thought and discussion. The discussion began with participant introductions.


Clinical characteristics and treatment outcome in a Taiwanese population of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.
Epstein-Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities. To define the clinical characteristics as well as the prognostic impact of Epstein-Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein-Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute. Using a cutoff point of positive nuclear staining of Epstein-Barr virus-encoded RNA-1-in situ hybridization in ≥20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein-Barr virus-positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein-Barr virus-positive and -negative diffuse large B-cell lymphoma patients. Univariate analysis showed patients with diffuse large B-cell lymphoma that were either Epstein-Barr virus-positive or had activated B-cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein-Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor. Taken together, we demonstrated that a higher frequency of Epstein-Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein-Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients.


Inequity in organ allocation for patients awaiting liver transplantation: Rationale for uncapping the model for end-stage liver disease.
The goal of organ allocation is to distribute a scarce resource equitably to the sickest patients. In the United States, the Model for End-stage Liver Disease (MELD) is used to allocate livers for transplantation. Patients with greater MELD scores are at greater risk of death on the waitlist and are prioritized for liver transplant (LT). The MELD is capped at 40 however, and patients with calculated MELD scores >40 are not prioritized despite increased mortality. We aimed to evaluate waitlist and post-transplant survival stratified by MELD to determine outcomes in patients with MELD >40. Using United Network for Organ Sharing data, we identified patients listed for LT from February 2002 through to December 2012. Waitlist candidates with MELD ⩾40 were followed for 30days or until the earliest occurrence of death or transplant. Of 65,776 waitlisted patients, 3.3% had MELD ⩾40 at registration, and an additional 7.3% had MELD scores increase to ⩾40 after waitlist registration. A total of 30,369 (46.2%) underwent LT, of which 2,615 (8.6%) had MELD ⩾40 at transplant. Compared to MELD 40, the hazard ratio of death within 30days of registration was 1.4 (95% CI 1.2-1.6) for patients with MELD 41-44, 2.6 (95% CI 2.1-3.1) for MELD 45-49, and 5.0 (95% CI 4.1-6.1) for MELD ⩾50. There was no difference in 1- and 3-year survival for patients transplanted with MELD >40 compared to MELD=40. A survival benefit associated with LT was seen as MELD increased above 40. Patients with MELD >40 have significantly greater waitlist mortality but comparable post-transplant outcomes to patients with MELD=40 and, therefore, should be given priority for LT. Uncapping the MELD will allow more equitable organ distribution aligned with the principle of prioritizing patients most in need. Lay summary: In the United States (US), organs for liver transplantation are allocated by an objective scoring system called the Model for End-stage Liver Disease (MELD), which aims to prioritize the sickest patients for transplant. The greater the MELD score, the greater the mortality without liver transplant. The MELD score, however, is artificially capped at 40 and thus actually disadvantages the sickest patients with end-stage liver disease. Analysis of the data advocates uncapping the MELD score to appropriately prioritize the patients most in need of a liver transplant.


The MeTeOR trial (Meniscal Tear in Osteoarthritis Research): rationale and design features.
This paper presents the rationale and design features of the MeTeOR Trial (Meniscal Tear in Osteoarthritis Research; Clinical Trials.gov NCT00597012). MeTeOR is an NIH-funded seven-center prospective randomized controlled trial (RCT) designed to establish the efficacy of arthroscopic partial meniscectomy combined with a standardized physical therapy program as compared with a standardized physical therapy program alone in patients with a symptomatic meniscal tear in the setting of mild to moderate knee osteoarthritic change (OA). The design and execution of a trial that compares surgery with a nonoperative treatment strategy presents distinctive challenges. The goal of this paper is to provide the clinical rationale for MeTeOR and to highlight salient design features, with particular attention to those that present clinical and methodologic challenges.


Cross-coupling in flow.
Until recently, cross-coupling reactions have been exclusively performed in batch processes. With the advent of microfluidics, significant effort has been devoted to develop a wide variety of continuous-flow techniques to facilitate organic synthesis. In this critical review, we attempt to give an overview of the different continuous-flow methodologies that have been developed and utilized for cross-coupling reactions. In addition, we attempt to point out the advantages of continuous-flow when compared with their batch counterparts (246 references).


