Mucosal IL-12 is more effective than systemic IL-12 in augmenting IFN-gamma expression and inhibiting allergic lung eosinophilia in murine lungs.
The relative efficacy of mucosal (intratracheal) and systemic (intraperitoneal) delivery of interleukin (IL)-12 was evaluated in a mouse model of allergic lung eosinophilia. Mucosal administration of IL-12 achieved 100- to 600-fold higher bronchoalveolar lavage (BAL) levels of IL-12, but 2- to 10-fold lower serum levels compared to systemic administration. Whereas both mucosal and systemic IL-12 inhibited BAL eosinophil recruitment at high doses (100-1000 ng), only mucosal IL-12 was effective at low doses (1-10 ng). Mucosal, but not systemic, administration of 1000 ng of IL-12 increased interferon (IFN)-gamma expression in BAL cells. In a model of ongoing eosinophilic inflammation, when mucosal or systemic IL-12 doses were initiated prior to peak eosinophilia, further eosinophil recruitment was inhibited. However, when IL-12 treatment was initiated after peak eosinophil recruitment occurred, recovery from eosinophilic inflammation was not facilitated. Our findings are the first to demonstrate that locally administered IL-12 inhibits eosinophil recruitment at 100-fold lower doses than systemic IL-12. The most likely mechanism of this enhanced inhibitory activity is a sustained increase in lung levels of IL-12 that augments IFN-gamma production from BAL cells. We suggest that future studies should evaluate the efficacy of low doses of nebulized IL-12 in inhibiting eosinophilic lung inflammation in asthma.


Temperament, recalled parenting styles, and self-regulation: testing the developmental postulates of self-discrepancy theory.
Self-discrepancy theory (SDT) postulates that self-regulatory systems corresponding to the ideal and ought self-domains emerge from the influences of temperament (e.g., sensitivity to stimuli for positive vs. negative outcomes) and socialization (e.g., parenting behaviors and interpersonal outcome contingencies). This article reports 2 studies testing the developmental postulates of SDT concurrently and retrospectively. Study 1 showed that self-regulation with reference to the ideal vs. the ought domain was differentially associated with recollections of parenting styles of warmth and rejection, respectively. In Study 2, these findings were replicated, and self-regulation with reference to the ideal vs. ought domain was discriminantly associated with questionnaire measures of positive vs. negative temperament. Findings support the developmental postulates of SDT, despite the limitations of retrospective studies.


Dynamics of two-dimensional dipole systems.
Using a combined analytical/molecular dynamics approach, we study the current fluctuation spectra and longitudinal and transverse collective mode dispersions of the classical two-dimensional (point) dipole system (2DDS) characterized by the ϕ{D}(r)=μ{2}/r{3} repulsive interaction potential; μ is the electric dipole strength. The interest in the 2DDS is twofold. First, the quasi-long-range 1/r{3} interaction makes the system a unique classical many-body system, with a remarkable collective mode behavior. Second, the system may be a good model for a closely spaced semiconductor electron-hole bilayer, a system that is in the forefront of current experimental interest. The longitudinal collective excitations, which are of primary interest for the liquid phase, are acoustic at long wavelengths. At higher wave numbers and for sufficiently high coupling strength, we observe the formation of a deep minimum in the dispersion curve preceded by a sharp maximum; this is identical to what has been observed in the dispersion of the zero-temperature bosonic dipole system, which in turn emulates so-called roton-maxon excitation spectrum of the superfluid 4He . The analysis we present gives an insight into the emergence of this apparently universal structure, governed by strong correlations. We study both the liquid and the crystalline solid state. We also observe the excitation of combination frequencies, resembling the roton-roton, roton-maxon, etc. structures in 4He .


Expression of cysLT1 and cysLT2 receptor in chronic hyperplastic eosinophilic sinusitis.
Elevated production of cysteinyl leukotrienes (cysLTs) from sinus tissues and abundant sinus eosinophils are characteristic features of chronic hyperplastic eosinophilic sinusitis (CHS). CysLTs exert their action through G-protein-coupled receptors named cysLTs receptor type I (cysLT1R) and type II (cysLT2R). These expressions of cysLT receptors in the sinus mucosa have yet to be clarified and the relationship between eosinophilia and the expression of these receptors remains obscure. We compared the expressions of cysLT1R and cysLT2R in the sinus mucosa in patients with CHS, non-eosinophilic chronic sinusitis (NECS), and control sinus tissues; and analyzed the correlation between the expression of CysLTRs and the presence of sinus eosinophils by immunohistochemistry and real-time PCR. A significantly higher percentage of eosinophils expressing cysLT2R protein was observed in patients with CHS compared with NECS and controls. In addition, cysLT2R mRNA expression in CHS was significantly higher than in NECS and controls. Furthermore, a positive correlation was observed between cysLT2R mRNA expression and the number of infiltrated eosinophils. In contrast, the cysLT1R mRNA expression did not differ significantly among these groups. The effect of cysLTs on sinus eosinophils may be mediated through the cysLT2R in patients with CHS. These results may suggest the therapeutic benefit of cysLT2R antagonists in CHS.


The Relationship Between Humor Styles and Forgiveness.
Research has shown that a factor in a victim's forgiveness of an offender is the victim's ability to make more positive, or at least less negative, attributions of the offender's behavior and that perspective-taking can be a factor in facilitating that process. Self-enhancing humor has been found to be positively correlated with perspective-taking empathy and aggressive humor found to be negatively correlated with perspective-taking empathy. Therefore it was predicted that self-enhancing humor would be positively correlated with forgiveness and aggressive humor negatively correlated with forgiveness. The Humor Styles Questionnaire, the Absence of Negative and Presence of Positive subscales of the Forgiveness Scale, and the Forgiveness Likelihood Scale were administered to 112 college undergraduates. Self-enhancing humor was significantly and positively correlated with all of the forgiveness measures, aggressive humor and self-defeating humor were significantly and negatively correlated with some of the forgiveness measures and affiliative humor was not significantly correlated with any of the forgiveness measures. The results were interpreted in terms of previous findings for humor styles, perspective-taking empathy, depression, self-esteem and anxiety. Future research involving the extent to which other personality variables, such as perspective-taking empathy, mediate the relationship between self-enhancing humor and forgiveness was suggested.


Endothelial superoxide production is altered in sheep programmed by early gestation dexamethasone exposure.
Animal models have demonstrated that maternal undernutrition or early gestation glucocorticoid exposure induces endothelial dysfunction in the offspring. We sought to determine whether early gestation dexamethasone (DEX) exposure is further associated with increased vascular superoxide anion production. DEX (0.28 mg/kg/day i.v. for 48 h) was administered to pregnant ewes at 27-28 days' gestation (term 145 days). Tissues were harvested from DEX-exposed and control lambs at 125 days' gestation (n = 6 for each group) and 4 months following delivery (n = 9 and 12, respectively). By lucigenin-enhanced chemiluminescence, coronary and mesenteric arteries from DEX-exposed fetuses exhibited diminished basal superoxide production (both p < 0.01). Similarly, DEX-exposed carotid arteries from 4-month-old lambs had decreased superoxide production (p < 0.01) that localized to the endothelium by endothelial cell culture and dihydroethidium fluorescence. In contrast, DEX-exposed coronary arteries from the 4-month-old sheep had increased superoxide production (p < 0.05). Although early gestation DEX exposure did not alter lipid peroxidation, DEX exposure was associated with significantly increased renal and cerebral cortex aconitase activity (consistent with decreased protein oxidation). These changes occurred in the absence of alterations in renal cortex superoxide dismutase activity. We conclude that in a DEX-exposure model of fetal programming, endothelial superoxide production and protein oxidation are decreased in the mesenteric and carotid circulation. This contrasts with the postnatal coronary artery-specific increase in superoxide production.


Multifractal long-range dependence pattern of functional magnetic resonance imaging in the human brain at rest.
Long-range dependence is a prevalent phenomenon in various biological systems that characterizes the long-memory effect of temporal fluctuations. While recent research suggests that functional magnetic resonance imaging signal has fractal property, it remains unknown about the multifractal long-range dependence pattern of resting-state functional magnetic resonance imaging signals. The current study adopted the multifractal detrended fluctuation analysis on highly sampled resting-state functional magnetic resonance imaging scans to investigate long-range dependence profile associated with the whole-brain voxels as specific functional networks. Our findings revealed the long-range dependence's multifractal properties. Moreover, long-term persistent fluctuations are found for all stations with stronger persistency in whole-brain regions. Subsets with large fluctuations contribute more to the multifractal spectrum in the whole brain. Additionally, we found that the preprocessing with band-pass filtering provided significantly higher reliability for estimating long-range dependence. Our validation analysis confirmed that the optimal pipeline of long-range dependence analysis should include band-pass filtering and removal of daily temporal dependence. Furthermore, multifractal long-range dependence characteristics in healthy control and schizophrenia are different significantly. This work has provided an analytical pipeline for the multifractal long-range dependence in the resting-state functional magnetic resonance imaging signal. The findings suggest differential long-memory effects in the intrinsic functional networks, which may offer a neural marker finding for understanding brain function and pathology.


Hemostatic system in early respiratory distress syndrome: reduced fibrinolytic state?
Previous studies suggest that there is a systemic activation of clotting and fibrinolysis in preterm infants with advanced respiratory distress syndrome (RDS). However, there are no data on the hemostatic status in the early stages of the disease; therefore, we studied some of the hemostatic parameters in these patients and made several studies at different times in preterm infants who did or did not develop RDS, using similar protocols. We found normal plasma fibrinogen, protein C, protein S, C4b-binding protein, thrombomodulin, antithrombin III, thrombin-antithrombin III complex, prothrombin fragment 1.2, plasminogen, tissue plasminogen activator, alpha-1 antitrypsin, alpha-2-macroglobulin and protein Z. However, lower D-dimer and higher plasminogen activator inhibitor and von Willebrand factor antigen levels were found within six hours of life in infants who later developed RDS compared to the control group. These findings suggest that disseminated intravascular coagulation is not prominent in the early stages of RDS. Moreover, reduced D-dimer and increased plasminogen activator inhibitor and von Willebrand factor antigen levels are probably related to the abnormalities in the fibrinolytic mechanism due to lung damage in RDS, but further studies are needed to show their pathogenic significance in RDS.


