Inhibition of ferroptosis underlies EGCG mediated protection against Parkinson's disease in a Drosophila model.
Ferroptosis, a new type of cell death accompanied by iron accumulation and lipid peroxidation, is implicated in the pathology of Parkinson's disease (PD), which is a prevalent neurodegenerative disorder that primarily occurred in the elderly population. Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea with known neuroprotective effects in PD patients. But whether EGCG-mediated neuroprotection against PD involves regulation of ferroptosis has not been elucidated. In this study, we established a PD model using PINK1 mutant Drosophila. Iron accumulation, lipid peroxidation and decreased activity of GPX, were detected in the brains of PD flies. Additionally, phenotypes of PD, including behavioral defects and dopaminergic neurons loss, were ameliorated by ferroptosis inhibitor ferrostatin-1 (Fer-1). Notably, the increased iron level, lipid peroxidation and decreased GPX activity in the brains of PD flies were relieved by EGCG. We found that EGCG exerted neuroprotection mainly by restoring iron homeostasis in the PD flies. EGCG inhibited iron influx by suppressing Malvolio (Mvl) expression and simultaneously promoted the upregulation of ferritin, the intracellular iron storage protein, leading to a reduction in free iron ions. Additionally, EGCG downregulated the expression of Duox and Nox, two NADPH oxidases that produce ROS and increased SOD enzyme activity. Finally, modulation of intracellular iron levels or regulation of oxidative stress by genetic means exerted great influence on PD phenotypes. As such, the results demonstrated that ferroptosis has a role in the established PD model. Altogether, EGCG has therapeutic potentials for treating PD by targeting the ferroptosis pathway, providing new strategies for the prevention and treatment of PD and other neurodegenerative diseases.


A surgical oncology perspective on AIDS.
During the summer of 1981 reports of unusual opportunistic infections among male homosexuals first began to appear in the literature and by December 1983, 3000 cases has been reported to the Center for Disease Control in Atlanta, Georgia. Homosexual and bisexual men comprise 71% of the reported cases, while 17% are known intravenous drug users, and the remaining 12% made up of persons with other risk factors. Approximately 80% of AIDS patients with Kaposi's sarcoma have identifiable gastrointestinal lesions. Specific risk factors for Kaposi's sarcoma in AIDS patients have not been exclusively identified, but it is thought that repeated sexual involvement with multiple partners exposes the victim to the immunosuppressive effect of cytomegalovirus and allogenic sperm, which may in turn impair lymphoid cells. The immunological abnormalities associated with AIDS have included striking changes in T-cell ratios, with more profound changes in the Kaposi-AIDS groups. Increases in IgG, decreased antibody production by B-cells to challenge antigen, decreased B-cell proliferative responses to B-cell mitogens, abnormalities in macrophage function, and increased serum thymosin levels have been found. Various opportunistic infections afflict the patient with AIDS. Antimicrobial therapy, various interferons, interleukin-2, and immunomodulation with thymosin have all been used without much success. The distribution and transmission of AIDS parallels hepatitis B virus infection which is transmitted sexually and parenterally. On the whole the same precautions as for hepatitis B should be taken for AIDS. Health care personnel treating patients with AIDS should also wear masks and eye protection against the splatter of body fluids and secretions.(ABSTRACT TRUNCATED AT 250 WORDS)


Simulating longitudinal data from marginal structural models using the additive hazard model.
Observational longitudinal data on treatments and covariates are increasingly used to investigate treatment effects, but are often subject to time-dependent confounding. Marginal structural models (MSMs), estimated using inverse probability of treatment weighting or the g-formula, are popular for handling this problem. With increasing development of advanced causal inference methods, it is important to be able to assess their performance in different scenarios to guide their application. Simulation studies are a key tool for this, but their use to evaluate causal inference methods has been limited. This paper focuses on the use of simulations for evaluations involving MSMs in studies with a time-to-event outcome. In a simulation, it is important to be able to generate the data in such a way that the correct forms of any models to be fitted to those data are known. However, this is not straightforward in the longitudinal setting because it is natural for data to be generated in a sequential conditional manner, whereas MSMs involve fitting marginal rather than conditional hazard models. We provide general results that enable the form of the correctly specified MSM to be derived based on a conditional data generating procedure, and show how the results can be applied when the conditional hazard model is an Aalen additive hazard or Cox model. Using conditional additive hazard models is advantageous because they imply additive MSMs that can be fitted using standard software. We describe and illustrate a simulation algorithm. Our results will help researchers to effectively evaluate causal inference methods via simulation.


Predictive and explanatory factors of cardiovascular disease in people with adequately controlled type 2 diabetes.
Aims To explore the predictive and explanatory factors on the incidence of cardiovascular disease and the impact of visit-to-visit variability (VVV) of risk factors on incident cardiovascular disease in people with type 2 diabetes with no history of prior cardiovascular disease. Methods We performed a historical cohort study (2008-2011) on 481 people with type 2 diabetes and no history of cardiovascular disease. Cardiovascular risk factors were assessed at baseline and repeatedly during follow-up. The predictive analysis included the variables at enrollment, and explanatory analyses were based on mean of the variables measured repeatedly. VVV of the main variables was measured using the standard deviation and coefficient of variation of the measured variables. Separate multivariate binary logistic models were constructed for each parameter with the incident cardiovascular disease. Results Mean age of the participants was 54.9 years, mean glycated hemoglobin was 56 mmol/mol, and mean blood pressure was 125/78 mmHg. Incident cardiovascular disease developed in 14.3% of the participants. The 2-h post breakfast blood glucose was associated with incident cardiovascular disease (odds ratio 1.44; confidence interval = 1.08-1.90; p = 0.01). For each 1 mmol/l increase in postprandial glucose there was a 44% increase in risk of incident cardiovascular disease. VVV of glycemic indices, blood pressure, lipids, body mass index and creatinine were not associated with occurrence of cardiovascular events. Conclusion In this population of patients with type 2 diabetes and no history of cardiovascular disease in whom other cardiovascular risk factors are within or near to the recommended targets, 2-h post breakfast blood glucose level is associated with incident cardiovascular disease.


Dilation of cortical capillaries is not related to astrocyte calcium signaling.
The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca2+ signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca2+ signaling, but previous work suggests that Ca2+ increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca2+ signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca2+ signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca2+ signaling is substantially reduced. Compared to WT mice at rest, Ca2+ signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca2+ signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca2+ signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca2+ events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca2+ increases in the cerebral cortex.


Evaluation of AgHAP-containing polyurethane foam dressing for wound healing: synthesis, characterization, in vitro and in vivo studies.
Silver-containing dressings have been widely used to control wound infection. In this study, we developed various amounts of silver-hydroxyapatite (AgHAP)-containing polyurethane foams (PUFs) (AgHAP-PUFs), and their biological properties including biocompatibility, antibacterial activities, and in vivo wound healing properties were evaluated in the Sprague-Dawley rat model. From electron microscopy imaging, it was found that AgHAP particles are uniformly dispersed inside PUFs. The release of Ag from PUFs was dependent on both time and concentration, i.e., the amount of released Ag was significantly higher with increasing immersion time and Ag content in the PUFs. From the cytotoxicity test, AgHAP-PUFs exhibited high antibacterial efficacy against four pathogenic bacteria, and they were not cytotoxic against L-929 fibroblast cells. AgHAP-PUF treated groups exhibited scar-free wound healing by promoting re-epithelialization and collagen deposition in the infected excision wound model. Overall, it is evident that AgHAP-PUFs may be considered as a good antibacterial wound dressing for infected wounds due to their good antibacterial activity, biocompatibility, and wound healing rate.


Real life results of direct-acting oral anticoagulants recommended-dose in obese vs normal-weight patients with venous thromboembolism.
There is scarce evidence on the effectiveness and safety of recommended-dose direct acting oral anticoagulants (DOACs) in obese patients with venous thromboembolism (VTE). We used the data in the RIETE registry to compare the rates of VTE recurrences and major bleeding during long-term therapy with DOACs at recommended doses in patients with body mass index ≥30 kg/m2 (obese) vs. those with BMI 18.5-24.9 kg/m2 (normal weight). We performed regression models with competing risks for death. From January 2013 through October 2022, 2885 obese patients and 2676 with normal weight in RIETE received rivaroxaban (n = 3020), apixaban (n = 1754), edoxaban (n = 636) or dabigatran (n = 151). Median age was 63 years and 52 % were female. At baseline, obese patients were more likely to have diabetes (18.6 % vs. 8.4 %), hypertension (51.9 % vs. 31.4 %) or pulmonary embolism (67.7 % vs. 61 %), and less likely to have renal insufficiency (5.3 % vs. 16 %) or anaemia (21.8 % vs. 28 %%). During anticoagulation (median, 147 vs. 101 days), the obese had a similar rate of VTE recurrences (1.71 vs. 2.14 events per 100 patients-years; hazard ratio (HR): 0.81; 95 % CI: 0.49-1.34) or major bleeding (1.45 vs. 1.76 per 100 patients-years; HR: 0.91; 95 % CI: 0.52-1.59) than those with normal weight. These findings persisted after multivariable analysis (recurrent VTE, HR: 0.80; 95 % CI: 0.48-1.32; major bleeding, HR: 1.11; 95 % CI: 0.60-2.07). The use of DOACs at recommended doses in obese patients with VTE was associated with similar rates of VTE recurrences or major bleeding than in patients with normal weight.