Use of national and international growth charts for studying height in European children: development of up-to-date European height-for-age charts.
Growth charts based on data collected in different populations and time periods are key tools to assess children's linear growth. We analyzed the impact of geographic factors and the secular trend on height-for-age charts currently used in European populations, developed up-to-date European growth charts, and studied the effect of using different charts in a sample of growth retarded children. In an international survey we obtained 18 unique national height-for-age charts from 28 European countries and compared them with charts from the World Health Organization (WHO), Euro-Growth reference, and Centers of Disease Control and Prevention (CDC). As an example, we obtained height data from 3,534 children with end-stage renal disease (ESRD) from 13 countries via the ESPN/ERA-EDTA registry, a patient group generally suffering from growth retardation. National growth charts showed a clear secular trend in height (mean height increased on average 0.6 cm/decade) and a North-South height gradient in Europe. For countries without a recent (>1990) national growth chart novel European growth charts were constructed from Northern and Southern European reference populations, reflecting geographic height differences in mean final height of 3.9 cm in boys and 3.8 cm in girls. Mean height SDS of 2- to 17-year-old ESRD patients calculated from recent national or derived European growth charts (-1.91, 95% CI: -1.97 to -1.85) was significantly lower than when using CDC or WHO growth charts (-1.55, 95% CI: -1.61 to -1.49) (P<0.0001). Differences between height-for-age charts may reflect true population differences, but are also strongly affected by the secular trend in height. The choice of reference charts substantially affects the clinical decision whether a child is considered short-for-age. Therefore, we advocate using recent national or European height-for-age charts derived from recent national data when monitoring growth of healthy and diseased European children.


Preparation of γ-Fe2O3@C@MoO3 core/shell nanocomposites as magnetically recyclable catalysts for efficient and selective epoxidation of olefins.
Magnetic γ-Fe2O3@C@MoO3 core-shell structures were fabricated via a general approach and characterized by several techniques such as XRD, XPS, ICP-AES, Raman etc. The catalytic performance of them has been demonstrated in heterogeneously catalyzed oxidation of cyclooctene with tert-butyl hydroperoxide (tBuOOH) as an oxidant, and high conversion (100%) and selectivity (over 99%) were achieved with relatively low catalyst dosage under mild conditions. It should be emphasized that the hybrid catalyst could be easily separated by an external magnet and reused up to 9 times with no significant loss of activity and selectivity. The reaction mechanism over MoO3 is also discussed on the basis of the FTIR and XPS measurements. It is suggested that the high catalytic activity is related to the formation of the transition state, a Mo-alkyl peroxide and olefin complex, which is beneficial for an efficient oxygen atom transfer by converting the intermolecular process directly into an intramolecular process.


Multimeric soluble CD40 ligand and GITR ligand as adjuvants for human immunodeficiency virus DNA vaccines.
For use in humans, human immunodeficiency virus (HIV) DNA vaccines may need to include immunostimulatory adjuvant molecules. CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily (TNFSF), is one candidate adjuvant, but it has been difficult to use because it is normally expressed as a trimeric membrane molecule. Soluble trimeric forms of CD40L have been produced, but in vitro data indicate that multimeric, many-trimer forms of soluble CD40L are more active. This multimerization requirement was evaluated in mice using plasmids that encoded either 1-trimer, 2-trimer, or 4-trimer soluble forms of CD40L. Fusion with the body of Acrp30 was used to produce the 2-trimer form, and fusion with the body of surfactant protein D was used to produce the 4-trimer form. Using plasmids for secreted HIV-1 antigens Gag and Env, soluble CD40L was active as an adjuvant in direct proportion to the valence of the trimers (1 < 2 < 4). These CD40L-augmented DNA vaccines elicited strong CD8(+) T-cell responses but did not elicit significant CD4(+) T-cell or antibody responses. To test the applicability of the multimeric fusion protein approach to other TNFSFs, a 4-trimer construct for the ligand of glucocorticoid-induced TNF family-related receptor (GITR) was also prepared. Multimeric soluble GITR ligand (GITRL) augmented the CD8(+) T-cell, CD4(+) T-cell, and antibody responses to DNA vaccination. In summary, multimeric CD40L and GITRL are new adjuvants for DNA vaccines. Plasmids for expressing multimeric TNFSF fusion proteins permit the rapid testing of TNFSF molecules in vivo.