Cystometric analysis of the transplanted bladder.
cystometric evaluation of the bladder after autotransplant and isogeneic transplant in female rats. two groups were constituted: (A) bladder autotransplant with two subgroups: R1 - (control) and R2 - (bladder transplant); (B) isogeneic bladder transplant with three subgroups; T1 - (control); T2-T3, two subgroups observed for 30 and 60 days after transplant, respectively. All animals underwent cystometric evaluation. Afterwards, the bladders were removed for histological study. the transplanted bladders did not show significant changes in filling/storage and emptying/micturition functions after 30 and 60 days of evolution. Upon macroscopical evaluation, there was good revascularization and the tissue was well preserved. Cystometry results: did not show significant differences in the micturition pressure in subgroups T2-T3, but did between subgroups R1-R2, T1-T2, and T1-T3. Significant differences were verified in the micturition interval between T1-T3, T2-T3, but not between R1-R2, T1-T2. There was significant difference in the micturition duration between T1-T3 but not between R1-R2, T1-T2 and T2-T3. No fistula was noted on the suture site nor leakage of urine in the abdominal cavity or signs of necrosis or retraction were observed. transplant of the bladder was shown to be a viable procedure. The results indicate that there was structural and functional regeneration of transplanted bladders, and these results indicate that it is possible that vascular endothelium growth and neurogenesis factors are involved and activated in the process of the preservation or survival of the transplanted organ.


Fairness overrides group bias in children's second-party punishment.
Adults and children show ingroup favoritism in their 3rd-party punishment of cooperative norm violations, suggesting that group loyalty importantly shapes enforcement of cooperation. Ingroup favoritism additionally influences punishment of unfairness in the 2-party ultimatum game, in which people are directly affected by unfair behavior. However, the directionality of this relationship is unclear: In some cases, people are more forgiving of ingroup unfairness, whereas in others they are less forgiving. Here we aim to disambiguate this relationship by studying its origins in development, asking whether ingroup favoritism influences children's offers to others and whether it affects their responses to being treated unfairly. Six- to 10-year-olds played a group-based ultimatum game after being assigned to minimal groups and made proposals to-and responded to offers from-members of their in- and outgroups. We tested children's real bargaining behavior in the absence of deception. Results showed that, regardless of group membership, children's primary concern lay with fairness: Participants regularly offered equal splits and were more likely to reject unfair offers than fair offers. Consistent with past work, older children made more generous proposals than did younger children. Although our group manipulation successfully induced ingroup bias in participants, neither children's proposals nor responses were influenced by group membership. This suggests that second-party punishment of fairness norm violations is unbiased early in development and points to the potentially important role of experience with different groups in shaping later emerging bias in norm enforcement. We discuss implications for theories regarding when and to what extent group bias influences cooperation. (PsycINFO Database Record


Perpetration of violence, violent victimization, and severe mental illness: balancing public health concerns.
This review examined U.S. empirical studies published since 1990 of the perpetration of violence and of violent victimization among persons with severe mental illness and their relative importance as public health concerns. MEDLINE, PsycINFO, and Web of Science were searched for published empirical investigations of recent prevalence or incidence of perpetration or victimization among persons with severe mental illness. Studies of special populations were included if separate rates were reported for persons with and without severe mental illness. The search yielded 31 studies of violence perpetration and ten studies of violent victimization. Few examined perpetration and victimization in the same sample. Prevalence rates varied by sample type and time frame (recall period). Half of the studies of perpetration examined inpatients; of these, about half sampled only committed inpatients, whose rates of perpetration (17%-50%) were higher than those of other samples. Among outpatients, 2% to 13% had perpetrated violence in the past six months to three years, compared with 20% to 34% who had been violently victimized. Studies combining outpatients and inpatients reported that 12% to 22% had perpetrated violence in the past six to 18 months, compared with 35% who had been a victim in the past year. Perpetration of violence and violent victimization are more common among persons with severe mental illness than in the general population. Victimization is a greater public health concern than perpetration. Ironically, the discipline's focus on perpetration among inpatients may contribute to negative stereotypes.


Cardiomyopathy Phenotypes and Outcomes for Children With Left Ventricular Myocardial Noncompaction: Results From the Pediatric Cardiomyopathy Registry.
Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children. According to diagnoses from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups (P = .035). Time to listing for cardiac transplantation significantly differed by phenotype (P < .001), as did time to transplantation (P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval [CI] 0.78-23.3) for HCM, 6.35 (95% CI 1.52-26.6) for DCM, and 5.66 (95% CI 1.04-30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis. LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management.


Self-reported stomach upset in travellers on cruise-based and land-based package holidays.
International travellers are at a risk of infectious diseases not seen in their home country. Stomach upsets are common in travellers, including on cruise ships. This study compares the incidence of stomach upsets on land- and cruise-based holidays. A major British tour operator has administered a Customer Satisfaction Questionnaire (CSQ) to UK resident travellers aged 16 or more on return flights from their holiday abroad over many years. Data extracted from the CSQ was used to measure self-reported stomach upset in returning travellers. From summer 2000 through winter 2008, 6,863,092 questionnaires were completed; 6.6% were from cruise passengers. A higher percentage of land-based holiday-makers (7.2%) reported stomach upset in comparison to 4.8% of cruise passengers (RR = 1.5, p<0.0005). Reported stomach upset on cruises declined over the study period (7.1% in 2000 to 3.1% in 2008, p<0.0005). Over 25% of travellers on land-based holidays to Egypt and the Dominican Republic reported stomach upset. In comparison, the highest proportion of stomach upset in cruise ship travellers were reported following cruises departing from Egypt (14.8%) and Turkey (8.8%). In this large study of self-reported illness both demographic and holiday choice factors were shown to play a part in determining the likelihood of developing stomach upset while abroad. There is a lower cumulative incidence and declining rates of stomach upset in cruise passengers which suggest that the cruise industry has adopted operations (e.g. hygiene standards) that have reduced illness over recent years.


The rise of metal radionuclides in medical imaging: copper-64, zirconium-89 and yttrium-86.
Positron emission tomography, with its high sensitivity and resolution, is growing rapidly as an imaging technology for the diagnosis of many disease states. The success of this modality is reliant on instrumentation and the development of effective and novel targeted probes. Initially, research in this area was focused on what we will define in this article as 'standard' PET isotopes (carbon-11, nitrogen-13, oxygen-15 and fluorine-18), but the short half-lives of these isotopes limit radiopharmaceutical development to those that probe rapid biological processes. To overcome these limitations, there has been a rise in nonstandard isotope probe development in recent years. This review focuses on the biological probes and processes that have been examined, in additiom to the preclinical and clinical findings with nonstandard radiometals: copper-64, zirconium-89, and yttrium-86.


Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC. In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40. The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4+ and CD8+ T cells in the TME, and reduced frequencies of CD4+ regulatory T cells (Tregs) within the T-cell population. Importantly, CD8+ T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8+ T-cell infiltration, increased presence of Tregs, and poorer survival probability. Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC.


Emergence of chronic Lyme arthritis: putting the breaks on CD28 costimulation.
Lyme disease is a debilitating infection that is caused upon a bite of Borrelia burgdorferi (Bb)-infected ticks. One of the most prominent clinical manifestations is the development of chronic Lyme arthritis. Months after Bb infection, approximately 60% of untreated Lyme patients experience intermittent arthritic attacks that may last for years. The use of the CD28(-/-) mouse in Bb infection has helped to shed light into the mechanisms that govern this inflammatory process, which seems to be tightly regulated. In this current review, the effect of immunoregulation, as well as CD28 deficiency in the development of chronic Lyme arthritis is discussed.


[Effects of decreasing sick leave benefits--results of a survey of Social Health Insurance members].
In Germany, a sick employee usually continues to get his wages from his employer for six weeks either in full or reduced. After that period, he only receives "sick benefit payments" (so-called Krankengeld) from the statutory bodies, which, up to 31 December 1996, amounted to 80% of his original gross wage earnings. This has been cut down to 70% of the gross wage earnings effective 1 January 1997. The purpose of this study was to assess the consequences of this general cutdown of sick benefits. A standardised questionnaire was posted to a total of 7,036 female recipients of sick benefit who were members of a South German statutory health insurance body and who resided in various parts of Germany (membership as on 17 December 1996). 2,416 completed questionnaires were returned by 19 February 1997 (= 34.9%). The average daily sick benefit payment dropped from DM 91.95 in December 1996 to DM 82.39 in January 1997, which is equivalent to a sick benefit payment reduction by 10.4 per cent. The average extra cost caused by the illness and not covered by sick benefit amounted to DM 152 per month; one-quarter of the questioned patients were even compelled to pay DM 200 per month extra from their own pocket. Sick benefit recipients must accept a very substantial real monthly income loss. The average income of an employee who is ill for more than 6 weeks is more than a quarter below that of a healthy employee. 78.5% of the questioned persons rated the financial burden and privations caused by the sick benefit cutdown as "extremely heavy" or "considerable". It became evident that the majority of the female patients receiving sick benefit were chronically ill (62.6%). The most frequently reported diseases were diseases of the spine (30.3%) and joints (16.3%), injuries and accidents (14%) and psychiatric illnesses (8.5%). The results of the survey show that the political motive underlying the attempted modification of illness behaviour by means of economic incentives to be healthy, is far removed from reality, for the cutdown of sickness benefit severely affects a group of gainfully employed persons who are in the midst of a deep existential crisis and sorely in need of extensive physical and mental support. From the sociomedical aspect the sick benefit cutdown is highly problematical as far as this group of persons is concerned, since recovery and cure are impeded by measures that lower the status and are experienced as punitive.