HIV And HCV adherence and treatment outcomes among people who inject drugs receiving opioid agonist therapy.
Among people who inject drugs (PWID), 60% have HCV and 50-90% of HIV-infected PWID are co-infected with HCV. Data comparing adherence to direct-acting antiviral (DAA) therapy among HCV mono-infected and HIV/HCV co-infected PWID is limited. The impact of HCV treatment initiation on HIV antiretroviral therapy (ART) adherence is also poorly understood. We assessed DAA adherence in HCV mono-infected and HIV/HCV co-infected PWID and examined changes in ART adherence and HIV outcomes following HCV treatment. Study was conducted in three Medication for Opioid use Disorder (MOUD) programs in Bronx, New York. HCV treatment adherence was measured using electronic blister packs. 2-week DAA adherence rates were compared and controlled for study arm, psychiatric illness and alcohol intoxication within the past 30 days. ART adherence was measured using participant self-report and dichotomized to "excellent" or "other". ART adherence, CD4 count, and HIV viral load were identified six months prior to, during, and six months after HCV treatment. Statistical significance was assessed with mixed-effects regression linear or logistic models. Overall DAA adherence rates among HCV mono-infected and HIV/HCV co-infected PWID were 74% (95% CI=71-78%) and 76% (95%CI=70-83%), respectively (p=.55). There were no significant changes in ART adherence, CD4 counts, or HIV viral loads prior to, during, or after HCV treatment. This is the first study assessing the impact of DAA therapy on ART adherence and HIV treatment outcomes among PWID. It is one of the first to compare DAA adherence among HCV and HIV/HCV co-infected PWID. Our data demonstrate no significant difference in DAA adherence and no significant impact of HCV treatment on ART adherence or HIV outcomes.


[Awareness about medical expenses and certifications of eligibility for limited health insurance payments for chemotherapy among clinicians at the Ehime Cancer Care Network Priority Hospitals (Ehime Cancer Kyoten Hospitals)].
The "Cancer Chemotherapy and its Management" subcommittee at the Ehime Cancer Care Network Priority Hospitals (Ehime Cancer Kyoten Hospitals)with a focus on medical expenses associated with chemotherapy, surveyed awareness among 98 clinicians regarding certifications of eligibility for Limited Health Insurance Payments during cancer treatment. This committee also lists social and clinical problems encountered at the Ehime Cancer Care Network Priority Hospitals. In our survey, 78% of clinicians were consulted about medical expenses associated with chemotherapy and were actively involved in resolving medical expense problems and resulting correspondences. However, only 38% of clinicians could explain the details of the Japanese guideline on the catastrophic cap and the certifications of eligibility for Limited Health Insurance Payments. This knowledge deficit was more pronounced in younger residents. From our analyses of the awareness about medical expenses among clinicians, we recommend the establishment of the following systems for the management of cancer patients. First, establish a reporting system and early consultation on the catastrophic cap and the certifications of eligibility before initiating cancer treatment. Second, education regarding medical expenses should be mandatory for clinicians, especially for young residents. Third, patients with cancer suffering in the interval of the medical expense and the social system should be relieved with new systems.


[Interaction of systems generating spindles and delta waves as a possible mechanism for the development of slow-wave sleep].
Certain correlations between spindling and delta-activity during slow-wave sleep (SWS) development have been studied in experiments on man and animals. Interaction between systems of delta-activity and spindling generation is discussed as a possible mechanism underlying development of SWS. Amplitude-modulated stimulation of non-specific thalamic structures has been shown to influence this interaction and development of sleep processes.


Electronic structures of defects and magnetic impurities in MoS2 monolayers.
We provide a systematic and theoretical study of the electronic properties of a large number of impurities, vacancies, and adatoms in monolayer MoS2, including groups III and IV dopants, as well as magnetic transition metal atoms such as Mn, Fe, Co, V, Nb, and Ta. By using density functional theory over a 5 × 5 atomic cell, we identify the most promising element candidates for p-doping of MoS2. Specifically, we found VB group impurity elements, such as Ta, substituting Mo to achieve negative formation energy values with impurity states all sitting at less than 0.1 eV from the valence band maximum (VBM), making them the optimal p-type dopant candidates. Moreover, our 5 × 5 cell model shows that B, a group III element, can induce impurity states very close to the VBM with a low formation energy around 0.2 eV, which has not been reported previously. Among the magnetic impurities such as Mn, Fe, and Co with 1, 2, and 3 magnetic moments/atom, respectively, Mn has the lowest formation energy, the most localized spin distribution, and the nearest impurity level to the conduction band among those elements. Additionally, impurity levels and Fermi level for the above three elements are closer to the conduction band than the previous work (PCCP 16:8990-8996, 2014) which shows the possibility of n-type doping by Mn, thanks to our 5 × 5 cell model.


Surface-relief grating structures for efficient high bandwidth integrated photodetectors for optical interconnections in silicon VLSI.
Although many researchers have proposed optical solutions to interconnection and communication problems at the chip, board, and backplane levels, the integration of fast photodetectors within a silicon chip package has yet to be accomplished. The development of such devices is crucial to the feasibility of optical interconnection at hierarchical levels below backplane connection. In our photodetector design, the much faster drift photocurrent response for reverse-biased shallow p-n junctions is emphasized over the slower diffusion response by confining a higher percentage of photon absorption to the depletion region of the junction than expected for normal light propagation in the silicon substrate. A surface-relief grating structure diffracts light at the Si-SiO(2) interface to cause propagation at large angles from the surface normal. Since the absorption length for photons in the silicon is measured along the ray path, the average depth beneath the surface at which photons are absorbed to generate carriers for photocurrent is reduced, generating a higher percentage of carriers in the depletion region of the junction where drift effects dominate diffusion effects in carrier transport. The resulting drift photocurrent can be orders of magnitude faster in response than the usual diffusion photocurrent which results if light propagates normal to the silicon surface and absorption of a large number of photons occurs far away from the effects of the electric field present at the diode junction. We report simulation studies that indicate etched gratings of the order of 0.2 microm deep in the silicon surface can diffract an appreciable amount of light away from normal propagation in the silicon.


Stromal marker fibroblast activation protein drives outcome in T1 non-muscle invasive bladder cancer.
Fibroblast activation protein-α (FAP) is a transmembrane peptidase and a surrogate marker for cancer-associated fibroblasts (CAFs). FAP has been linked to worse prognosis and therapy resistance in several cancers. We hypothesised that FAP might have a prognostic 3biomarker potential to stratify patients with high-grade (HG) T1 non-muscle-invasive bladder cancer (NMIBC). We selected 30 patients with HG T1 NMIBC that progressed to ≥T2 disease which were pair-matched based on CUETO progression score variables with 90 patients that did not progress. After revision a final cohort of 86 patients was retained. Slides were stained for FAP, the luminal marker GATA3 and the basal marker CK5. All HG T1 tumour regions of interest (ROIs) within each patient were annotated, analysed and scored using image analysis software. FAP expression in HG T1 ROIs was significantly higher in progressors vs. non-progressors and was prognostic for recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival. FAP expression in HG T1 ROIs remained strongly prognostic for these outcomes in a bivariable model corrected for adequate BCG per FDA definition. Expression of GATA3 and CK5 did not differ between progressors vs. non-progressors, and were not prognostic for these outcomes. FAP might serve as an easily applicable prognostic biomarker to risk-stratify patients with HG T1 NMIBC if these results are prospectively validated in a larger series.


A multisubunit acetyl coenzyme A carboxylase from soybean.
A multisubunit form of acetyl coenzyme A (CoA) carboxylase (ACCase) from soybean (Glycine max) was characterized. The enzyme catalyzes the formation of malonyl CoA from acetyl CoA, a rate-limiting step in fatty acid biosynthesis. The four known components that constitute plastid ACCase are biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and the alpha- and beta-subunits of carboxyltransferase (alpha- and beta-CT). At least three different cDNAs were isolated from germinating soybean seeds that encode BC, two that encode BCCP, and four that encode alpha-CT. Whereas BC, BCCP, and alpha-CT are products of nuclear genes, the DNA that encodes soybean beta-CT is located in chloroplasts. Translation products from cDNAs for BC, BCCP, and alpha-CT were imported into isolated pea (Pisum sativum) chloroplasts and became integrated into ACCase. Edman microsequence analysis of the subunits after import permitted the identification of the amino-terminal sequence of the mature protein after removal of the transit sequences. Antibodies specific for each of the chloroplast ACCase subunits were generated against products from the cDNAs expressed in bacteria. The antibodies permitted components of ACCase to be followed during fractionation of the chloroplast stroma. Even in the presence of 0.5 M KCl, a complex that contained BC plus BCCP emerged from Sephacryl 400 with an apparent molecular mass greater than about 800 kD. A second complex, which contained alpha- and beta-CT, was also recovered from the column, and it had an apparent molecular mass of greater than about 600 kD. By mixing the two complexes together at appropriate ratios, ACCase enzymatic activity was restored. Even higher ACCase activities were recovered by mixing complexes from pea and soybean. The results demonstrate that the active form of ACCase can be reassembled and that it could form a high-molecular-mass complex.