Wisconsin Card Sorting Test deficits in schizotypic individuals.
The present study investigates executive functioning in schizotypic college students and control subjects using the Wisconsin Card Sorting Test (WCST). Inhibitory control and working memory, two aspects of executive functioning, were examined in deviantly high scorers on the Perceptual Aberration and Magical Ideation Scales (n=97), high scorers on the revised Social Anhedonia Scale (n=58), and in control subjects (n=104). The schizotypic groups displayed significantly more perseverative errors and achieved fewer categories than the control group. The two schizotypic groups did not differ from each other. We identified a subset of schizotypic individuals who also produced clinically deviant WCST profiles. The findings support the hypothesis that executive function deficits may precede the onset of schizophrenia and related illnesses.


Mesodermal anatomies in cnidarian polyps and medusae.
The cellular and developmental analysis of evolutionary-conserved genes directing bilaterian mesodermal and myogenic cell fate previously identified the hydromedusan entocodon and its differentiation product, the striated muscle, as mesodermal derivatives. In view of these findings we presented a hypothesis disputing the diploblast classification of cnidarians without providing further explanations for the apparent diploblasty of the polyp stage and the formation of the subepidermal striated muscle in those Medusozoa lacking the entocodon nodule (Seipel and Schmid, 2005). Hence we carried out a systematic review of the histological and experimental evidence for mesodermal differentiations in cnidarians. In anthozoan and scyphozoan but not in hydrozoan polyps the presumptive mesodermal elements include amoeboid cells, the mesentery retractor muscles and scleroblasts, all of which are embedded or deeply rooted in the extracellular matrix (mesoglea) and derive from the ectoblastemal cells invading the extracellular matrix from the gastrulation site during or shortly after endoderm formation. These data lend further support to the cnidarian mesodermate hypothesis, whereby cnidarians and bilaterians share a common triploblast ancestor, the Urtriploblast, a small, motile, possibly medusa-like organism that did not feature a sessile polyp stage in its life cycle. As a consequence the diploblasty of the hydrozoan polyps may represent a derived morphology resulting from heterochronic modulations of the gastrulation process after endoderm formation.


Motion correction of single-voxel spectroscopy by independent component analysis applied to spectra from nonanesthetized pediatric subjects.
For single-voxel spectroscopy, the acquisition of the spectrum is typically repeated n times and then combined with a factor sqrt[n] in order to improve the signal-to-noise ratio. In practice, the acquisitions are not only affected by random noise but also by physiologic motion and subject movements. Since the influence of physiologic motion such as cardiac and respiratory motion on the data is limited, it can be compensated for without data loss. Individual acquisitions hampered by subject movements, on the other hand, need to be rejected if no correction or compensation is possible. If the individual acquisitions are stored, it is possible to identify and reject the motion-disturbed acquisitions before averaging. Several automatic algorithms were investigated using a dataset of spectra from nonanesthetized infants with a gestational age of 40 weeks. Median filtering removed most subject movement artifacts, but at the cost of increased sensitivity to random noise. Neither independent component analysis nor outlier identification with multiple comparisons has this problem. These two algorithms are novel in this context. The peak height values of the metabolites were increased compared to the mean of all acquisitions for both methods, although primarily for the ICA method.


The Spanish Composer Manuel de Falla and His Eyes: The Musical Brain.
Manuel de Falla was a Spanish musician of the XIXth and XXth centuries who had international recognition likely due to his musical fusion talent. His knowledge about Spanish musical traditions gave to his early compositions a new and fresh intellectual interpretation for the typical Spanish folk music. However, in the middle of his musical career, he suffered a strange disease of his eyes named recurrent acute iridocyclitis. This eye flushing is caused by an inflammation of 2 structures of the anterior pole of the ocular globe, the iris, and the ciliary body. It is usually a symptom of another disease and it causes many psychological impairments and disabilities (severe eye pain in bright light, blurry vision, headache, stress for organization (orderliness), and depression in some cases). This soreness of his eyes had an effect over Falla's compositions and marked an inflection point in his line of musical creations. Eyes in music have been so relevant in another composers and musicians throughout history.