The nitrogen cycle in cryoconites: naturally occurring nitrification-denitrification granules on a glacier.
Cryoconites are microbial aggregates commonly found on glacier surfaces where they tend to take spherical, granular forms. While it has been postulated that the microbes in cryoconite granules play an important role in glacier ecosystems, information on their community structure is still limited, and their functions remain unclear. Here, we present evidence for the occurrence of nitrogen cycling in cryoconite granules on a glacier in Central Asia. We detected marker genes for nitrogen fixation, nitrification and denitrification in cryoconite granules by digital polymerase chain reaction (PCR), while digital reverse transcription PCR analysis revealed that only marker genes for nitrification and denitrification were abundantly transcribed. Analysis of isotope ratios also indicated the occurrence of nitrification; nitrate in the meltwater on the glacier surface was of biological origin, while nitrate in the snow was of atmospheric origin. The predominant nitrifiers on this glacier belonged to the order Nitrosomonadales, as suggested by amoA sequences and 16S ribosomal RNA pyrosequencing analysis. Our results suggest that the intense carbon and nitrogen cycles by nitrifiers, denitrifiers and cyanobacteria support abundant and active microbes on the Asian glacier.


Recent Advances in On-Line Methods Based on Extraction for Speciation Analysis of Chromium in Environmental Matrices.
The biological activity of Cr(III) and Cr(VI) species, their chemical behavior, and toxic effects are dissimilar. The speciation analysis of Cr(III) and Cr(VI) in environmental matrices is then of great importance and much research has been devoted to this area. This review presents recent developments in on-line speciation analysis of chromium in such samples. Flow systems have proved to be excellent tools for automation of sample pretreatment, separation/preconcentration of chromium species, and their detection by various instrumental techniques. Analytical strategies used in chromium speciation analysis discussed in this review are divided into categories based on selective extraction/separation of chromium species on solid sorbents and liquid-liquid extraction of chromium species. The most popular strategy is that based on solid-phase extraction. Therefore, this review shows the potential of novel materials designed and used for selective binding of chromium species. The progress in miniaturization of measurement systems is also presented.


Extracting phylogenetic signal from phylogenomic data: Higher-level relationships of the nightbirds (Strisores).
A well-resolved phylogeny would facilitate study of adaptation to nocturnality in the avian superorder Strisores, a group that includes both nocturnal and diurnal lineages. Based on previous estimates, it could be hypothesized that there were multiple independent origins of nocturnality in this group. In order to refine the Strisores phylogeny, we generated genome-scale datasets of 2289-4243 ultraconserved elements for 23 taxa representing all major living lineages in the group. Among the considerations for using genome-scale, molecular sequence data in phylogenomic analyses are issues related to GC content, GC variance and their effects on model selection. In this study, we employed a variety of analytical techniques to empirically investigate those issues in our data, as well as biases and errors resulting from alignment trimming, taxon selection, matrix completeness and evolutionary rate variation among sites and across lineages. Extensive analyses revealed conflict within the data, especially in regard to variation in GC content, that would not have been detected by more cursory study. Our results indicate that readily available models of molecular evolution are insufficient to encapsulate all phenomena present in genome-scale matrices, and that this problem may be at the root of many current issues in phylogenomic analysis. The analytical methods employed in this study are relevant to phylogenomic analysis of any large, heterogeneous matrix. In conclusion, we present a strongly supported estimate of the Strisores tree, and discuss visual adaptations for, and potential evolutionary pathways to, nocturnality in this clade.


Behavioral Characteristics of Adult Zebrafish (Danio rerio) after MS222 Anesthesia for Fin Excision.
The health of laboratory animals is an ethical responsibility of researchers and a critical determinant of experimental outcome. Therefore, all husbandry procedures should be evaluated for their effects on mortality, behavior, and physiology to maximize animal welfare and minimize experimental variability. For adult zebrafish, the excision of a small portion of the caudal fin (that is, 'fin clipping') under MS222 anesthesia is a common procedure to obtain tissue for genotyping. The potential effect of this procedure on behavioral and physiologic assays of feeding, anxiety, and stress has not previously been assessed. Here, we evaluated feeding behavior, anxiety-associated behaviors, and physiologic indicators of stress at multiple time points within 24 h after performing a standard fin-clip procedure under MS222 anesthesia. Within 1 h of the procedure, fin-clipped fish showed a mild increase in anxiety and exhibited reduced feeding; however, these effects were short-lived, and the fish exhibited baseline levels of anxiety and feeding by 6 and 24 h after fin clipping. Together with the zebrafish's ability to regenerate fin tissue and the low mortality associated with fin clipping, our data support the continued practice of this technique under MS222 anesthesia as a routine husbandry procedure that is unlikely to alter experimental outcomes related to feeding, anxiety, or stress.


ENHANCEMENTS OF ANTIBIOTIC ACTIVITY OF COLICINE K AND ALTERATION OF SEROLOGICAL PROPERTIES OF COLICINE K AND ENDOTOXINS.
Hemoglobin, its chains, and myoglobin enhance the antibiotic activity of colicine K. These proteins also interact with colicine K and other O antigens to alter their serological activity. The hemoglobin proteins did not alter the serological activities of three Pneumococcus polysaccharides or T4 bacteriophage DNA antigens but did alter the antigenic activity of fetuin. Interaction of hemoglobin and colicine K resulted in a retardation of colicine K antibiotic moiety as measured by gel filtration but did not affect the gel filtration properties of the lipopolysaccharide moiety.


Sexuality education in North American medical schools: current status and future directions.
Both the general public and individual patients expect healthcare providers to be knowledgeable and approachable regarding sexual health. Despite this expectation there are no universal standards or expectations regarding the sexuality education of medical students. To review the current state of the art in sexuality education for North American medical students and to articulate future directions for improvement. Evaluation of: (i) peer-reviewed literature on sexuality education (focusing on undergraduate medical students); and (ii) recommendations for sexuality education from national and international public health organizations. Current status and future innovations for sexual health education in North American medical schools. Although the importance of sexuality to patients is recognized, there is wide variation in both the quantity and quality of education on this topic in North American medical schools. Many sexual health education programs in medical schools are focused on prevention of unwanted pregnancy and sexually transmitted infection. Educational material on sexual function and dysfunction, female sexuality, abortion, and sexual minority groups is generally scant or absent. A number of novel interventions, many student initiated, have been implemented at various medical schools to improve the student's training in sexual health matters. There is a tremendous opportunity to mold the next generation of healthcare providers to view healthy sexuality as a relevant patient concern. A comprehensive and uniform curriculum on human sexuality at the medical school level may substantially enhance the capacity of tomorrow's physicians to provide optimal care for their patients irrespective of gender, sexual orientation, and individual sexual mores/beliefs.


Increased blood pressure variability in menopause.
Blood pressure variability represents an independent risk factor for cardiovascular diseases. To detect possible blood pressure variability changes from fertile to menopausal status, we enrolled consecutively 219 women: 104 fertile women (46.6 +/- 3.4 years) and 115 menopausal women (53.9 +/- 3.98 years). We evaluated for each patient the body mass index (BMI), 24 h, daytime, night-time systolic and diastolic mean blood pressure values and blood pressure variability data by means of an Ambulatory Blood Pressure Monitoring device. We found a significant higher mean age, body mass index, systolic and diastolic 24 h, day and night-time blood pressure variability in menopausal women when compared to fertile women. Age and BMI were significantly correlated to most blood pressure variability data with the Spearman Rank test. The multivariate logistic regression with dichotomic variables showed that the menopausal status is independently correlated to 24 h systolic (p < 0.0005) and diastolic (p < 0.05) variability, systolic (p < 0.05) and diastolic (p < 0.05) daytime pressure variability and systolic night-time pressure variability (p < 0.05). Furthermore, we found independent correlations between age 24 h systolic (p < 0.05) and night-time diastolic blood pressure variability (p < 0.05), while the BMI was indepententely correlated to BMI 24h diastolic (p < 0.01), daytime systolic (p < 0.01) and diastolic (p < 0.05) blood pressure variability. These data show a significant increase of blood pressure variability in menopausal women when compared to fertile women, even after exclusion of confounding factors, such as aging and BMI. Menopausal status, aging and BMI increase may all, independently, contribute to the enhanced blood pressure variability we found in menopausal women.


Too much or too little: neonatal ocular misalignment frequency can predict later abnormality.
214 orthoptists' infants have been followed for up to 15 years, relating neonatal misalignment (NMs) and first convergence onset to later childhood ocular abnormalities. NMs are shown in a companion paper to reflect the onset of first convergence, but if frequent or absent may predict a higher risk of refractive error and esodeviation. In a prospective postal survey, orthoptist mothers observed their own infants during the first months of life and regularly reported ocular behaviour and alignment, visual development, and any subsequent ocular abnormalities. Later strabismus and refractive error were less common in infants who showed NMs occasionally compared with those who never or frequently did. There was a significant linear trend for fewer ocular abnormalities to be found in children with more frequent NMs (p<0.001). Hypermetropes were later to show first convergence than emmetropes or myopes (p = 0.006) NMs usually reflect an emerging and normally developing vergence system. This study suggests that delayed onset of convergence (and lack of NMs) is associated with later defects, especially hyperopia. Possible causal relations are discussed.


Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation.
Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient-specific, in vitro models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three-dimensional matrigel-based culture to induce formation of cholangioids. RNA sequencing (RNA-seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA-seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three-dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC-derived cholangioids. Congruent with this, PSC-derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin-6, and chemokine (C-C motif) ligand 2. Conditioned media (CM) from PSC-derived iDCs more potently activated hepatic stellate cells compared to control CM. Conclusion: We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease-specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids.


Biological consequences of stress: conflicting findings on the association between job strain and blood pressure.
The primary objective is to verify the relation between job strain and clinic blood pressure in a working population from the Milan municipality (1,909 men, 3,786 women) enrolled from 1992 to 1996. Job strain was investigated through the Karasek model. Clinic blood pressure was evaluated using standard procedures from the MONICA project. The association between the two was calculated controlling for age, education, smoking, body mass index, total and high-density lipoprotein (HDL) cholesterol. Significantly, associations were found for systolic blood pressure in men and for both systolic and diastolic blood pressure in women. However, these results do not reflect biological plausibility. The relationship between job strain and blood pressure is an unfinished business: sample characteristics and measurement methods should be carefully considered.


A randomized controlled trial of plasma real-time PCR and antigenemia assay for monitoring CMV infection after unrelated BMT.
Preemptive therapy is the standard strategy for preventing CMV disease after allogeneic hematopoietic SCT. In this study, unrelated BMT recipients were randomly assigned to a plasma real-time PCR group or an antigenemia group to compare the value of these monitoring tools for CMV reactivation. Ganciclovir (GCV) was started at 5 mg/kg/day when PCR reached 300 copies per ml or when antigenemia reached three positive cells per two slides. A total of 88 patients were randomized into the antigenemia group (n=45) or the PCR group (n=43). A significantly higher number of patients reached the threshold in the antigenemia group than in the PCR group (73.3 vs 44.2%, P=0.0089). However, only three patients (one in the antigenemia group and two in the PCR group) developed early CMV disease. These patients exclusively had colitis and were successfully treated with GCV or foscarnet. The median number of antigenemia-positive cells at the start of GCV was 47 in the PCR group. These findings suggest that antigenemia assay with the current cutoff was too sensitive and led to unnecessary use of GCV. However, the appropriateness of the threshold may be different by the methodology used, and therefore, it is difficult to generalize.


Costimulatory pathways as a basic mechanisms of activating a tolerance signal in T cells.
Immune tolerance is an active response leading to the T cell unresponsiveness in the presence of the graft, which may develop through a couple of mechanisms including costimulation blockade. The CD28/B7 and CD40L/CD40 costimulatory pathways have been described as the critical for T cell activation. When activated T cell upregulate CTLA4, which importance as a negative regulatory costimulatory molecule is highlighted by the recent evidence suggesting that CTLA4 may function as a master switch for peripheral T cell tolerance. The effects of CTLA4 engagement are directed at the inhibition of CD28 signaling. Modulation of proximal TCR signals and down-stream effector pathways of T cell activation result in altered T cell differentiation and downregulation of immune responses. CTLA4 may regulate signal transduction in a rare subset of CD4+CD25 + T cells which leads to differentiation into regulatory cells. CD40L/CD40 interaction provides a bi-directional signal for T and B cell activation. A possible mechanisms of tolerance induction by CD40L/CD40 blockade involve reduction in expression of B7 molecules, effects on bcl-xL gene and APC function modification. The role of the new discovered pathways: ICOS/B7RP-I and PD-I/PD-LI in regulation of T cell response in transplantation is becoming apparent.


Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey.
Data from the Third National Health and Nutrition Examination Survey (1988-1994) were used to examine the relation between obesity and depression. Past-month depression was defined using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, and was measured with the Diagnostic Interview Schedule. Obesity was defined as a body mass index (weight (kg)/height (m)2) of 30 or higher. The authors compared risks of depression in obese and normal-weight (body mass index 18.5-24.9) persons. Obesity was associated with past-month depression in women (odds ratio (OR)=1.82, 95% confidence interval (CI): 1.01, 3.3) but was not significantly associated in men (OR=1.73, 95% CI: 0.56, 5.37). When obesity was stratified by severity, heterogeneity in the association with depression was observed. Class 3 (severe) obesity (body mass index > or =40) was associated with past-month depression in unadjusted analyses (OR=4.98, 95% CI: 2.07, 11.99); the association remained strong after results were controlled for age, education, marital status, physician's health rating, dieting for medical reasons, use of psychiatric medicines, cigarette smoking, and use of alcohol, marijuana, and cocaine. These findings suggest that obesity is associated with depression mainly among persons with severe obesity. Prospective studies will be necessary to clarify the obesity-depression relation but await the identification of potential risk factors for depression in the obese.


Digenic Inheritance of Shortened Repeat Units of the D4Z4 Region and a Loss-of-Function Variant in SMCHD1 in a Family With FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder which is typically transmitted by an autosomal dominant pattern, although reduced penetrance and sporadic cases caused by de novo mutations, are often observed. FSHD may be caused by a contraction of a repetitive element, located on chromosome 4 (4q35). This locus is named D4Z4 and consists of 11 to more than 100 repeated units (RU). The D4Z4 is normally hypermethylated and the genes located on this locus are silenced. In case of FSHD, the D4Z4 region is characterized by 1-10 repeats and results in the region being hypomethylated. However, 5% of FSHD cases do not carry the short allele of D4Z4 region. To date, two forms of FSHD (FSHD1 and FSHD2) are known. FSHD2 is usually observed in patients without the D4Z4 fragment contraction and carrying variants in SMCHD1 (18p11.32) gene. We report the case of a young adult patient who shows severe symptoms of FSHD. Preliminary genetic analysis did not clarify the phenotype, therefore we decided to study the family members by genetic and epigenetic approaches. The analysis of D4Z4 fragment resulted to be 8 RU in the affected proband and in his father; 26 RU in the mother and 25 RU in the maternal uncle. SMCHD1 analysis revealed a heterozygous variation within the exon 41. The variant was detected in the proband, her mother and the uncle. Furthermore, epigenetic analysis of CpG6 methylation regions showed significant hypomethylation in the affected patient (54%) and in the mother (56%), in contrast to the father (88%) and the uncle (81%) carrying higher methylation levels. The analysis of DR1 methylation levels reported hypomethylation for the proband (19%), the mother (11%), and the uncle (16%). The father showed normal DR1 methylation levels (>30%). Given these results, the combined inheritance of SMCHD1 variant and the short fragment might explain the severe FSHD phenotype displayed by the proband. On this subject, SMCHD1 analysis should be promoted in a larger number of patients, even in presence of D4Z4 contractions, to facilitate the genotype-phenotype correlation as well as, to enable a more precise diagnosis and prognosis of the disease.


In silico discovery and virtual screening of multi-target inhibitors for proteins in Mycobacterium tuberculosis.
Mycobacterium tuberculosis (MTB) is the principal pathogen which causes tuberculosis (TB), a disease that remains as one of the most alarming health problems worldwide. An active area for the search of new anti-TB therapies is concerned with the use of computational approaches based on Chemoinformatics and/or Bioinformatics toward the discovery of new and potent anti-TB agents. These approaches consider only small series of structurally related compounds and the studies are generally realized for only one target like a protein. This fact constitutes an important limitation. The present work is an effort to overcome this problem. We introduce here the first chemo-bioinformatic approach by developing a multi-target (mt) QSAR discriminant model, for the in silico design and virtual screening of anti-TB agents against six proteins in MTB. The mt-QSAR model was developed by employing a large and heterogeneous database of compounds and substructural descriptors. The model correctly classified more than 90% of active and inactive compounds in both, training and prediction series. Some fragments were extracted from the molecules and their contributions to anti-TB activity through inhibition of the six proteins, were calculated. Several fragments were identified as responsible for anti-TB activity and new molecular entities were designed from those fragments with positive contributions, being suggested as possible anti-TB agents.


Hypoxia-Responsive Golgi-Targeted Prodrug Assembled with Anthracycline for Improved Antitumor and Antimetastasis Efficacy.
Tumor metastasis is an intricate multistep process regulated via various proteins and enzymes modified and secreted by swollen Golgi apparatus in tumor cells. Thus, Golgi complex is considered as an important target for the remedy of metastasis. Currently, Golgi targeting technologies are mostly employed in Golgi-specific fluorescent probes for diagnosis, but their applications in therapy are rarely reported. Herein, we proposed a prodrug (INR) that can target and destroy the Golgi apparatus, which consisted of indomethacin (IMC) as the Golgi targeting moiety and retinoic acid (RA), a Golgi disrupting agent. The linker between IMC and RA was designed as a hypoxia-responsive nitroaromatic structure, which ensured the release of the prototype drugs in the hypoxic tumor microenvironment. Furthermore, INR could be assembled with pirarubicin (THP), an anthracycline, to form a carrier-free nanoparticle (NP) by emulsion-solvent evaporation method. A small amount of mPEG2000-DSPE was added to shield the positive charges and improve the stability of the nanoparticle to obtain PEG-modified nanoparticle (PNP). It was proved that INR released the prototype drugs in tumor cells and hypoxia promoted the release. The Golgi destructive effect of RA in INR was amplified owing to the Golgi targeting ability of IMC, and IMC also inhibited the protumor COX-2/PGE2 signaling. Finally, PNP exhibited excellent curative efficacy on 4T1 primary tumor and its pulmonary and hepatic metastasis. The small molecular therapeutic prodrug targeting Golgi apparatus could be adapted to multifarious drug delivery systems and disease models, which expanded the application of Golgi targeting tactics in disease treatment.