A combination turbidity and supernatant microplate assay to rank-order the supersaturation limits of early drug candidates.
A unique opportunity exists at the drug discovery stage to overcome inherently poor solubility by selecting drug candidates with superior supersaturation propensity. Existing supersaturation assays compare either precipitation-resistant or precipitation-inhibiting excipients, or higher-energy polymorphic forms, but not multiple compounds or multiple concentrations. Furthermore, these assays lack sufficient throughput and compound conservation necessary for implementation in the discovery environment. A microplate-based combination turbidity and supernatant concentration assay was therefore developed to determine the extent to which different compounds remain in solution as a function of applied concentration in biorelevant media over a specific period of time. Dimethyl sulfoxide stock solutions at multiple concentrations of four poorly soluble, weak base compounds (Dipyridamole, Ketoconazole, Albendazole, and Cinnarizine) were diluted with pH 6.5 buffer as well as FaSSIF. All samples were monitored for precipitation by turbidity at 600 nm over 1 h and the final supernatant concentrations were measured. The maximum supersaturation ratio was calculated from the supersaturation limit and the equilibrium solubility in each media. Compounds were rank-ordered by supersaturation ratio: Ketoconazole > Dipyridamole > Cinnarizine ∼ Albendazole. These in vitro results correlated well with oral AUC ratios from published in vivo pH effect studies, thereby confirming the validity of this approach.


Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers.
Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.


When data are not missing at random: implications for measuring health conditions in the Behavioral Risk Factor Surveillance System.
To examine the effect on estimated levels of health conditions produced from large-scale surveys, when either list-wise respondent deletion or standard demographic item-level imputation is employed. To assess the degree to which further bias reduction results from the inclusion of correlated ancillary variables in the item imputation process. Large cross-sectional (US level) household survey. 218 726 US adults (18 years and older) in the 2006 Behavioral Risk Factor Surveillance System Survey. This survey is the largest US telephone survey conducted by the Centers for Disease Control and Prevention. Estimated rates of severe depression among US adults. The use of list-wise respondent deletion and/or demographic imputation results in the underestimation of severe depression among adults in the USA. List-wise deletion produces underestimates of 9% (8.7% vs 9.5%). Demographic imputation produces underestimates of 7% (8.9% vs 9.5%). Both of these differences are significant at the 0.05 level. The use of list-wise deletion and/or demographic-only imputation may produce significant distortion in estimating national levels of certain health conditions.


SIRT2 knockout exacerbates insulin resistance in high fat-fed mice.
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.


Circumcision and HIV infection: assessment of causality.
Whether the observed association between male circumcision and HIV infection is causal or not has not been verified. We did a meta-analysis of published data and applied Hill's criteria for causality on all available evidence to assess presence of a causal association. Analysis was by the random effects method. Summary estimates were calculated for all studies combined and for sub groups stratified by type of study population, study design, and method of ascertaining circumcision status. Thirteen studies were included. Circumcised men had a reduced risk for HIV infection (adjusted RRoverall = 0.42, 95% CI 0.33-0.53; RR(RCT) = 0.43 95% CI 0.32-0.59, RRobservational = 0.39, 95% CI 0.27-0.56). Available evidence satisfies six of Hill's criteria: strength of association, consistency, temporality, coherence, biological plausibility, and experiment. These results provide unequivocal evidence that circumcision plays a causal role in reducing the risk of HIV infection among men.


Does front-loading taxation increase savings? Evidence from Roth 401(k) introductions.
Can governments increase private savings by taxing savings up front instead of in retirement? Roth 401(k) contributions are not tax-deductible in the contribution year, but withdrawals in retirement are untaxed. The more common before-tax 401(k) contribution is tax-deductible in the contribution year, but both principal and investment earnings are taxed upon withdrawal. Using administrative data from eleven companies that added a Roth contribution option to their existing 401(k) plan between 2006 and 2010, we find no evidence that total 401(k) contribution rates differ between employees hired before versus after Roth introduction, which implies that take-home pay declines and the amount of retirement consumption being purchased by 401(k) contributions increases after Roth introduction. We reject several neoclassical explanations for our null finding. Results from a survey experiment suggest two behavioral explanations: (1) employee confusion about and neglect of the tax properties of Roth balances and (2) partition dependence.


Protein-coding repeat polymorphisms strongly shape diverse human phenotypes.
Hundreds of the proteins encoded in human genomes contain domains that vary in size or copy number due to variable numbers of tandem repeats (VNTRs) in protein-coding exons. VNTRs have eluded analysis by the molecular methods-SNP arrays and high-throughput sequencing-used in large-scale human genetic studies to date; thus, the relationships of VNTRs to most human phenotypes are unknown. We developed ways to estimate VNTR lengths from whole-exome sequencing data, identify the SNP haplotypes on which VNTR alleles reside, and use imputation to project these haplotypes into abundant SNP data. We analyzed 118 protein-altering VNTRs in 415,280 UK Biobank participants for association with 791 phenotypes. Analysis revealed some of the strongest associations of common variants with human phenotypes including height, hair morphology, and biomarkers of human health; for example, a VNTR encoding 13-44 copies of a 19-amino-acid repeat in the chondroitin sulfate domain of aggrecan (ACAN) associated with height variation of 3.4 centimeters (s.e. 0.3 cm). Incorporating large-effect VNTRs into analysis also made it possible to map many additional effects at the same loci: for the blood biomarker lipoprotein(a), for example, analysis of the kringle IV-2 VNTR within the LPA gene revealed that 18 coding SNPs and the VNTR in LPA explained 90% of lipoprotein(a) heritability in Europeans, enabling insights about population differences and epidemiological significance of this clinical biomarker. These results point to strong, cryptic effects of highly polymorphic common structural variants that have largely eluded molecular analyses to date.


You are when you eat: on circadian timing and energy balance.
The neuronal mechanisms that establish 24-hour rhythms in feeding and metabolism remain incompletely understood. In this issue of the JCI, Adlanmerini and colleagues explored the relationship between temporal and homeostatic control of energy balance by focusing on mice that lacked the genes encoding the clock repressor elements REV-ERBα and -β, specifically in the tuberal hypothalamus. Notably, the clock transcription cycle mediated intraneuronal response to the adipostatic hormone leptin. These results show that REV-ERBα and -β in the hypothalamus are necessary for maintaining leptin responsiveness and metabolic homeostasis and lay the foundation to explore how transcriptional changes may link energy-sensing cell types with day/night rhythms. Such information may lead to therapeutics that alleviate the adverse effects of chronic shift work.


Loss to follow-up in a longitudinal study on urogenital tract symptoms in Dutch older men.
To describe loss to follow-up (LTFU) in a longitudinal community-based study on urogenital tract dysfunction in older men. A cohort study of men recruited from a Dutch municipality was performed. A baseline study and two follow-up rounds--all with questionnaires and additional measurements--were performed with, on average, 2.1-year intervals. Baseline characteristics were compared between participants and non-participants in the first and in the second follow-up study. The response rates in the first and in the second follow-up were 78.0 and 80.0%, respectively. Various characteristics were found to be related to LTFU (i.e., more than 5% difference in response rate). Lower urinary tract symptoms were related to LTFU in the first and second follow-up. Sexual dysfunction was related to LTFU only in the second follow-up. Adjustment for confounders yielded odds ratios for the primary outcome variables (lower urinary tract symptoms, sexual dysfunction, and health status) that approximated the value of 1. LTFU according to these variables was different in men with and without other chronic illnesses. LTFU seems not to be related to the primary outcome variables in this study. Describing response patterns in longitudinal studies is important, especially in studies involving older participants, as often is the case in urological research.


Laminin Peptide-Immobilized Hydrogels Modulate Valve Endothelial Cell Hemostatic Regulation.
Valve endothelial cells (VEC) have unique phenotypic responses relative to other types of vascular endothelial cells and have highly sensitive hemostatic functions affected by changes in valve tissues. Furthermore, effects of environmental factors on VEC hemostatic function has not been characterized. This work used a poly(ethylene glycol) diacrylate (PEGDA) hydrogel platform to evaluate the effects of substrate stiffness and cell adhesive ligands on VEC phenotype and expression of hemostatic genes. Hydrogels of molecular weights (MWs) 3.4, 8, and 20 kDa were polymerized into platforms of different rigidities and thiol-modified cell adhesive peptides were covalently bound to acrylate groups on the hydrogel surfaces. The peptide RKRLQVQLSIRT (RKR) is a syndecan-1 binding ligand derived from laminin, a trimeric protein and a basement membrane matrix component. Conversely, RGDS is an integrin binding peptide found in many extracellular matrix (ECM) proteins including fibronectin, fibrinogen, and von Willebrand factor (VWF). VECs adhered to and formed a stable monolayer on all RKR-coated hydrogel-MW combinations. RGDS-coated platforms supported VEC adhesion and growth on RGDS-3.4 kDa and RGDS-8 kDa hydrogels. VECs cultured on the softer RKR-8 kDa and RKR-20 kDa hydrogel platforms had significantly higher gene expression for all anti-thrombotic (ADAMTS-13, tissue factor pathway inhibitor, and tissue plasminogen activator) and thrombotic (VWF, tissue factor, and P-selectin) proteins than VECs cultured on RGDS-coated hydrogels and tissue culture polystyrene controls. Stimulated VECs promoted greater platelet adhesion than non-stimulated VECs on their respective culture condition; yet stimulated VECs on RGDS-3.4 kDa gels were not as responsive to stimulation relative to the RKR-gel groups. Thus, the syndecan binding, laminin-derived peptide promoted stable VEC adhesion on the softer hydrogels and maintained VEC phenotype and natural hemostatic function. In conclusion, utilization of non-integrin adhesive peptide sequences derived from basement membrane ECM may recapitulate balanced VEC function and may benefit endothelialization of valve implants.