Establishment of two interleukin 6 (B cell stimulatory factor 2/interferon beta 2)-dependent human bone marrow-derived myeloma cell lines.
Two IL-6-dependent human multiple myeloma cell lines, ILKM2 and ILKM3, were established from the bone marrow of patients with IgG-K multiple myeloma. Both cell lines had the typical morphology and immunocytochemical features of myeloma cells. The surface phenotype of both cell lines was PCA-1+, OKT10+, CD10(J-5)-, CD19(B4)-, CD20(B1)-, CD21(B2)-, and OKIa-1-. A monoclonal cytoplasmic Ig, IgG-K or K L chain, was positive in ILKM2 or ILKM3, respectively. EBV nuclear antigen was negative in both cell lines. They proliferated in the presence of macrophages or macrophage-derived factors (MDF). Among the recombinant cytokines examined, IL-6 most strongly augmented the growth of both cell lines. The anti-IL-6 antibody completely inhibited the IL-6-dependent growth and almost completely inhibited the MDF- or purified MDF-dependent growth of both cell lines, ILKM2 and ILKM3 are now being maintained in the culture medium containing 2 ng/ml rIL-6. These results suggest that IL-6 produced by macrophages may play an important role in the growth of myeloma cells in vivo and that macrophages or IL-6 can be used for establishing human myeloma cell lines.


Characterization of monoclonal antibodies to an immunodominant protein of the etiologic agent of human granulocytic ehrlichiosis.
Immunodominant proteins in the range of 42-45 kD are important for the serodiagnosis of human granulocytic ehrlichiosis (HGE). Antigens from human isolates of the etiologic agent of HGE cultivated in HL-60 cells were used to immunize BALB/c mice and generate a panel of hybridomas secreting monoclonal antibodies. Using an enzyme immunoassay, an immunofluorescent assay (IFA), and Western blotting, we showed that culture supernatants and ascites of these hybridomas were reactive with human isolates of the etiologic agent of HGE, Ehrlichia equi and E. phagocytophila. Following screening and subcloning, we selected three stable hybridomas, R1B10, R5E4, and R5A9, which were determined to be of the isotypes IgG3, IgG1, and IgG2a, respectively. These results suggest that the epitopes of the 42-45-kD protein recognized by these three monoclonal antibodies are conserved among E. equi, E. phagocytophila, and the etiologic agent of HGE. Western blot analysis showed reactivity with the 44-kD protein of human isolates of the HGE agent. None of the monoclonal antibodies were reactive with HL-60 cells that were not infected with the HGE agent. No cross-reactivity with related intracellular pathogens could be detected when undiluted supernatants from hybridoma cultures were allowed to react by IFA with antigens from E. chaffeensis, E. risticii, E. platys, Rickettsia rickettsii, R. prowazekii, or Coxiella burnetii. The additivity index of two antibodies, R5E4 and R1B10 was near zero, suggesting that these two antibodies may compete for the same epitope of the 44-kD protein, while monoclonal antibody R5A9 appears to interact with a different epitope. The antibodies secreted by these hybridomas may be useful as immunologic agents in serodiagnostic, immunohistochemical, and other studies of the etiologic agent of HGE.


Graphene-modulated photo-absorption in adsorbed azobenzene monolayers.
The impact of graphene on the photo-absorption properties of trans- and cis-azobenzene monolayers is studied in the framework of density-functional theory and many-body perturbation theory. We find that, despite the weak hybridization between the electronic bands of graphene and those of the azobenzene monolayers, graphene remarkably modulates the absorption spectra of the adsorbates. The excitation energies are affected via two counteracting mechanisms: substrate polarization reduces the band-gap of azobenzene, and enhanced dielectric screening weakens the attractive interaction between electrons and holes. The competition between these two effects gives rise to an overall blueshift of peaks stemming from intramolecular excitations, and a redshift of peaks from intermolecular ones. Even more interesting is that excitations corresponding to intermolecular electron-hole pairs, which are dark in the isolated monolayers, are activated by the graphene substrate. Our results demonstrate that the photoisomerization process of weakly adsorbed azobenzene undergoes notable changes on a carbon-based substrate.