Transapical mitral valved stent implantation.
Transcatheter aortic and pulmonary valve replacement is currently being tested in human trials. Efforts to create a valved stent to replace the atrioventricular valves have shown limited success. This is due to their their complex anatomy and function. A self-expanding valved stent was created for transapical replacement of the atrioventricular valve. Ten pigs underwent transapical off-pump mitral valved stent implantation. Data were gathered to assess the animals' hemodynamic stability for 60 minutes after implantation. The valved stent function was assessed by transesophageal echocardiography (TEE) and contrast left ventriculogram. All animals exhibited normal hemodynamics immediately after mitral valved stent implantation and maintained stability for the entire period of monitoring. Accurate positioning of the valved stent was established in all animals. Mild paravalvular regurgitation was found in three out of ten animals by TEE and in two animals during left ventriculogram. No left ventricular outflow tract obstruction was encountered. Transapical off-pump mitral valved stent implantation is feasible in an acute experimental setting. Long-term function of the new valved stent remains to be established.


Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling.
Recent studies indicate that insulin resistance and type 2 diabetes result from the accumulation of lipids in tissues not suited for fat storage, such as skeletal muscle and the liver. To elucidate the mechanisms linking exogenous fats to the inhibition of insulin action, we evaluated the effects of free fatty acids (FFAs) on insulin signal transduction in cultured C2C12 myotubes. As we described previously (Chavez, J. A., and Summers, S. A. (2003) Arch. Biochem. Biophys. 419, 101-109), long-chain saturated FFAs inhibited insulin stimulation of Akt/protein kinase B, a central regulator of glucose uptake and anabolic metabolism. Moreover, these FFAs stimulated the de novo synthesis of ceramide and sphingosine, two sphingolipids shown previously to inhibit insulin action. To determine the contribution of either sphingolipid in FFA-dependent inhibition of insulin action, we generated C2C12 myotubes that constitutively overexpress acid ceramidase (AC), an enzyme that catalyzes the lysosomal conversion of ceramide to sphingosine. AC overexpression negated the inhibitory effects of saturated FFAs on insulin signaling while blocking their stimulation of ceramide accumulation. By contrast, AC overexpression stimulated the accrual of sphingosine. These results support a role for aberrant accumulation of ceramide, but not sphingosine, in the inhibition of muscle insulin sensitivity by exogenous FFAs.


Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane.
Nucleotide prodrugs (ProTides) based on phosphate or phosphonate compounds are potent and successfully marketed antiviral drugs. Although their biological properties are well explored, experimental evidence on the mechanism of their activation pathway is still missing. In this study, we synthesized two ProTide analogues, which can be activated by UV light. Using 31P and 13C NMR spectroscopy with in situ irradiation, we followed the ProTide activation pathway in various solvents, and we detected the first proposed intermediate and the monoamidate product. Furthermore, we used mass spectrometry (MS) coupled with infrared spectroscopy in the gas phase to detect and to characterize the elusive cyclic pentavalent phosphorane and cyclic acyl phosphoramidate intermediates. Our combined NMR and MS data provided the first experimental evidence of the cyclic intermediates in the activation pathway of ProTide prodrugs.


An audit of the time to initial treatment in avulsion injuries.
The prognosis of avulsed teeth depends on prompt and appropriate treatment. Good outcome requires education of the general public and non-dental professionals. Retrospective observational survey of case records of avulsion injuries attending a dental hospital trauma clinic. Data collected included: hospital number, date of birth, gender, source of patient's referral, date of trauma, number of avulsed teeth, place of initial presentation, storage, hours till initial presentation, and initial treatment. One hundred and twenty teeth with avulsion were identified in 75 children. The mean age of the patients was 9.8 years (SD = 2.3 years) at the time of trauma with avulsions recorded in 44 (58.7%) boys and in 31 (41.3%) girls. Only 51 (42.5%) teeth were stored in an appropriate medium before attendance at any site and only 48 (40%) of the teeth were seen within 1 h. 83.3% received emergency treatment at general hospital, 89.7% in dental practice and 92.9% at dental hospital. A minority of avulsion injuries were seen within the first hour and a minority were in appropriate storage medium at presentation. Geographical location plays a huge role in the time taken to reach secondary care. However, improving public and non-dental professional knowledge about tooth storage in avulsion injuries is critical to long-term prognosis of the teeth.


The gill chamber epibiosis of deep-sea shrimp Rimicaris exoculata: an in-depth metagenomic investigation and discovery of Zetaproteobacteria.
The gill chamber of deep-sea hydrothermal vent shrimp Rimicaris exoculata hosts a dense community of epibiotic bacteria dominated by filamentous Epsilonproteobacteria and Gammaproteobacteria. Using metagenomics on shrimp from the Rainbow hydrothermal vent field, we showed that both epibiont groups have the potential to grow autotrophically and oxidize reduced sulfur compounds or hydrogen with oxygen or nitrate. For carbon fixation, the Epsilonproteobacteria use the reductive tricarboxylic acid cycle, whereas the Gammaproteobacteria use the Calvin-Benson-Bassham cycle. Only the epsilonproteobacterial epibionts had the genes necessary for producing ammonium. This ability likely minimizes direct competition between epibionts and also broadens the spectrum of environmental conditions that the shrimp may successfully inhabit. We identified genes likely to be involved in shrimp-epibiont interactions, as well as genes for nutritional and detoxification processes that might benefit the host. Shrimp epibionts at Rainbow are often coated with iron oxyhydroxides, whose origin is intensely debated. We identified 16S rRNA sequences and functional genes affiliated with iron-oxidizing Zetaproteobacteria, which indicates that biological iron oxidation might play a role in forming these deposits. Fluorescence in situ hybridizations confirmed the presence of active Zetaproteobacteria in the R. exoculata gill chamber, thus providing the first evidence for a Zetaproteobacteria-invertebrate association.


Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion.
Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. Immunofluorescence studies revealed that at 30 microM levels estramustine blocked type IV collagenase secretion by partial disruption of the MAP-1A microtubule networks. Immunoprecipitation studies with polyclonal antibodies provided quantitative evidence that 30-60 microM estramustine blocked secretion of a 105 x 10(3) Mr type IV collagenase. Pulse-labeling experiments confirmed that the effect was not a result of inhibition of either protein synthesis or altered rates of type IV collagenase turnover. Finally, drug uptake studies with [3H]estramustine, scintillation counting and fluorography demonstrated that the principal target of the drug was MAP-1A. For the first time we have shown that the drug blocks secretion by binding MAP-1A and causing incomplete disruption of the microtubule networks.


Vaccination with SesC decreases Staphylococcus epidermidis biofilm formation.
The increased use of medical implants has resulted in a concomitant rise in device-related infections. The majority of these infections are caused by Staphylococcus epidermidis biofilms. Immunoprophylaxis and immunotherapy targeting in vivo-expressed, biofilm-associated, bacterial cell surface-exposed proteins are promising new approaches to prevent and treat biofilm-related infections, respectively. Using an in silico procedure, we identified 64 proteins that are predicted to be S. epidermidis surface exposed (Ses), of which 36 were annotated as (conserved) hypothetical. Of these 36 proteins, 5 proteins-3 LPXTG motif-containing proteins (SesL, SesB, and SesC) and 2 of the largest ABC transporters (SesK and SesM)-were selected for evaluation as vaccine candidates. This choice was based on protein size, number of antigenic determinants, or the established role in S. epidermidis biofilm formation of the protein family to which the candidate protein belongs. Anti-SesC antibodies exhibited the greatest inhibitory effect on S. epidermidis biofilm formation in vitro and on colonization and infection in a mouse jugular vein catheter infection model that includes biofilms and organ infections. Active vaccination with a recombinant truncated SesC inhibited S. epidermidis biofilm formation in a rat model of subcutaneous foreign body infection. Antibodies to SesC were shown to be opsonic by an in vitro opsonophagocytosis assay. We conclude that SesC is a promising target for antibody mediated strategies against S. epidermidis biofilm formation.


[Forecasting of severity of functional disorders in patients of advanced age with a cardiovascular pathology].
The cardiovascular system of a person functions in close interrelation with all structures of an organism, providing their metabolic requirements, homeostatic mechanisms. In majority of elderly patients with cardiovascular diseases the accelerated ageing can be observed. The highest biological age, a functional class of a circulatory insufficiency is registered in patients with a cardiologic pathology complex. The analysis of correlation interrelations of functional parameters with an estimation of total, force and an orientation of connections enablesto understand mechanisms of indemnification, fastness and intensity of functioning of a system of circulation. The established limits of homeostatic fluctuations of parameters of a circulatory system of growing old patients integrated to it with cardiovascular diseases serve as a reference point for forecasting risk of advance of their functional heart failure, restrictions of vital activity.


Purification and Transcriptomic Analysis of Mouse Fetal Leydig Cells Reveals Candidate Genes for Specification of Gonadal Steroidogenic Cells.
Male sex determination hinges on the development of testes in the embryo, beginning with the differentiation of Sertoli cells under the influence of the Y-linked gene SRY. Sertoli cells then orchestrate fetal testis formation including the specification of fetal Leydig cells (FLCs) that produce steroid hormones to direct virilization of the XY embryo. As the majority of XY disorders of sex development (DSDs) remain unexplained at the molecular genetic level, we reasoned that genes involved in FLC development might represent an unappreciated source of candidate XY DSD genes. To identify these genes, and to gain a more detailed understanding of the regulatory networks underpinning the specification and differentiation of the FLC population, we developed methods for isolating fetal Sertoli, Leydig, and interstitial cell-enriched subpopulations using an Sf1-eGFP transgenic mouse line. RNA sequencing followed by rigorous bioinformatic filtering identified 84 genes upregulated in FLCs, 704 genes upregulated in nonsteroidogenic interstitial cells, and 1217 genes upregulated in the Sertoli cells at 12.5 days postcoitum. The analysis revealed a trend for expression of components of neuroactive ligand interactions in FLCs and Sertoli cells and identified factors potentially involved in signaling between the Sertoli cells, FLCs, and interstitial cells. We identified 61 genes that were not known previously to be involved in specification or differentiation of FLCs. This dataset provides a platform for exploring the biology of FLCs and understanding the role of these cells in testicular development. In addition, it provides a basis for targeted studies designed to identify causes of idiopathic XY DSD.