On the use and computation of likelihood ratios in clinical chemistry.
The clinical relevance of likelihood ratios (L-values) for revising the physician's diagnostic probabilities has been recognized. However, the calculation of L-values, particularly in the case of quantitative or mixed quantitative-binary test results, raises problems that have not yet been addressed. Based on a very general assumption that yields a simple functional form for the likelihood ratio, a method is developed that allows such calculations regardless of the nature and the number of clinical laboratory tests to be interpreted simultaneously. Hence the notion of predictive value (posterior probability) is extended from binary or dichotomized tests to quantitative tests, and from univariate to multivariate clinical laboratory results. The simplicity and flexibility of this approach eliminates difficulties in computation arising from the addition of new data to an existing data base. It is hoped that this method will now allow L-values to be reported along with the original test results in daily laboratory practice.


Value of the future: Discounting in random environments.
We analyze how to value future costs and benefits when they must be discounted relative to the present. We introduce the subject for the nonspecialist and take into account the randomness of the economic evolution by studying the discount function of three widely used processes for the dynamics of interest rates: Ornstein-Uhlenbeck, Feller, and log-normal. Besides obtaining exact expressions for the discount function and simple asymptotic approximations, we show that historical average interest rates overestimate long-run discount rates and that this effect can be large. In other words, long-run discount rates should be substantially less than the average rate observed in the past, otherwise any cost-benefit calculation would be biased in favor of the present and against interventions that may protect the future.


Differential requirements for conserved E2 binding sites in the life cycle of oncogenic human papillomavirus type 31.
Human papillomavirus (HPV) E2 proteins regulate viral replication by binding to sites in the upstream regulatory region (URR) and by complex formation with the E1 origin recognition protein. In the genital HPV types, the distribution and location of four E2 binding sites (BS1 to BS4) which flank a single E1 binding site are highly conserved. We have examined the roles of these four E2 sites in the viral life cycle of HPV type 31 (HPV31) by using recently developed methods for the biosynthesis of papillomaviruses from transfected DNA templates (M. G. Frattini et al., Proc. Natl. Acad. Sci. USA 93:3062-3067, 1996). In transient assays, no single site was found to be necessary for replication, and mutation of the early promoter-proximal site (BS4) led to a fourfold increase in replication. Cotransfection of the HPV31 wild-type (HPV-wt) and mutant genomes with expression vectors revealed that E1 stimulated replication of HPV31-wt as well as the HPV31-BS1, -BS2, and -BS3 mutants. In contrast, increased expression of E2 decreased replication of these genomes. Replication of the HPV31-BS4 mutant genome was not further increased by cotransfection of E1 expression vectors but was stimulated by E2 coexpression. In stably transfected normal human keratinocytes, mutation of either BS1, BS3, or BS4 resulted in integration of viral genomes into host chromosomes. In contrast, mutation of BS2 had no effect on stable maintenance of episomes or copy number. Following growth of stably transfected lines in organotypic raft cultures, the differentiation-dependent induction of late gene expression and amplification of viral DNA of the BS2 mutant was found to be similar to that of HPV31-wt. We were unable to find a role for BS2 in our assays for viral functions. We conclude that at least three of the four E2 binding sites in the URRs of HPVs are essential for the productive viral life cycle. The specific arrangement of E2 binding sites within the URR appears to be more important for viral replication than merely the number of sites.


Improved method to measure urinary alkoxyacetic acids.
To simplify the current preparation of samples, and to improve the specificity and reliability of the conventional analytical methods to measure urinary alkoxyacetic acids. Samples containing alkoxyacetic acids including methoxy, ethoxy, and butoxyacetic acids (MAA, EAA, and BAA) were acidified with HCl and extracted with a mixed solvent of methylene chloride and isopropyl alcohol, then analysed by gas chromatography/mass spectrometry (GC/MS). Optimal results were obtained when pH was 1.05-1.45, the ratio of methylene chloride and isopropyl alcohol was 2:1, and when extraction time was 10 minutes. Over the concentration range 0.3-200 micrograms/ml, MAA, EAA, and BAA could be determined with a pooled coefficient of variation (nine concentrations, six replicate samples) of 5.55%, 6.37%, and 6.41%, respectively. Urine samples were stable for at least 5 months and 3 freeze-thaw cycles at -20 degrees C. The limits of detection of MAA, EAA, and BAA were 0.055, 0.183, and 0.009 microgram/ml, respectively. The matrix effect of urine samples was negligible for MAA and EAA, but were marginally significant for BAA. The average recoveries of alkoxyacetic acids were 99%-101%. In urine samples MAA from 15 exposed workers showed a strong linear correlation (r = 0.999, slope = 1.01) between the new GC/MS method and Sakai's GC method. The simplified non-derivatisation pretreatment of samples coupled with GC/MS can provide a specific, sensitive, simple, safe, and reliable method for the biological monitoring of occupational exposure of ethylene glycol ethers.


Effects of fentanyl on the response of plasma beta-endorphin immunoreactivity to surgery.
Beta-endorphin appears to play a definite role in the biologic response to stress and in the endogenous mechanism of pain perception. Opiates exogenously administered during surgery decrease or even suppress the activation of "stress hormones" such as ACTH and cortisol. In the present study, the authors tried to assess the effects of fentanyl administration on plasma beta-endorphin immunoreactivity PBE(ir) during surgical stress. In one group of nine patients, a standard enflurane-based general anesthetic technique without opiates was used for a staging laparotomy. A second group of ten patients undergoing the same type of surgery received fentanyl (10-20 micrograms/kg) as the primary anesthetic drug. In both groups, multiple blood samples were collected prior to, during, and after surgery, following the same time protocol. PBE(ir), plasma cortisol and, in five patients, plasma ACTH were determined by radioimmunoassay. There was no significant change in PBE(ir) in either group after anesthetic induction. Unlike the enflurane group, the fentanyl group did not demonstrate any significant increase from baseline in PBE(ir) during surgery. There was a significant group difference between enflurane and fentanyl in PBE(ir) levels for both "early" and "late" surgery values, but not for the "awake" values (recovery period) where both groups had elevated PBE(ir) levels. Plasma cortisol and plasma ACTH changes followed a trend similar to those of PBE(ir). The suppression of both cortisol and PBE(ir) responses during surgery after administration of fentanyl provides further evidence for the involvement of the endorphin system in the stress response and for its physiologic association with the hypothalamo pituitary axis.


Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration?
Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the "powerhouse of the cell" turns into the "factory of death" is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction with its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer's Disease and Parkinson's Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.


Lack of serological specificity of recombinant heat shock protein of Leishmania donovani.
In order to identify a specific recombinant antigen of Leishmania donovani with potential use for diagnosis, a cDNA library was constructed in lambda ZAP II expression vector. On screening the cDNA library using pooled sera from Indian patients with kala azar, 20 antibody reactive clones were identified. These were subcloned into pBluescript phagemid by an in vivo excision procedure. The molecular weights of the expressed recombinant proteins varied from 15 to 70 kDa and the cDNA insert sizes varied from 0.5 kb to the largest size of approximately 2.0 kb which was designated as the E2b clone. The nucleotide sequencing revealed that 50% of the clones had sequence homology to the heat shock protein gene of L. donovani. The serological studies conducted with the kala azar positive sera and sera from healthy laboratory workers using the recombinant protein from the E2b clone and having sequence homology to Ldhsp 70, indicated that although all the kala azar sera was positive, 12 of 20 healthy individuals also showed antibodies against the recombinant hsp70, indicating that this antigen is not suitable for serological diagnosis of kala azar.


[Efficacy of bacteriophages in complex treatment of patients with burn wounds].
Results of clinical and laboratory evaluation of the treatment with pyobacteriophage in tablets of the patients with burn wounds are presented. It was shown that phagotherapy provided more rapid cure of pyoseptic complications, temperature normalization, wounds purification and lower lethality Bacteriological analysis of wound secretions revealed that after the treatment staphylococci and streptococci were cultured 2 times rarely, Proteus spp. Were isolated 1.5 times rarely, E. coli was not isolated. The amount of positive haemocultures also diminished. Investigation of immunologic status demonstrated statistically significant normalization of immunity on cell level. Phagocytosis level didn't change while in control group (without bacteriophage use) it became lower. Antibody level enhanced but less extensively than in control group. The results of trial demonstrates positive effect of phagotherapy use at the patients with burns.


Temperature-triggered shape-transformations in layer-by-layer microtubes.
One-dimensional layer-by-layer (LbL) nano- and microtubes have been extensively studied for energy and biomedical applications. Here, we report a temperature-triggered transformation in shape for LbL microtubes consisting of poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA). PAH/PAA microtubes were assembled onto porous sacrificial templates. Released microtubes transform to closed ellipsoids upon heating in water. On the other hand, unreleased microtubes (remaining within the template) exhibit a completely different behavior in which periodic perforations appear, suggestive of Rayleigh instabilities. In both cases, the transformations occurred near and above the glass transition temperature (Tg) of the hydrated PAH/PAA LbL assembly, suggesting that the transformation in shape is tied to the thermal properties of the LbL assembly.