Antitumor effect of sikokianin C, a selective cystathionine β-synthase inhibitor, against human colon cancer in vitro and in vivo.
Cystathionine β-synthase (CBS) overexpression is related to the proliferation and migration of human colon cancers. Targeted therapy that inhibits CBS has achieved promising effects in colon cancer treatments, but no selective inhibitor of CBS is available. In our previous study, a natural biflavonoid compound, sikokianin C, was identified as a potent and selective inhibitor of CBS. However, the mode of action of this compound and its antitumor efficacy in vivo remain unknown. In the present study, we have demonstrated that sikokianin C selectively inhibits CBS activity in a competitive manner, and the five key residues involved in the binding of sikokianin C to the substrate channel of CBS protein were identified via a combination of molecular docking and site-directed mutagenesis. Additionally, we analyzed the antitumor efficacy of sikokianin C against human colon cancer cells in vitro and in vivo. Sikokianin C greatly suppressed the proliferation of HT29 colon cancer cells with an IC50 value of 1.6 μM, and CBS is the target of sikokianin C in mammalian cells, as evidenced by CBS knockdown analyses. Moreover, sikokianin C induced the apoptosis of HT29 cancer cells in a dose dependent manner. Treating mice with sikokianin C dramatically reduced the tumor volume and the weight of the colon cancer xenograft in vivo. These results indicate that the selective CBS inhibitor sikokianin C can potentially be used for the treatment of colon cancer.


Nonlinear dimensionality reduction by locally linear inlaying.
High-dimensional data is involved in many fields of information processing. However, sometimes, the intrinsic structures of these data can be described by a few degrees of freedom. To discover these degrees of freedom or the low-dimensional nonlinear manifold underlying a high-dimensional space, many manifold learning algorithms have been proposed. Here we describe a novel algorithm, locally linear inlaying (LLI), which combines simple geometric intuitions and rigorously established optimality to compute the global embedding of a nonlinear manifold. Using a divide-and-conquer strategy, LLI gains some advantages in itself. First, its time complexity is linear in the number of data points, and hence LLI can be implemented efficiently. Second, LLI overcomes problems caused by the nonuniform sample distribution. Third, unlike existing algorithms such as isometric feature mapping (Isomap), local tangent space alignment (LTSA), and locally linear coordination (LLC), LLI is robust to noise. In addition, to evaluate the embedding results quantitatively, two criteria based on information theory and Kolmogorov complexity theory, respectively, are proposed. Furthermore, we demonstrated the efficiency and effectiveness of our proposal by synthetic and real-world data sets.


Effects of alkaloidal extract of Phyllanthus niruri on HIV replication.
Phyllanthus niruri has been found to exhibit marked inhibitory effect on hepatitis B virus evident by its exhaustive utility in cases of chronic jaundice. However, till date, research has not been focused on identification and validation of active pharmacophores of Phyllanthus niruri responsible for the reported inhibitory effect of its aqueous extract on anti-human immunodeficiency virus. The present investigation examines the anti-HIV effects of the alkaloidal extract of Phyllanthus niruri in human cell lines. The inhibitory effect on HIV replication was monitored in terms of inhibition of virus induced cytopathogenecity in MT-4 cells. The alkaloidal extract of Phyllanthus niruri showed suppressing activity on strains of HIV-1 cells cultured on MT-4 cell lines. The CC50 for the extract was found to be 279.85 microgmL(-1) whereas the EC50 was found to be 20.98 microgmL(-1). Interestingly the Selectivity Index (SI) was found to be 13.34, which showed a clear selective toxicity of the extract for the viral cells. The alkaloidal extract of Phyllanthus niruri was thus found to exhibit sensitive inhibitory response on cytopathic effects induced by both the strains of human immunodeficiency virus on human MT-4 cells in the tested concentrations.


Wikipedia: a key tool for global public health promotion.
The Internet has become an important health information resource for patients and the general public. Wikipedia, a collaboratively written Web-based encyclopedia, has become the dominant online reference work. It is usually among the top results of search engine queries, including when medical information is sought. Since April 2004, editors have formed a group called WikiProject Medicine to coordinate and discuss the English-language Wikipedia's medical content. This paper, written by members of the WikiProject Medicine, discusses the intricacies, strengths, and weaknesses of Wikipedia as a source of health information and compares it with other medical wikis. Medical professionals, their societies, patient groups, and institutions can help improve Wikipedia's health-related entries. Several examples of partnerships already show that there is enthusiasm to strengthen Wikipedia's biomedical content. Given its unique global reach, we believe its possibilities for use as a tool for worldwide health promotion are underestimated. We invite the medical community to join in editing Wikipedia, with the goal of providing people with free access to reliable, understandable, and up-to-date health information.