Sucrose: metabolite and signaling molecule.
Sucrose is a molecule that is synthesized only by oxygenic photosynthetic organisms. In plants, sucrose is synthesized in source tissues and then can be transported to sink tissues, where it is utilized or stored. Interestingly, sucrose is both a metabolite and a signaling molecule. Manipulating the rate of the synthesis, transport or degradation of sucrose affects plant growth, development and physiology. Altered sucrose levels changes the quantity of sucrose derived metabolites and sucrose-specific signaling. In this paper, these changes are summarized. Better understanding of sucrose metabolism and sucrose sensing systems in plants will lead to opportunities to adapt plant metabolism and growth.


Simultaneous detection of 10-Gbit/s QPSK × 2-ch. Fourier-encoded synchronous OCDM signals with digital coherent receiver.
We experimentally demonstrate the simultaneous detection of 10-Gbit/s quadrature phase shift keying (QPSK) × 2-channel Fourier-encoded synchronous optical code division multiplexing (FE-SOCDM) signals using a digital coherent receiver, for the first time. First, we analytically verify that simultaneous detection can be achieved with an N-point discrete Fourier transform (DFT) using digital signal processing (DSP) because the N-channel Fourier encoding corresponds to an N × N inverse DFT, then the operation is experimentally confirmed. Simultaneous detection of 10-Gbit/s QPSK × 2-channel FE-SOCDM signals is evaluated. The proposed scheme dramatically expands the capability of OCDM systems.


Methods in the evaluation of cardiovascular renin angiotensin aldosterone activation and oxidative stress.
Renin angiotensin aldosterone system (RAAS) activation plays an essential role in the development of cardiovascular disease (CVD). Multiple pathophysiologic processes are able to activate RAAS, among which hypertension, obesity, diabetes mellitus 2, and chronic kidney disease deserve special attention, because they are the main contributors to CVD. Adding to the well-known effects of RAAS overactivity on the vasculature and water and electrolyte balance, current evidence links abnormal activation of the RAAS to increased production of reactive oxygen species (ROS) and oxidative stress. This association is mediated at least partially through interaction of angiotensin II (Ang II) with its receptor angiotensin receptor 1 (AT1R) in cardiovascular tissue, and subsequent activation of the nicotinamide adenine dinucleotide phosphate (NADPH) enzymatic complex, which finally leads to increased ROS production. This resulting state of enhanced oxidative stress contributes largely to generalized atherosclerosis and finally to CVD. The generation of animal models of increased RAAS and Ang II expression, in particular the Ren2 rodent model, provides important opportunities to better characterize the relationship between this system and the production of ROS. This chapter describes methods to evaluate, characterize, and quantify the activity of the RAAS and NADPH oxidase, as well as the production of ROS production in animal model of RAAS.


Diketopyrrolopyrrole-porphyrin conjugates as broadly absorbing sensitizers for dye-sensitized solar cells.
A series of four new push-pull zinc porphyrin-based dyes was synthesised for hybrid photovoltaic solar cells with a view to enhancing the light-harvesting efficiency at approximately 550 nm with a diketopyrrolopyrrole (DPP) unit. The strength of the donor side of the push-pull porphyrin was tuned by affixing the electron-rich 4,4'-dimethoxydiphenylamine group at the meso position of the macrocycle, and the influence of the distance between the semiconductor surface and the porphyrin chromophore was assessed by introducing different π-conjugated spacers. Charge-transfer transitions over great distances were characterised by electronic absorption spectroscopy and DFT calculations. The absorption and photoactivity spectra of the new bichromophoric dyes spans the whole visible spectrum to the red, implying a better light-harvesting efficiency than regular porphyrin as the absorption spectra of DPP and porphyrin complement one another. Photovoltaic conversion efficiencies accordingly increase from 2.40 to 5.19 %. Interestingly, the best overall efficiency was reached with dye 3, which lacks the powerful donating group in the meso position of the porphyrin core. Optical and electrochemical measurements coupled to time dependent (TD)-DFT calculations give insight into the deleterious effect of the 4,4'-dimethoxydiphenylamine unit on the photovoltaic performances, paving the way towards the design of efficient push-pull porphyrin-based sensitizers.


Changes in left ventricular wall motion after coronary artery bypass surgery: signal or noise?
We evaluated changes in ventricular wall motion after surgery by comparing smoothed, filtered measurements of regional percent shortening (RPS) from right anterior oblique ventriculograms in 37 patients before and after surgery. After surgery there was a significant (p less than 0.05) decrease in the number of regions with hypokinetic wall motion. The distribution of RPS values was also different (p less than 0.005). However, the mean value of RPS for the surgery group as a whole was not significantly altered. These data were contrasted with RPS data from 11 control patients, who were each studied twice but did not have surgical intervention. Similar analysis of the control group did not show any significant change between studies in the number of hypokinetic regions, and the distributions of RPS for the first and second angiograms were not different. We found a 10.3% absolute mean change in repeated measurements of RPS in the control group. We conclude that significant changes occurred after surgery that were not evident in the control group, and the amount of variability in repeated measurements of RPS suggests that analysis should be applied to group rather than individual data.


Improving Initiation and Tracking of Research Projects at an Academic Health Center: A Case Study.
Research service cores at academic health centers are important in driving translational advancements. Specifically, biostatistics and research design units provide services and training in data analytics, biostatistics, and study design. However, the increasing demand and complexity of assigning appropriate personnel to time-sensitive projects strains existing resources, potentially decreasing productivity and increasing costs. Improving processes for project initiation, assigning appropriate personnel, and tracking time-sensitive projects can eliminate bottlenecks and utilize resources more efficiently. In this case study, we describe our application of lean six sigma principles to our biostatistics unit to establish a systematic continual process improvement cycle for intake, allocation, and tracking of research design and data analysis projects. The define, measure, analyze, improve, and control methodology was used to guide the process improvement. Our goal was to assess and improve the efficiency and effectiveness of operations by objectively measuring outcomes, automating processes, and reducing bottlenecks. As a result, we developed a web-based dashboard application to capture, track, categorize, streamline, and automate project flow. Our workflow system resulted in improved transparency, efficiency, and workload allocation. Using the dashboard application, we reduced the average study intake time from 18 to 6 days, a 66.7% reduction over 12 months (January to December 2015).


Stenting for obstructing colon cancer: fewer complications and colostomies.
Colonic stenting has been used in the setting of malignant obstruction to avoid an emergent colectomy. We sought to determine whether preoperative placement of a colonic stent decreases morbidity and the rate of colostomy formation. Cases of obstructing sigmoid, rectosigmoid, and rectal cancer from January 1, 2010, to December 31, 2011, were identified in the Nationwide Inpatient Sample (NIS) database. All patients were treated at hospitals in the United States, and the database generated national estimates. Postoperative complications, mortality, and the rate of colostomy formation were analyzed. Of the estimated 7891 patients who presented with obstructing sigmoid, rectosigmoid, or rectal cancer necessitating intervention, 12.1% (n = 956) underwent placement of a colonic stent, and the remainder underwent surgery without stent placement. Of the patients who underwent stenting, 19.9% went on to have colon resection or stoma creation during the same admission. Patients who underwent preoperative colonic stent placement had a lower rate of total postoperative complications (10.5% vs 21.7%; P < .01). There was no significant difference in mortality (4.7% vs 4.2%; P = .69). The rate of colostomy formation was more than 2-fold higher in patients who did not undergo preoperative stenting (42.5% vs 19.5%; P < .01). Preoperative stenting was associated with increased use of laparoscopy (32.6% vs 9.7%; P < .01). Our study characterizes the national incidence of preoperative placement of a colonic stent in the setting of malignant obstruction. Preoperative stent placement is associated with lower postoperative complications and a lower rate of colostomy formation. The results support the hypothesis that stenting as a bridge to surgery may benefit patients by converting an emergent surgery into an elective one.


[Illness-induced early retirement of municipal civil servants].
The present study can't be but an impulse to initiate further investigations on officials' health and it's effects on employment. There are two reasons to do so: 1. The public frequently considers the system of civil servants to be unprofitable--clear facts can only be obtained by precise analysis in comparison with different employees. 2. Up to now, civil servants in Germany have been dealt with as stepchildren of occupational medicine; before including them into regular preventive medical check-ups, it would be efficient to realise relevant requirements.