A defined, controlled culture system for primary bovine chromaffin progenitors reveals novel biomarkers and modulators.
We present a method to efficiently culture primary chromaffin progenitors from the adult bovine adrenal medulla in a defined, serum-free monolayer system. Tissue is dissociated and plated for expansion under support by the mitogen basic fibroblast growth factor (bFGF). The cultures, although not homogenous, contain a subpopulation of cells expressing the neural stem cell marker Hes3 that also propagate. In addition, Hes3 is also expressed in the adult adrenal medulla from where the tissue is taken. Differentiation is induced by bFGF withdrawal and switching to Neurobasal medium containing B27. Following differentiation, Hes3 expression is lost, and cells acquire morphologies and biomarker expression patterns of chromaffin cells and dopaminergic neurons. We tested the effect of different treatments that we previously showed regulate Hes3 expression and cell number in cultures of fetal and adult rodent neural stem cells. Treatment of the cultures with a combination of Delta4, Angiopoietin2, and a Janus kinase inhibitor increases cell number during the expansion phase without significantly affecting catecholamine content levels. Treatment with cholera toxin does not significantly affect cell number but reduces the ratio of epinephrine to norepinephrine content and increases the dopamine content relative to total catecholamines. These data suggest that this defined culture system can be used for target identification in drug discovery programs and that the transcription factor Hes3 may serve as a new biomarker of putative adrenomedullary chromaffin progenitor cells.


Sex differences in primary Sjögren's syndrome.
To examine the clinical and serologic characteristics of 14 men compared to 28 women with primary Sjögren's syndrome (SS) and contrast these findings with studies evaluating sex differences in primary SS. Patient information was collected from patients seen at the National Institutes of Health Salivary Gland Dysfunction Clinic from 1987 to 1998. A total of 14 male patients were diagnosed with primary SS during this period. The control group consisted of 28 female patients matched according to focus score of the labial minor salivary gland biopsy. Women had significantly higher antinuclear antibody titers and erythrocyte sedimentation rate than men. A significant sex difference was also noted in extraglandular manifestations, with more women reporting fatigue compared to men (68 vs 21%, respectively). This study indicates that women may have more positive serological findings than men and a higher prevalence of fatigue. No sex differences could be established with other extraglandular manifestations of SS.


[The essence of infection by opportunistic microorganisms].
Infection is regarded as an imbalance between microbial pathogenicity factors and the host defense systems. Opportunistic infections are defined as infections rarely observed in humans with normal immune responses. The term immunocompromised (compromised) host refers to host in which one or more defence mechanisms are inactive and in which the probability of infection is therefore increased. Hospital patients are often compromised host. Compromised hosts exist even outside the hospital (smoking, intravenous drug use, poor nutrition and other). A good example is HIV (human immunodeficiency virus). HIV causes acquired immunodeficiency syndrome (AIDS) by destroying the CD4 T lymphocytes, involved in the immune response. The most common AIDS-associated opportunistic infections include pneumonia caused by the fungus Pneumocystis carinii, systemic candidiasis (Candida albicans) and cryptococcosis (Cryptococcus neoformans), protozoal infections such as cryptosporidiosis (Cryptosporidium spp.) and toxoplasmosis (Toxoplasma gondii), viral infections due to HSV, CMV, EBV, HPV or HHV8, tuberculosis and other bacterial infections. Pneumocystis carinii pneumonia (PCP) is the most common opportunistic disease observed in AIDS patients. Disease does not necessarily follow exposure to a given causal agent (pathogen 01 opportunistic pathogen). In fact, the occurrence (or otherwise) of disease typically depends on various factors--including the degree of sensitivity of the host (as above) and the virulence factors of the pathogens. Overtly aggressive products such as toxins and aggressins are clearly virulence factors. However, so too are those products and strategies which help a pathogen to become established in the host and to evade the host's defences. Certain virulence factors can be induced in the pathogen via signal transduction pathways from environment.


Treating psoriatic arthritis: how effective are TNF antagonists?
Psoriatic arthritis (PsA) is a seronegative spondyloarthropathy that commonly appears after the onset of the characteristic cutaneous lesions. This complication affects about 40% of patients with moderate to severe cutaneous disease. Analysis of synovial fluid and tissue in patients with PsA demonstrates a profile of high levels of tumor necrosis factor (TNF) plus other cytokines similar to those seen in patients with rheumatoid arthritis (RA). In the past, medical management of patients with this disease consisted of treatment with nonsteroidal anti-inflammatory agents. Patients with more severe disease have tried a number of different disease-modifying drugs including methotrexate, azathioprine, and gold salts. However, there is no evidence that these agents can arrest the progress of structural joint damage. Infliximab and etanercept are TNF antagonists that have demonstrated significant efficacy and safety in patients with RA. Clinical trials with these two agents in patients with PsA have shown significant improvement in the rheumatologic and cutaneous manifestations of the disease.


Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy.
The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2nuc) expression was significantly associated with nuclear expression of Chk1 (p = 0.046), whereas cytoplasmic pMST1/2 (pMST1/2cyt) expression was marginally associated with cytoplasmic TAZ staining (p = 0.053). Patients whose tumors expressed pMST1/2nuc were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2cyt)seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.


Cobalt(III) Complexes for Light-Activated Delivery of Acetylacetonate-BODIPY, Cellular Imaging, and Photodynamic Therapy.
Cobalt(III) complexes [Co(TPA)(L1)](ClO4)2 (1), [Co(4-COOH-TPA)(L1)](ClO4)2 (2), [Co(TPA)(L2)]Cl2 (3), and [Co(4-COOH-TPA)(L2)]Cl2 (4) having acetylacetonate-linked boron-dipyrromethene ligands (L1, acac-BODIPY; L2, acac-diiodo-BODIPY) were prepared and characterized, and their utility as bioimaging and phototherapeutic agents was evaluated (TPA, tris-(2-pyridylmethyl)amine; 4-COOH-TPA, 2-((bis-(2-pyridylmethyl)amino)methyl)isonicotinic acid). HL1, HL2, and complex 1 were structurally characterized by X-ray crystallography. Complexes 1 and 2 on photoactivation or in a reducing environment (excess GSH, ascorbic acid, and 3-mercaptopropionic acid) released the acac-BODIPY ligand. They exhibited strong absorbance near 501 nm (ε ∼ (5.2-5.8) × 104 M-1 cm-1) and emission bands near 513 nm (ΦF ∼ 0.13, λex = 490 nm) in dimethyl sulfoxide (DMSO). Complexes 3 and 4 with absorption maxima at ∼536 and ∼538 nm (ε ∼ (1.2-1.8) × 104 M-1 cm-1), respectively, afforded high singlet oxygen quantum yield (ΦΔ ∼ 0.79) in DMSO. Complexes 1-4 showed Co(III)-Co(II) redox responses near -0.2 V versus saturated calomel electrode (SCE) in dimethylformamide (DMF)-0.1 M tetrabutylammonium perchlorate (TBAP). The photocleavage of pUC19 DNA by complex 4 revealed the formation of both singlet oxygen and superoxide anion radicals as the reactive oxygen species (ROS). Confocal fluorescence microscopy showed the selective accumulation of complex 1 in the endoplasmic reticulum (ER) in A-549 cells. Complex 4 exhibited a high phototherapeutic index value (PI > 7000) in HeLa cancer cells (IC50 ∼ 0.007 μM in visible light of 400-700 nm, total dose ∼5 J cm-2). The ancillary ligands in the complexes demonstrated a structure-activity relationship and modulated the Co(III)-Co(II) redox potential, the complex solubility, acac-BODIPY ligand release kinetics, and phototherapeutic efficacy.


A colourimetric sensor for the simultaneous determination of oxidative status and antioxidant activity on the same membrane: N,N-dimethyl-p-phenylene diamine (DMPD) on Nafion.
A colourimetric sensor capable of simultaneously measuring oxidative status (OS) in terms of the hazard produced by reactive oxygen species (ROS) and antioxidant activity (AOA) in regard to ROS-scavenging ability of antioxidant compounds was developed. The coloured cationic semi-quinone derivatives, caused by ROS oxidative degradation of N,N-dimethyl-p-phenylene diamine hydrochloride (DMPD) in pH 5.7 acetate-buffered medium, were formed in solution and immobilized on a perfluorosulfonate-based Nafion membrane. ROS, namely hydroxyl (·OH) and superoxide (O2(·-)) radicals, were produced by Fenton/UV and xanthine/xanthine oxidase methods, respectively. The pink-coloured, (+)-charged chromophore (referred to as DMPD-quinone or DMPDQ), resulting from the reaction between DMPD and ROS, could be completely retained on the solid membrane sensor by electrostatic interaction with the anionic sulfonate groups of Nafion. After equilibration, the Nafion membrane surface was homogeneously coloured enabling an absorbance measurement at 514 nm, while the aqueous phase completely lacked colour. Antioxidants, when present, caused an absorbance decrease on the membrane due to their ROS scavenging action, giving rise to less DMPDQ production. The absorbance decrease on the sensor was linearly dependent on antioxidant concentration over a reasonable concentration range, enabling the simultaneous determination of OS and AOA-against ROS. The proposed antioxidant sensing method was tested in synthetic and real antioxidant mixtures, and validated against standard antioxidant capacity assays (i.e. ABTS and CUPRAC) for a variety of polyphenolic and antioxidant compounds. The dynamic linear ranges of antioxidants with the DMPD sensor in protection against hydroxyl and superoxide radicals generally varied within the micromolar to a few tens of micromolar concentration interval over one order-of-magnitude. Choosing three representative compounds in the high (epigallocatechin gallate), medium (quercetin) and low (p-coumaric acid) molar absorptivity range, the detection limits ranged within the concentration intervals of 0.2-0.9 μM, 0.3-0.8 μM, and 4-14 μM, respectively, depending on the radical scavenged.