A critical analysis of the literature on the Internet and consumer health information.
A critical review of the published literature investigating the Internet and consumer health information was undertaken in order to inform further research and policy. A qualitative, narrative method was used, consisting of a three-stage process of identification and collation, thematic coding, and critical analysis. This analysis identified five main themes in the research in this area: (1) the quality of online health information for consumers; (2) consumer use of the Internet for health information; (3) the effect of e-health on the practitioner-patient relationship; (4) virtual communities and online social support and (5) the electronic delivery of information-based interventions. Analysis of these themes revealed more about the concerns of health professionals than about the effect of the Internet on users. Much of the existing work has concentrated on quantifying characteristics of the Internet: for example, measuring the quality of online information, or describing the numbers of users in different health-care settings. There is a lack of qualitative research that explores how citizens are actually using the Internet for health care.


Curcumin relieves TPA-induced Th1 inflammation in K14-VEGF transgenic mice.
Curcumin has been confirmed to have anti-inflammatory properties in addition to the ability to decrease the expression of pro-inflammatory cytokines in keratinocytes. It was suggested that the interleukin-23 (IL-23)/IL-17A cytokine axis played a critical role in the pathogenesis of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate (TPA)-induced K14-VEGF transgenic psoriasis-like mice model. Here, we report that topical use of a curcumin gel formulation inhibited TPA-induced Th1 inflammation in K14-VEGF transgenic mice ears but not Th17 inflammation as expected. Real-time PCR showed that mRNA levels of IL-23, IL-17A, IL-22, IL-6 and TNFα cytokines failed to increase after TPA-induction in K14-VEGF transgenic mice ear skin; but the mRNA level of IFNγ increased significantly at the same time. Furthermore, TPA-induction up-regulated the TCRγδ protein but failed to impact the CCR6 protein, which means that the proliferation of γδ T cells is incapable of IL-17A production. We find that curcumin is capable of relieving TPA-induced inflammation by directly down-regulating IFNγ production. In conclusion, curcumin inhibits TPA-induced Th1 inflammation in K14-VEGF transgenic mice which has not been previously described.


Safety and efficacy of early thromboembolism chemoprophylaxis after intracranial hemorrhage from traumatic brain injury.
Patients with traumatic brain injury (TBI) are at risk for development of thromboembolic disease. The use of chemoprophylaxis in this patient group has not fully been characterized. The authors hypothesize that early chemoprophylaxis in patients with TBI is safe and efficacious. In May 2009, a protocol was instituted for patients with TBI where chemoprophylaxis for thromboembolic disease (either 30 mg of Lovenox twice daily or 5000 U of heparin 3 times a day) was initiated 24 hours after an intracranial hemorrhage (ICH) was demonstrated as stable on head CT image. Two cohorts were evaluated: Cohort A included patients from May 2008 through April 2009 who had no routine administration of chemoprophylaxis, and Cohort B included patients from May 2009 through May 2010 after the protocol was instituted. The groups were compared, with the major outcomes being deep venous thrombosis (DVT), pulmonary embolism, and increase in size of ICH. Of the 312 patients with TBI who were seen during the study course, 236 patients met criteria for inclusion in the study: 107 patients in Cohort A and 129 patients in Cohort B. The DVT rate was 6 occurrences (5.61%) in Cohort A and 0 occurrences (0%) in Cohort B, which was a statistically significant difference (p = 0.0080). Pulmonary embolism was found in 4 patients (3.74%) in Cohort A and 1 patient (0.78%) in Cohort B, a difference that did not reach statistical significance (p = 0.18). Three instances (2.8%) in Cohort A and 1 instance (0.7%) in Cohort B of increased ICH occurred after starting anticoagulation for chemoprophylaxis; this was not statistically different (p = 0.33). Use of chemoprophylaxis in TBI 24 hours after stable head CT is safe and decreases the rate of DVT formation.