Continuous passive motion for preventing venous thromboembolism after total knee arthroplasty.
Total knee arthroplasty (TKA) is a common form of orthopaedic surgery. Venous thromboembolism (VTE), which consists of deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major and potentially fatal complication after TKA. The incidence of DVT after TKA is 40% to 80% and the incidence of PE is approximately 2%. It is generally agreed that thromboprophylaxis should be used in patients who undergo TKA. Both pharmacological and mechanical methods are used in the prevention of DVT. Pharmacological methods alter the blood coagulation profile and may increase the risk of bleeding complications. When pharmacological methods cannot be used the mechanical methods become crucial for VTE prophylaxis. Continuous passive motion (CPM) is provided through an external motorised device which enables a joint to move passively throughout a preset arc of motion. Despite the theoretical effectiveness and widespread use of CPM, there are still differing views on the effectiveness of CPM as prophylaxis against thrombosis after TKA. This is an update of the review first published in 2012. The aim of this review was to determine the effectiveness of continuous passive motion (CPM) therapy for preventing venous thromboembolism (VTE) in patients after total knee arthroplasty (TKA). For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched February 2014), CENTRAL (2014, Issue 1), Ovid MEDLINE (to week 1 February 2014) and EMBASE (to Week 07 2014). Randomised controlled trials (RCTs) comparing the use of CPM with control in preventing DVT or PE after TKA. People aged 18 years and older who had undergone TKA were included in this review. We excluded studies of patients who presented with DVT at baseline. The experimental and control groups received similar postoperative care and therapy other than the CPM. Two review authors independently assessed the citations retrieved by the search strategies for reports of relevant RCTs. They independently selected trials that satisfied the inclusion criteria, extracted data and undertook quality assessment. Effects were estimated as risk ratios (RRs), mean differences or standardised mean differences with 95% confidence intervals (CIs). Meta-analyses were performed using a fixed-effect model for continuous variables. Where heterogeneity existed (determined by the I(2) statistic) a random-effects model was used. Eleven RCTs involving 808 participants met the inclusion criteria. The methodological quality of the included studies was variable and most of the predefined outcomes were reported by only one or two studies, therefore the quality of the evidence was low. Five studies with a total of 405 patients reported the incidence of DVT. In the CPM group (205 patients) 36 developed DVT (18%) compared to 29 (15%) in the control group (200 patients). The results of the meta-analysis showed no evidence that CPM had any effect on preventing VTE after TKA (RR 1.22, 95% CI 0.84 to 1.79). One trial (150 participants) did not find PE in any of the patients during hospitalisation or in the subsequent three months. PE was not reported in the other included studies. None of the trials reported deaths among the included participants. There is not enough evidence from the available RCTs to conclude that CPM reduces VTE after TKA. We cannot assess the effect of CPM on mortality because no such events occurred amongst the participants of these trials. The quality of the evidence was low. The results are supported by only a small number of studies, most of which are of low to moderate quality.


Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5.
Since HIV requires CD4 and a co-receptor, most commonly C-C chemokine receptor 5 (CCR5), for cellular entry, targeting CCR5 expression is an attractive approach for therapy of HIV infection. Treatment of CD4(+) T cells with zinc-finger protein nucleases (ZFNs) specifically disrupting chemokine receptor CCR5 coding sequences induces resistance to HIV infection in vitro and in vivo. A chimeric Ad5/F35 adenoviral vector encoding CCR5-ZFNs permitted efficient delivery and transient expression following anti-CD3/anti-CD28 costimulation of T lymphocytes. We present data showing CD3/CD28 costimulation substantially improved transduction efficiency over reported methods for Ad5/F35 transduction of T lymphocytes. Modifications to the laboratory scale process, incorporating clinically compatible reagents and methods, resulted in a robust ex vivo manufacturing process capable of generating >10(10) CCR5 gene-edited CD4+ T cells from healthy and HIV+ donors. CD4+ T-cell phenotype, cytokine production, and repertoire were comparable between ZFN-modified and control cells. Following consultation with regulatory authorities, we conducted in vivo toxicity studies that showed no detectable ZFN-specific toxicity or T-cell transformation. Based on these findings, we initiated a clinical trial testing the safety and feasibility of CCR5 gene-edited CD4+ T-cell transfer in study subjects with HIV-1 infection.


Laminin-5 induces osteogenic gene expression in human mesenchymal stem cells through an ERK-dependent pathway.
The laminin family of proteins is critical for managing a variety of cellular activities including migration, adhesion, and differentiation. In bone, the roles of laminins in controlling osteogenic differentiation of human mesenchymal stem cells (hMSC) are unknown. We report here that laminin-5 is found in bone and expressed by hMSC. hMSC isolated from bone synthesize laminin-5 and adhere to exogenous laminin-5 through alpha3beta1 integrin. Adhesion to laminin-5 activates extracellular signal-related kinase (ERK) within 30 min and leads to phosphorylation of the osteogenic transcription factor Runx2/CBFA-1 within 8 d. Cells plated on laminin-5 for 16 d express increased levels of osteogenic marker genes, and those plated for 21 d deposit a mineralized matrix, indicative of osteogenic differentiation. Addition of the ERK inhibitor PD98059 mitigates these effects. We conclude that contact with laminin-5 is sufficient to activate ERK and to stimulate osteogenic differentiation in hMSC.


Continuity created by nurses in the perioperative dialogue--a literature review.
This literature review analyses eight research reports dealing with perioperative dialogues conducted between patients and nurses. The aim of this study was to summarise studies concerned with the perioperative dialogue as an organisation model for bringing safe operative practices and caring into perioperative nursing, by creating continuity for both patients and nurses in perioperative praxis and its research. How do patients and perioperative nurses experience the perioperative dialogue as a model? Perioperative nursing should be perceived as a caring profession emphasising that the focus is on perioperative caring. The perioperative dialogue has a humanistic and caring perspective and presents an ideal model on which to base perioperative nursing. There is general acceptance of the value of the perioperative dialogue for both patients and nurses as means of alleviating suffering and creating a safety nursing, with continuity in the process provided by nursing staff. This study suggests further research and that a means of measuring caring in the perioperative dialogue should be more developed.


Assembly of a tRNA splicing complex: evidence for concerted excision and joining steps in splicing in vitro.
Splicing of tRNA precursors in Saccharomyces cerevisiae extracts proceeds in two steps; excision of the intervening sequence and ligation of the tRNA halves. The ability to resolve these two steps and the distinct physical properties of the endonuclease and ligase suggested that the splicing steps may not be concerted and that these two enzymes may act independently in vivo. A ligase competition assay was developed to examine whether the excision and ligation steps in tRNA splicing in vitro are concerted or independent. The ability of either yeast ligase or T4 ligase plus kinase to join the tRNA halves produced by endonuclease and the distinct structures of the reaction products provided the basis for the competition assay. In control reactions, joining of isolated tRNA halves formed by preincubation with endonuclease was measured. The ratio of yeast to T4 reaction products in these control assays reflected the ratio of the enzyme activities, as would be expected if each has equal access to the substrate. In splicing competition assays, endonuclease and pre-tRNA were added to ligase mixtures, and joining of the halves that were formed was measured. In these assays the products were predominantly those of the yeast ligase even when the T4 enzymes were present in excess. These results demonstrate preferential access of yeast ligase to the endonuclease products and provide evidence for the assembly of a functional tRNA splicing complex in vitro. This observation has important implications for the organization of the splicing components and of the gene expression pathway in vivo.


Pregnancy outcomes for women with myasthenia gravis and their newborns: A nationwide register-based cohort study.
Few large-scale studies examine whether maternal myasthenia gravis (MG) is a risk factor for complications during pregnancy and childbirth. This study evaluated whether maternal MG is associated with an increased risk of adverse pregnancy, delivery, and neonatal outcomes. We conducted a nationwide Swedish register-based cohort study of women who gave birth to singleton infants (≥22 gestational weeks) during 1987-2019. Exposed women were diagnosed with MG before or during the index pregnancy (N = 443). Unexposed women comprised 4249 women without a diagnosis of MG, matched for age, parity, hospital, and year of childbirth. The risks of adverse pregnancy, delivery, and neonatal outcomes for women with MG were estimated using regression modeling and presented as adjusted odds ratios (aOR). There was no increased risk of pregnancy complications in women with MG. Women with MG had a spontaneous onset of labor less often than women without MG (69.8% vs. 79.5%; aOR 0.59; p < 0.001) as well as higher labor induction rates and elective cesarean section deliveries (16.0% vs. 12.3%, aOR 1.42; p = 0.02 and 12.0% vs. 8.1%, aOR 1.59; p = 0.009). Infants of women with MG were born on average 2 days earlier (p = 0.002); however, these infants did not have a higher risk of having low APGAR, being small for gestational age, or having a congenital malformation. This first nationwide study of pregnancy in women with MG in Sweden demonstrates reassuring results overall, suggesting generally safe pregnancy outcomes for women with MG and their infants.


Cross-day analysis of Multicode Surface Electromyography based Biometrics for Personal Identification.
Recently, surface electromyography (sEMG) has emerged as a novel biometric trait for personal identification, potentially providing a superior spoof-resistant solution over existing traits. The sEMG possesses a unique dual-mode security: they differ between individuals (biometric-mode), and different gestures have different sEMG characteristics (knowledge-mode). To leverage the knowledge-mode facet of the dual-mode security, the previous studies have utilized a multicode framework involving the fusion of codes (gestures), however, the analysis involved data recorded on a single day and from a small subject-pool. In this study, wrist EMG data collected from 43 participants over three different days while performing static hand/wrist gestures was utilized in two cross-day analyses, where the training and testing data were from different days. Three levels of fusion, score, rank, and decision were investigated to determine the optimal fusion scheme. The results showed that the score-level fusion scheme resulted in a median rank-1 accuracy of 77.9% and rank-5 accuracy of 99.6%, all significantly higher (p<0.001) than the respective single-code gesture. Our results showed that the multicode sEMG biometric framework provides superior identification performance in a more realistic cross-day scenario.