Computerized assessment of coronary lumen and atherosclerotic plaque dimensions in three-dimensional intravascular ultrasound correlated with histomorphometry.
Intravascular ultrasound (IVUS), which depicts both lumen and plaque, offers the potential to improve on the limitations of angiography for the assessment of the natural history of atherosclerosis and progression or regression of the disease. To facilitate measurements and increase the reproducibility of quantitative IVUS analyses, a computerized contour detection system was developed that detects both the luminal and external vessel boundaries in 3-dimensional sets of IVUS images. To validate this system, atherosclerotic human coronary segments (n = 13) with an area obstruction > or = 40% (40% to 61%) were studied in vitro by IVUS. The computerized IVUS measurements (areas and volumes) of the lumen, total vessel, plaque-media complex, and percent obstruction were compared with findings by manual tracing of the IVUS images and of the corresponding histologic cross sections obtained at 2-mm increments (n = 100). Both area and volume measurements by the contour detection system agreed well with the results obtained by manual tracing, showing low mean between-method differences (-3.7% to 0.3%) with SDs not exceeding 6% and high correlation coefficients (r = 0.97 to 0.99). Measurements of the lumen, total vessel, plaque-media complex, and percent obstruction by the contour detection system correlated well with histomorphometry of areas (r = 0.94, 0.88, 0.80, and 0.88) and volumes (r = 0.98, 0.91, 0.83, and 0.91). Systematic differences between the results by the contour detection system and histomorphometry (29%, 13%, -9%, and -22%, respectively) were found, most likely resulting from shrinkage during tissue fixation. The results of this study indicate that this computerized IVUS analysis system is reliable for the assessment of coronary atherosclerosis in vivo.


Optimization of a New Design of Molten Salt-to-CO2 Heat Exchanger Using Exergy Destruction Minimization.
One of the ways to make cost-competitive electricity, from concentrated solar thermal energy, is increasing the thermoelectric conversion efficiency. To achieve this objective, the most promising scheme is a molten salt central receiver, coupled to a supercritical carbon dioxide cycle. A key element to be developed in this scheme is the molten salt-to-CO2 heat exchanger. This paper presents a heat exchanger design that avoids the molten salt plugging and the mechanical stress due to the high pressure of the CO2, while improving the heat transfer of the supercritical phase, due to its compactness with a high heat transfer area. This design is based on a honeycomb-like configuration, in which a thermal unit consists of a circular channel for the molten salt surrounded by six smaller trapezoidal ducts for the CO2. Further, an optimization based on the exergy destruction minimization has been accomplished, obtained the best working conditions of this heat exchanger: a temperature approach of 50 °C between both streams and a CO2 pressure drop of 2.7 bar.


Carbon nanotube dielectrophoresis: Theory and applications.
Carbon nanotubes (CNTs) are one of the most extensively studied nanomaterials in the 21st century. Since their discovery in 1991, many studies have been reported advancing our knowledge in terms of their structure, properties, synthesis, and applications. CNTs exhibit unique electrothermal and conductive properties which, combined with their mechanical strength, have led to tremendous attention of CNTs as a nanoscale material in the past two decades. To introduce the various types of CNTs, we first provide basic information on their structure followed by some intriguing properties and a brief overview of synthesis methods. Although impressive advances have been demonstrated with CNTs, critical applications require purification, positioning, and separation to yield desired properties and functional elements. Here, we review a versatile technique to manipulate CNTs based on their dielectric properties, namely dielectrophoresis (DEP). A detailed discussion on the DEP aspects of CNTs including the theory and various technical microfluidic realizations is provided. Various advancements in DEP-based manipulations of single-walled and multiwalled CNTs are also discussed with special emphasis on applications involving separation, purification, sensing, and nanofabrication.


Measurement of contractile and electrical properties of single human thenar motor units in response to intraneural motor-axon stimulation.
1. A method is described for measuring contractile properties of single human motor units. Conventional human microneurographic techniques were adapted to stimulate individual motor axons in the median nerve, with the use of negative current pulses and a tungsten microelectrode, while recording motor-unit electromyographic activity (EMG) and isometric force responses from the thenar muscles. 2. EMG signals were recorded from both proximal and distal thenar muscle surfaces. Force was recorded in two directions (thumb flexion and abduction). This allowed calculation of the direction and magnitude of resultant force exerted by each unit. 3. Data accepted as originating from a single unit satisfied all the traditional "all-or-none" criteria. Additional criteria also required the following: 1) a wide safety margin between the threshold for unit activation and the current intensity needed to elicit responses from other units; 2) that the characteristic direction in which each unit generated force did not change during the recording period; and 3) whenever F-responses were encountered, the second EMG waveform was identical to the first--a highly improbable event if more than one unit had been excited. 4. Respiration and blood pressure waves introduced baseline fluctuations that distorted the force measurements. These fluctuations were minimized by synchronizing stimuli to the pulse pressure cycle and resetting the baseline electronically just before stimulus onset. 5. Combining motor-axon stimulation at a site remote from the muscle with electronic resetting of the force baseline and delivery of stimuli at fixed intervals after the pulse pressure waves allowed the full time course of human motor-unit twitch and tetanic force and EMG signals to be recorded accurately without signal averaging.


Network Analysis Provides Insight into Tomato Lipid Metabolism.
Metabolic correlation networks have been used in several instances to obtain a deeper insight into the complexity of plant metabolism as a whole. In tomato (Solanum lycopersicum), metabolites have a major influence on taste and overall fruit quality traits. Previously a broad spectrum of metabolic and phenotypic traits has been described using a Solanum pennellii introgression-lines (ILs) population. To obtain insights into tomato fruit metabolism, we performed metabolic network analysis from existing data, covering a wide range of metabolic traits, including lipophilic and volatile compounds, for the first time. We provide a comprehensive fruit correlation network and show how primary, secondary, lipophilic, and volatile compounds connect to each other and how the individual metabolic classes are linked to yield-related phenotypic traits. Results revealed a high connectivity within and between different classes of lipophilic compounds, as well as between lipophilic and secondary metabolites. We focused on lipid metabolism and generated a gene-expression network with lipophilic metabolites to identify new putative lipid-related genes. Metabolite-transcript correlation analysis revealed key putative genes involved in lipid biosynthesis pathways. The overall results will help to deepen our understanding of tomato metabolism and provide candidate genes for transgenic approaches toward improving nutritional qualities in tomato.


The impact of age, sex and socioeconomic deprivation on outcomes in a colorectal cancer screening programme.
Population-based colorectal cancer screening has been shown to reduce cancer specific mortality and is used across the UK. Despite evidence that older age, male sex and deprivation are associated with an increased incidence of colorectal cancer, uptake of bowel cancer screening varies across demographic groups. The aim of this study was to assess the impact of age, sex and deprivation on outcomes throughout the screening process. A prospectively maintained database, encompassing the first screening round of a faecal occult blood test screening programme in a single geographical area, was analysed. Overall, 395,096 individuals were invited to screening, 204,139 (52%) participated and 6079 (3%) tested positive. Of the positive tests, 4625 (76%) attended for colonoscopy and cancer was detected in 396 individuals (9%). Lower uptake of screening was associated with younger age, male sex and deprivation (all p<0.001). Only deprivation was associated with failure to proceed to colonoscopy following a positive test (p<0.001). Despite higher positivity rates in those that were more deprived (p<0.001), the likelihood of detecting cancer in those attending for colonoscopy was lower (8% most deprived vs 10% least deprived, p = 0.003). Individuals who are deprived are less likely to participate in screening, less likely to undergo colonoscopy and less likely to have cancer identified as a result of a positive test. Therefore, this study suggests that strategies aimed at improving participation of deprived individuals in colorectal cancer screening should be directed at all stages of the screening process and not just uptake of the test.


[Morphologic signs of adaptation of the microcirculatory bed of the liver to denervation].
The effect of mixed denervation on the hepatic microcirculatory bed was studied in dogs and rats. Seven days after denervation, dilated sinusoid capillaries and spaces around the sinuses (Disse's space), disorders in structure of the sinusoid reticular carcass were revealed in the liver of the dogs and rats. The labelled nuclei index in the stellate endotheliocytes is statistically increasing; one month later, in the sinusoid wall the number of cells containing glicosaminoglicanes in the cytoplasm is increasing, outgrowth of the reticular fibres in the perisinusoid spaces and reorganization of the reticular type of the hepatic stroma from the radial into the alveolar one is noted. All the signs mentioned above demonstrate certain adaptation of the microcirculatory bed in the denervated liver to the altered conditions of hemodynamics.