[Efficacy of Lactated Ringer's versus Normal Saline in Treating Patients with Septic Shock].
Objective To compare the clinical efficacy of lactated Ringer's (LR) and normal saline (NS) in treating patients with septic shock. Methods The clinical data of 198 patients with septic shock who received fluid resuscitation in the Intensive Care Unit of Quzhou People's Hospital from January 2014 to January 2016 were retrospectively analyzed. These patients were divided into NS group (n=100) and LR group (n=98) according to fluids used. The amounts of trial fluid,other liquids,and blood products and the average total fluid volume were recorded. The oxygenation index (PO2/FiO2),mean artery pressure (MAP),central venous pressure (CVP),and B-type natriuretic peptide (BNP) before and after treatment as well as the early goal-directed therapy (EGDT) 8 h (EGDT8),EGDT 24 h recovery rate,EGDT recovery time,28-day mortality rate were compared. Other secondary outcomes including bleeding,allergic reaction,acute kidney injury (AKI),venous blood filtration (RRT) rate,hyperkalemia,and ICU stay were also recorded. The 28-day survival rate was calculated using the Kaplan-Maier method,and the difference in survival rate was compared by log-rank test. Results The two groups showed no significant difference in gender,age,body weight,source of admission to ICU,procalcitonin level,source of sepsis,Acute Physiology and Chronic Health Evaluation Ⅱ score,number of AKI patients,amount of white blood cells,and C-reactive protein level (all P>0.05). The amount of blood products on the first day [(782±357)ml vs.(606±273)ml;t=2.044,P=0.046] and the average total amount of liquid on the first three days [(5470±1078)ml vs.(5092±929) ml;t=2.640,P=0.009] were significantly higher in NS group than in LR group. The amount of trial fluid and the volumes of other fluids were not significantly different (both P>0.05). The PO2/FiO2,MAP,CVP,and BNP levels significantly increased after treatment in both groups (all P<0.05);however,they were not significantly different between LR group and NS group at different time points before and after treatment (all P>0.05). The incidences of hyperlactacidemia (86.0% vs.71.4%,OR:2.457,95%CI:1.202-5.023,P=0.012) and hyperchloremia (25.0% vs.13.2%,OR:2.179,95%CI:1.041-4.562,P=0.036) were significantly higher in NS group than in LR group. These two groups showed no significant difference in EGDT8,24 h recovery rate,EGDT recovery time,28-day mortality rate,AKI,RRT rate,hyperkalemia,and ICU stay (all P>0.05). Kaplan-Meier survival analysis showed that the 28-day survival rate was not significantly different (χ2 log-rank=0.012,P=0.911). Conclusion When liquid resuscitation is applied in patients with septic shock,the use of LR can lower blood transfusion requirement on the first day and total liquid dosage on the first three days (compared with NR), along with lower incidences of hyperlactacidemia and hyperchloremia,although there was no significant difference in the 28-day mortality rate.


Lignin radicals in the plant cell wall probed by Kerr-gated resonance Raman spectroscopy.
Lignin radicals are crucial intermediates for lignin biosynthesis in the cell wall of vascular plants. In this work they were for the first time, to our knowledge, selectively observed in wood cell walls by laser-based Kerr-gated resonance Raman spectroscopy, and the observations were supported by density functional theory prediction of their vibrational properties. For dry wood cells a lignin radical Raman band is observed at 1,570 cm(-1) irrespective of species. For wet beech cells they were generated in situ and observed at 1,606 cm(-1). DFT/B3LYP/6-31+G(d) modeling results support that in beech they are formed from syringyl (S) phenolic moieties and in spruce from guaiacyl (G) phenolic moieties. The observed lignin radical band is predicted as G is approximately 1,597 cm(-1) and S is approximately 1,599 cm(-1), respectively, and is assigned the (Wilson notation) nu(8a) phenyl ring mode. The RR band probes lignin radical properties, e.g., spin density distribution, and these respond to charge polarization or hydrogen bonding to proximate water molecules. These observations can be crucial for an understanding of the factors that control cell wall structure during biosynthesis of vascular plants and demonstrate the unique potential of RR spectroscopy of lignin radicals.


Direct genomic sequencing of bacterial DNA: the pyruvate kinase I gene of Escherichia coli.
The genomic sequencing procedure is applied to the direct sequencing of uncharacterized regions of bacterial DNA by a "multiplex walking" approach. Samples of bulk Escherichia coli DNA are cut with various restriction enzymes, subjected to chemical sequencing degradations, run in a sequencing gel, and transferred to nylon membranes. When a labeled oligomer is hybridized to a membrane, a sequence ladder appears wherever the probe lies near a restriction cut. New probes, based on sequence that lies beyond other restriction sites, are then synthesized, and the membranes are reprobed to reveal new sequence. Repeated cycles of oligomer probe synthesis and subsequent reprobing permit rapid sequence walking along the genome. This oligomer walking technique was used to sequence the pyruvate kinase (EC 22.214.171.124) gene in E. coli without resorting to cloning or to library construction. The sequenced region was amplified by the polymerase chain reaction and subsequently transcribed and translated using both in vivo and in vitro systems, and the resultant gene product characterized to show that the gene encodes the type I isoform of pyruvate kinase.