Transcriptome and metabolomics analysis of adaptive mechanism of Chinese mitten crab (Eriocheir sinensis) to aflatoxin B1.
Aflatoxin B1 (AFB1), with the strong toxicity and carcinogenicity, has been reported to great toxicity to the liver and other organs of animals. It cause huge economic losses to breeding industry, including the aquaculture industry. Chinese mitten crabs (Eriocheir sinensis), as one of important species of freshwater aquaculture in China, are deeply disturbed by it. However, the molecular and metabolic mechanisms of hepatopancreas and ovary in crabs underlying coping ability are still unclear. Hence, we conducted targeted injection experiment with or without AFB1, and comprehensively analyzed transcriptome and metabolomics of hepatopancreas and ovary. As a result, 210 and 250 DEGs were identified in the L-C vs. L-30 m and L-C vs. L-60 m comparison, among which 14 common DEGs were related to six major functional categories, including antibacterial and detoxification, ATP energy reaction, redox reaction, nerve reaction, liver injury repair and immune reaction. A total of 228 and 401 DAMs in the ML-C vs. ML-30 m and ML-C vs. ML-60 m comparison both enriched 12 pathways, with clear functions of cutin, suberine and wax biosynthesis, tyrosine metabolism, purine metabolism, nucleotide metabolism, glycine, serine and threonine metabolism, ABC transporters and tryptophan metabolism. Integrated analysis of metabolomics and transcriptome in hepatopancreas discovered three Co-enriched pathways, including steroid biosynthesis, glycine, serine and threonine metabolism, and sphingolipid metabolism. In summary, the expression levels and functions of related genes and metabolites reveal the regulatory mechanism of Chinese mitten crab (Eriocheir sinensis) adaptability to the Aflatoxin B1, and the findings contribute to a new perspective for understanding Aflatoxin B1 and provide some ideas for dealing with it.


Less invasive management of deep neck infection and descending necrotizing mediastinitis: A single-center retrospective study.
By a 7-year retrospective review, we reported our experience in management of descending necrotizing mediastinitis (DNM) and deep neck infection (DNI). A retrospective design was used to reveal the clinical characteristics of DNI and DNM. The clinical outcome was analyzed to validate less invasive management. We reviewed 82 patients between 2009 and 2016, 12 of which were diagnosed as DNM by clinical and computed tomography findings. A total of 35 patients had relevant systemic conditions, mainly diabetes mellitus (19 patients). Most cases were secondary to oropharyngeal or dental infections. All patients underwent transcervical drainage, and 10 DNM patients were treated with additional closed thoracic drainage simultaneously. Twenty patients accepted more than 1 operation. Seven patients died as a result of sepsis and/or multiple organ failure. The mortality rate in our study was similar to that in other studies. In our opinion, less invasive therapies are useful to most patients. Transcervical drainage alone is optimal management for all DNI cases and some DNM cases. Additional closed thoracic drainage is enough for type I and IIA DNM with pleural effusion or empyema.


Self-Help Plus for refugees and asylum seekers: an individual participant data meta-analysis.
Refugees and asylum seekers are at high risk of mental disorders due to various stressors before, during and after forceful displacement. The WHO Self-Help Plus (SH+) intervention was developed to manage psychological distress and a broad range of mental health symptoms in vulnerable populations. This study aimed to examine the effects and moderators of SH+ compared with Enhanced Care as Usual (ECAU) in reducing depressive symptoms among refugees and asylum seekers. Three randomised trials were identified with 1795 individual participant data (IPD). We performed an IPD meta-analysis to estimate the effects of SH+, primarily on depressive symptoms and second on post-traumatic stress, well-being, self-identified problems and functioning. Effects were also estimated at 5-6 months postrandomisation (midterm). There was no evidence of a difference between SH+ and ECAU+ in reducing depressive symptoms at postintervention. However, SH+ had significantly larger effects among participants who were not employed (β=1.60, 95% CI 0.20 to 3.00) and had lower mental well-being levels (β=0.02, 95% CI 0.001 to 0.05). At midterm, SH+ was significantly more effective than ECAU in improving depressive symptoms (β=-1.13, 95% CI -1.99 to -0.26), self-identified problems (β=-1.56, 95% CI -2.54 to -0.59) and well-being (β=6.22, 95% CI 1.60 to 10.90). Although SH+ did not differ significantly from ECAU in reducing symptoms of depression at postintervention, it did present benefits for particularly vulnerable participants (ie, unemployed and with lower mental well-being levels), and benefits were also evident at midterm follow-up. These results are promising for the use of SH+ in the management of depressive symptoms and improvement of well-being and self-identified problems among refugees and asylum seekers.


Pharmacologic Restraint Use During Mental Health Admissions to Children's Hospitals.
Primary mental health admissions are increasing across US children's hospitals. These patients may experience agitation requiring pharmacologic restraint. This study characterized pharmacologic restraint use in medical inpatient units by primary mental health diagnosis. This retrospective, cross-sectional study used the Pediatric Health Information System database. The study included children aged 5 to 17 years admitted with a primary mental health diagnosis between 2016 and 2021. Rates of pharmacologic restraint use per 1000 patient days were determined for 13 mental health diagnoses and trended over time with Poisson regression. Of 91 898 hospitalizations across 43 hospitals, 3% of admissions and 1.3% of patient days involved pharmacologic restraint. Trends in the rate of pharmacologic restraint use remained stable (95% confidence interval [CI], 0.7-2.1), whereas the incidence increased by 141%. Diagnoses with the highest rates of pharmacologic restraint days per 1000 patient days included autism (79.4; 95% CI, 56.2-112.3), substance-related disorders (45.0; 95% CI, 35.9-56.4), and disruptive disorders (44.8; 95% CI, 25.1-79.8). The restraint rate significantly increased in disruptive disorders (rate ratio [RR], 1.4; 95% CI, 1.1-1.6), bipolar disorders (RR, 2.0; 95% CI, 1.4-3.0), eating disorders (RR, 2.4; 95% CI, 1.5-3.9), and somatic disorders (RR, 4.2; 95% CI, 1.9-9.1). The rate significantly decreased for autism (RR, 0.8; 95% CI, 0.6-1.0) and anxiety disorders (RR, 0.3; 95% CI, 0.2-0.6). Pharmacologic restraint use among children hospitalized with a primary mental health diagnosis increased in incidence and varied by diagnosis. Characterizing restraint rates and trends by diagnosis may help identify at-risk patients and guide targeted interventions to improve pharmacologic restraint utilization.


Social isolation affects the development of obesity and type 2 diabetes in mice.
Social isolation is associated with increased risks of mortality and morbidity. In this study, we show that chronic individual housing accelerated body weight gain and adiposity in KK mice but not C57BL6J mice, and fully developed diabetes in KKA(y) mice. Individually housed KK and KKA(y) mice increased body weight gain over the initial 2 wk without increased daily average food consumption compared with group-housed animals. The individually housed KK and KKA(y) mice then gradually increased food consumption for the next 1 wk. The chronic social isolation-induced obesity (SIO) was associated with hyperleptinemia and lower plasma corticosterone and active ghrelin levels but not hyperinsulinemia. Elevated plasma leptin in the SIO suppressed expression of 5-HT2C receptor in white adipose tissue. The SIO was also associated with decreased expression of beta3-adrenergic receptors in white adipose tissue and hypothalamic leptin receptor, which might be secondary to the enhanced adiposity. Interestingly, social isolation acutely reduced food consumption and body weight gain compared with group-housed obese db/db mice with leptin receptor deficiency. Social isolation-induced hyperglycemia in KKA(y) mice was associated with increased expression of hepatic gluconeogenetic genes independent of insulin. These findings suggest that social isolation promotes obesity due to primary decreased energy expenditure and secondary increased food consumption, which are independent of the disturbed leptin signaling, in KK mice, and develops into insulin-independent diabetes associated with increased expression of hepatic gluconeogenetic genes in KKA(y) mice. Thus, social isolation can be included in the environmental factors that contribute to the development of obesity and type 2 diabetes.


Site-directed C3a receptor antibodies from phage display libraries.
Recent cloning of the human C3a receptor (C3aR) revealed that this receptor belongs to the large family of rhodopsin-type receptors. A unique feature of the C3aR is the large second extracellular loop comprising about 175 amino acid residues. We constructed combinatorial phage Ab libraries expressing single chain Fv Abs from BALB/c mice immunized with the affinity-purified second extracellular loop of the C3aR, fused to glutathione-S-transferase. A panel of anti-C3aR single chain Fv fragments (scFvs) was selected after four rounds of panning using the second extracellular loop of the C3aR, fused to the maltose binding protein as Ag. Sequencing of the clones obtained revealed three different groups of scFvs, the epitopes of which were mapped to two distinct regions within the loop, i.e., positions 185 to 193 and 218 to 226, representing the immunodominant domains of the loop. By flow cyotmetric analyses, the scFvs bound to RBL-2H3 cells transfected with the C3aR, but not to cells transfected with the C5aR or to nontransfected RBL-2H3 cells. In addition, the scFvs bound to the human mast cell line HMC-1. Immunofluorescence studies showed C3aR expression on polymorphonuclear granulocytes and monocytes, but not on lymphocytes. In addition, no C3aR expression was observed on human erythrocytes or platelets. Surprisingly, none of the scFvs alone or in combination inhibited C3a-induced Ca2+ mobilization from RBL-2H3 cells transfected with the C3aR. In addition, C3a did not displace binding of the scFvs to the receptor, strongly suggesting that the N-terminal part of the second extracellular loop is not involved in ligand binding.


Isolated Second and Third Carpometacarpal Joint Injuries: A Report of 2 Cases.
Two high-level male athletes with isolated second and third carpometacarpal (2, 3 CMC) joint injuries presented with mid-dorsal wrist pain, decreased grip strength, and painful wrist motion. Both reported inciting trauma-1 acutely and the other months after the original injury. Both exhibited 2, 3 CMC joint tenderness and positive provocative testing on exam. Advanced imaging confirmed 2, 3 CMC joint injuries. Both patients returned to preinjury level of play 3 months after diagnosis and surgical treatment. 2, 3 CMC joint injuries should be considered when evaluating radial/mid-dorsal wrist pain. Surgical treatments range from pin stabilization to fusion depending on chronicity and associated degenerative joint changes.