Ganciclovir as a potential treatment for glioma: a systematic review and meta-analysis.
Glioma is a challenging malignant tumor with a low survival rate and no effective treatment. Recently, ganciclovir, an antiviral drug, combined with gene therapy and its own antiviral ability, has been proposed as a potential treatment for glioma. However, there are differences in the results of various clinical trials. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy of ganciclovir in treating glioma. We searched databases such as PubMed, EMBASE, and Cochrane Library before March 30, 2023. The search terms included glioma, ganciclovir, valganciclovir and treatment. Calculated 1, 2 and 4-year survival rate by risk difference (RD), and overall survival (OS) by odds ratio (OR). Five randomized controlled trials (RCTs) with a total of 606 high-grade glioma patients were included. The results showed that ganciclovir can improve 2-yeaer (RD = 0.179, 95% CI 0.012-0.346, P = 0.036) and 4-year survival rate (RD = 0.185, 95% CI 0.069-0.3, P = 0.002) and OS (OR 2.393, 95% CI 1.212-4.728, P = 0.012) compared with the control group. This meta-analysis showed that ganciclovir significantly improved the prognosis of glioma patients. Therefore, we suggest that more cases of ganciclovir as a glioma treatment can be conducted, or a large clinical trial can be designed.


DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C. Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.


[Occurrence de Leishmania spp. in domestic cats from Araçatuba, SP].
This study had the purpose to compare the occurrence of Leishmania spp. in felines through two methods (cytological and serological), as well as to associate the occurrence of this protozoan with the sex, age and breed variables. Serum samples from 283 domestic felines were processed by means of Indirect Immunofluorescence Reaction (IIR), and the direct parasitological test for linfonodes was also carried out in order to verify positivity for Leishmania spp. Occurrence of 0.7% (2/283) was observed in the tested felines by means of linfonode imprinting and no animal showed title of antibodies for Leishmania spp. The two positive females were mongrel, a young female and an adult female feline. From the obtained results, no statistically significant difference was observed as regards the sex, breed and age variables in this research (p > 0.05). Occurrence of Leishmania spp. in the cats of this study was low. Such low incidence suggests that these hosts has no epidemiological relevance in the study area.


Artificial intelligence-driven antimicrobial peptide discovery.
Antimicrobial peptides (AMPs) emerge as promising agents against antimicrobial resistance, providing an alternative to conventional antibiotics. Artificial intelligence (AI) revolutionized AMP discovery through both discrimination and generation approaches. The discriminators aid in the identification of promising candidates by predicting key peptide properties such as activity and toxicity, while the generators learn the distribution of peptides and enable sampling novel AMP candidates, either de novo or as analogs of a prototype peptide. Moreover, the controlled generation of AMPs with desired properties is achieved by discriminator-guided filtering, positive-only learning, latent space sampling, as well as conditional and optimized generation. Here we review recent achievements in AI-driven AMP discovery, highlighting the most exciting directions.


[Drug prescription in internal medicine: an analysis of the influencing factors].
The amount and quality of drugs prescribed after hospitalization in Internal Medicine and the factors which influence them have been rarely evaluated in Spain. We study prospectively drugs prescribed in patients hospitalized in Internal Medicine analyzing amount of drugs before admission (BAD), on discharge (DD), end drugs after temporal drugs were removed (ED), drugs prescribed as chronic treatment (CTD), symptomatic drugs (SD), acute-use drugs (AUD) and low therapeutic utility drugs (LTUD). We also evaluated the sort of drugs and the factors implicated in increase or decrease of prescription volume. Two hundred and eighty-five patients were evaluated [164 males, 121 females, mean age 68.08 (SD 15.27)]. They had mean BAD 3.42(SD 2.67)7 DD 3.92 (SD 2.36) (p < 0.001) and ED 3.65 (SD 2.30) (No differences with BAD). The amount of drugs were higher in patients 65 years old and elder (p < 0.001). LTUD were decreased from 62(22%) patients on admission to 21 (7%) on discharge (p < 0.001). Compounded drugs were reduced from 36 (13%) patients to 17 (6%) (p < 0.05). Age older 65, length of stay greater 7 days, need for intravenous administration of drugs, comorbidities and complications during hospitalization all caused increase in prescription volume on discharge. Logistic-regression analysis showed that CTD and AUD were the main causes of increase of drugs while BAD and LTUD were protective. Drugs reduced in higher proportion were mucolytics (p < 0.005) drugs to treat plant-based hyperplasia benign of prostate (p < 0.05), brain vasodilators (p < 0.001) and peripheral vasodilators (p < 0.01). Hospitalization in Internal Medicine results in an increase of prescription volume though it is short-term. The higher number of drugs is accumulated in elderly. Factors implicated in increasing are length of stay, need for intravascular access, complications during inpatient, drugs to treat acute diseases and chronic use drugs. Low therapeutic utility drugs are used before admission in outpatients.


Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis.
Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes.Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis.Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen.Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468-81. ©2018 AACR.


An approach to building research capacity for health practitioners in a public health environment: an organisational perspective.
A unique opportunity to engage in research capacity-building strategies for health practitioners arose within public sector health services during the negotiations for an industrial agreement. A research capacity-building initiative for health practitioners that is allied health, oral health and scientist practitioners was funded and the components of this initiative are described. The initiative was implemented using a research capacity-building framework developed from a review of the literature and stakeholder consultations. The framework included leadership and governance, support to researchers and translation of evidence into practice and was contextualised to public health environments. There were several phases of implementation. An evaluation of the preliminary phase of establishing research positions and research activity was conducted and several successes of the capacity-building strategies were identified. These successes (e.g. solid partnerships with universities) are discussed, as are future concerns, such as sustainability of the initiative in a tighter fiscal context.


High resolution structure of Deinococcus bacteriophytochrome yields new insights into phytochrome architecture and evolution.
Phytochromes are red/far red light photochromic photoreceptors that direct many photosensory behaviors in the bacterial, fungal, and plant kingdoms. They consist of an N-terminal domain that covalently binds a bilin chromophore and a C-terminal region that transmits the light signal, often through a histidine kinase relay. Using x-ray crystallography, we recently solved the first three-dimensional structure of a phytochrome, using the chromophore-binding domain of Deinococcus radiodurans bacterial phytochrome assembled with its chromophore, biliverdin IXalpha. Now, by engineering the crystallization interface, we have achieved a significantly higher resolution model. This 1.45A resolution structure helps identify an extensive buried surface between crystal symmetry mates that may promote dimerization in vivo. It also reveals that upon ligation of the C3(2) carbon of biliverdin to Cys(24), the chromophore A-ring assumes a chiral center at C2, thus becoming 2(R),3(E)-phytochromobilin, a chemistry more similar to that proposed for the attached chromophores of cyanobacterial and plant phytochromes than previously appreciated. The evolution of bacterial phytochromes to those found in cyanobacteria and higher plants must have involved greater fitness using more reduced bilins, such as phycocyanobilin, combined with a switch of the attachment site from a cysteine near the N terminus to one conserved within the cGMP phosphodiesterase/adenyl cyclase/FhlA domain. From analysis of site-directed mutants in the D. radiodurans phytochrome, we show that this bilin preference was partially driven by the change in binding site, which ultimately may have helped photosynthetic organisms optimize shade detection. Collectively, these three-dimensional structural results better clarify bilin/protein interactions and help explain how higher plant phytochromes evolved from prokaryotic progenitors.


Functional ACL bracing. A survey of current opinion and practice.
Since most studies designed to prove the efficacy of functional anterior cruciate ligament (ACL) bracing have been equivocal, we felt it would be helpful to know the practices of orthopedic sports medicine physicians. Physicians were questioned about their brace prescription practices via a mailed survey. The response rate was 56% (114/205). Most physicians use functional braces for ACL patients, prefer custom braces, and brace patients for 9 months after reconstruction. Thirty-six percent reported having recently made changes in their brace prescription practices, including using bracing less often. There was no effort made in this study to determine the best bracing practice. Researchers must continue studying brace efficacy in an effort to provide some rationale for bracing regimens.


Enhancing Physical and Psychosocial Health of Older Adults in Saudi Arabia through Walking: Comparison between Supervised Group-Based and Non-Supervised Individual-Based Walking.
Walking is widely recognized as one of the most common and effective forms of physical activity, particularly for older adults. This study examined the comparative effects of two types of walking interventions, including supervised group-based intervention (SGBI) and non-supervised individual-based intervention (NSIBI), on frailty syndrome, cognitive functions or skills, and health-related quality of life among sedentary older Saudi individuals. A 15-week double-blinded, randomized controlled trial (RCT) including three groups (two were intervention groups while the other was the control group) was conducted among older adults who were inactive to examine the effect of different forms of walking interventions on frailty syndrome, cognitive functions, and health-related quality of life. A total of 107 participants, including 65 males and 42 females, were divided into three groups, which include SGBI, NSIBI, and the control group. Frailty syndrome was measured using the physical performance test (PPT), while cognitive function and health-related quality of life were assessed using the Mini-mental State Examination (MMSE) and the Short Form 36 (SF 36) health survey questionnaire. One-way repeated measures analysis of variance (ANOVA) and one-way analysis of covariance (ANCOVA) with the pre- and post-tests were performed for within- and between-group differences. while post-test data for the control group participants were absent due to the change in elderly center regulation, and they were excluded from the analysis. Hence, the comparison was stated only between the intervention groups. Both of the intervention groups (SGBI and NSIBI) showed significant within-subject differences in the Physical Function subscale of the health-related quality of life scale only, with F(1,20) = 23.03, p < 0.001, and F(1,18) = 27.22, p < 0.001, respectively. On the other hand, the Physical Performance Test revealed significant [F(2,51) = 9.21, p < 0.001] between-group differences in the post-test based on the baseline values. In addition, the average step count of older adults was increased from 4000 steps per session to around 7000 steps per session in the intervention group. The average heart rate of the NSIBI group did not show a visible change, and the resting heart rate of both groups showed a slightly declining trend throughout the intervention period. The walking intervention significantly increased participants' physical function, which is a component of health-related quality of life and physical performance (frailty level), along with average daily step counts for older adults in Saudi Arabia. Regular engagement in the recommended level of walking is strongly advisable for Saudi Arabian older adults to maintain their overall quality of life at this stage.


Ultralong pure longitudinal magnetization needle induced by annular vortex binary optics.
In this Letter, based on the Richards and Wolf diffraction theory, an ultralong optical needle with pure transverse polarization is numerically generated by tightly focusing an azimuthally polarized beam through an annular vortex binary filter. Such an ultralong transversely polarized optical needle is generated through the π phase shift between adjacent rings of the binary filter. We show that such a pure transverse optical needle can induce pure longitudinal magnetization with a subwavelength lateral size (0.38λ) and an ultralong longitudinal depth (7.48λ) through the inverse Faraday effect. The corresponding needle aspect ratio of 20 is twice as large as that of the longitudinal magnetization needle generated by electron beam lithography.


"Eczema coxsackium" and unusual cutaneous findings in an enterovirus outbreak.
To characterize the atypical cutaneous presentations in the coxsackievirus A6 (CVA6)-associated North American enterovirus outbreak of 2011-2012. We performed a retrospective case series of pediatric patients who presented with atypical cases of hand, foot, and mouth disease (HFMD) from July 2011 to June 2012 at 7 academic pediatric dermatology centers. Patients were included if they tested positive for CVA6 or if they met clinical criteria for atypical HFMD (an enanthem or exanthem characteristic of HFMD with unusual morphology or extent of cutaneous findings). We collected demographic, epidemiologic, and clinical data including history of skin conditions, morphology and extent of exanthem, systemic symptoms, and diagnostic test results. Eighty patients were included in this study (median age 1.5 years, range 4 months-16 years). Seventeen patients were CVA6-positive, and 63 met clinical inclusion criteria. Ninety-nine percent of patients exhibited a vesiculobullous and erosive eruption; 61% of patients had rash involving >10% body surface area. The exanthem had a perioral, extremity, and truncal distribution in addition to involving classic HFMD areas such as palms, soles, and buttocks. In 55% of patients, the eruption was accentuated in areas of eczematous dermatitis, termed "eczema coxsackium." Other morphologies included Gianotti-Crosti-like (37%), petechial/purpuric (17%) eruptions, and delayed onychomadesis and palm and sole desquamation. There were no patients with serious systemic complications. The CVA6-associated enterovirus outbreak was responsible for an exanthem potentially more widespread, severe, and varied than classic HFMD that could be confused with bullous impetigo, eczema herpeticum, vasculitis, and primary immunobullous disease.


Silicon photosensitisation using molecular layers.
Silicon photosensitisation via energy transfer from molecular dye layers is a promising area of research for excitonic silicon photovoltaics. We present the synthesis and photophysical characterisation of vinyl and allyl terminated Si(111) surfaces decorated with perylene molecules. The functionalised silicon surfaces together with Langmuir-Blodgett (LB) films based on perylene derivatives were studied using a wide range of steady-state and time resolved spectroscopic techniques. Fluorescence lifetime quenching experiments performed on the perylene modified monolayers revealed energy transfer efficiencies to silicon of up to 90 per cent. We present a simple model to account for the near field interaction of a dipole emitter with the silicon surface and distinguish between the 'true' FRET region (<5 nm) and a different process, photon tunnelling, occurring for distances between 10-50 nm. The requirements for a future ultra-thin crystalline solar cell paradigm include efficient surface passivation and keeping a close distance between the emitter dipole and the surface. These are discussed in the context of existing limitations and questions raised about the finer details of the emitter-silicon interaction.


Hip Rotations' Influence of Electromyographic Activity of Gluteus Medius Muscle During Pelvic-Drop Exercise.
Pelvic-drop exercises are often used to strengthen the gluteus medius (GM) muscle with the aim of increasing or prioritizing its recruitment. However, the effect of hip rotation on the performance of the action of the GM is unknown. To evaluate the effect of hip rotation on the recruitment of the GM, tensor fasciae latae (TFL), and quadratus lumborum (QL). Seventeen healthy subjects performed 2 sets of 4 repetitions of pelvic-drop exercise in random order with pelvic-drop lateral, medial, and neutral rotation of the hip. The electromyographic (EMG) activity of the GM, TFL, and QL was evaluated using surface electromyography. There were significant increases in the activation of the GM with medial and neutral rotation compared with lateral rotation (P = .03, P = .01, respectively), and there was no difference between medial and neutral rotation (P = 1.00). There was no difference in EMG activity of the TFL and QL in any of the positions. The GM:TFL ratio was the same in all analyzed positions. Regarding the GM:QL ratio, there was a significant increase with medial rotation compared with lateral rotation (P = .02). Pelvic-drop exercises are more efficient for activating the GM when the hip is in medial rotation and neutral position.


TALE nucleases and next generation GM crops.
Site-specific and adaptable DNA binding domains are essential modules to develop genome engineering technologies for crop improvement. Transcription activator-like effectors (TALEs) proteins are used to provide a highly specific and adaptable DNA binding modules. TALE chimeric nucleases (TALENs) were used to generate site-specific double strand breaks (DSBs) in vitro and in yeast, Caenorhabditis elegans, mammalian and plant cells. The genomic DSBs can be generated at predefined and user-selected loci and repaired by either the non-homologous end joining (NHEJ) or homology dependent repair (HDR). Thus, TALENs can be used to achieve site-specific gene addition, stacking, deletion or inactivation. TALE-based genome engineering tools should be powerful to develop new agricultural biotechnology approaches for crop improvement. Here, we discuss the recent research and the potential applications of TALENs to accelerate the generation of genomic variants through targeted mutagenesis and to produce a non-transgenic GM crops with the desired phenotype.


Violence Against Children in Afghanistan: Community Perspectives.
Violence against children (VAC) is a significant international problem and, in Afghanistan, is particularly complex given the country has suffered armed conflict and extreme poverty for more than 30 years. The aim of this study was to examine the level of knowledge and observation of VAC by community leaders, professional groups, and business owners in three Afghan districts. A survey of community and religious leaders; health, socio-legal, and education professionals; and business owners from Kabul, Jalalabad, and Torkham (n = 182) was conducted. Structured interviews included qualitative and quantitative components. Questions related to knowledge and experience of VAC, and to perceptions of consequences, causes, and strategies for preventing VAC. The statistical significance of differences between participant groups and measures of association were assessed by Pearson's chi-square test, the Mann-Whitney test, and the Kruskall-Wallis one-way ANOVA. Qualitative responses were analyzed thematically. VAC was reported to occur mostly in the home, community, and workplace. The scale of the problem varied, with religious and community leaders underreporting VAC by 30% to 40% compared with other participant groups (p < .001). Business owners also significantly underreported VAC in the workplace, despite admitting to acts of discipline that included physical contact. There were some regional differences, with lower reporting of violence in Jalalabad compared with the two other locations (p < .001). Causes of VAC were consistently attributed to poverty, lack of education, and the effects of war. The findings of this study indicate that VAC is a serious and complex problem in Afghanistan. Decades of armed conflict and entrenched poverty influence how violence is perceived and recognized. Consideration should be given to initiatives that build on the existing strengths within the community while raising awareness and recognition of the nature, extent, and burden of VAC in the community.


The Enzymatic Activity of APOBE3G Multimers.
APOBEC3G (A3G) belongs to the family of cytosine deaminases that play an important role in the innate immune response. Similar to other, two-domain members of the APOBEC family, A3G is prone to concentration-dependent oligomerization, which is an integral for its function in the cell. It is shown that oligomerization of A3G is related to the packing mechanism into virus particle and, is critical for the so-called roadblock model during reverse transcription of proviral ssDNA. The role of oligomerization for deaminase activity of A3G is widely discussed in the literature; however, its relevance to deaminase activity for different oligomeric forms of A3G remains unclear. Here, using Atomic Force Microscopy, we directly visualized A3G-ssDNA complexes, determined their yield and stoichiometry and in parallel, using PCR assay, measured the deaminase activity of these complexes. Our data demonstrate a direct correlation between the total yield of A3G-ssDNA complexes and their total deaminase activity. Using these data, we calculated the relative deaminase activity for each individual oligomeric state of A3G in the complex. Our results show not only similar deaminase activity for monomer, dimer and tetramer of A3G in the complex, but indicate that larger oligomers of A3G retain their deaminase activity.