Disability in chronic migraine with medication overuse: treatment effects through 5 years.
Chronic migraine accompanied by medication overuse is particularly difficult to treat. The number of treatment investigations is limited, few have included follow-up beyond 6 months and almost none has examined whether treatment leads to concurrent improvements in disability and functional impairment. This open-label study addresses these limitations. We have been prospectively following an initial cohort of 84 chronic migraine patients with medication overuse, who at the time of this evaluation had been reduced to 58, for an extended period to assess longer-term maintenance of effects, using measurement procedures identical to those in the original investigation. Thus, the specific aim was to determine the clinical status, with respect to pain indices and disability level, of chronic migraine patients with medication overuse who were treated and followed prospectively for 5 years. All patients completed a brief inpatient treatment programme, in which they were withdrawn from their offending medications and subsequently placed on more appropriate preventive antimigraine medications. Both end-point, wherein missing data points were estimated, and continuer analyses, wherein data analysis was limited to the 58 individuals with complete datasets, revealed significant improvement on all measures studied-headache days per month, analgesic consumption and Migraine Disability Assessment (MIDAS) total score. The percentage reduction from baseline to 5 years for the MIDAS total score was 76.0%, while the percentage of individuals revealing improvements of clinically significant magnitude (≥ 50%) on the MIDAS was 91.9%. MIDAS total scores were lower at 5 years than at some of the intervening follow-up intervals. Comparisons of those who completed the 5-year follow-up (n = 58) with those who did not revealed no differences at baseline. This finding, coupled with the nearly identical results for the end-point and continuers analyses, suggests that attrition did not have a bearing on outcome. None of the patients completing the 5-year follow-up had relapsed since the prior 3-year follow-up assessment. High levels of maintenance were revealed at 5 years, with disability scores showing some continued improvement over time. The implications of these findings and the limitations of the study are discussed.


A controversy that has been tough to swallow: is the treatment of achalasia now digested?
Esophageal achalasia is a rare neurodegenerative disease of the esophagus and the lower esophageal sphincter that presents within a spectrum of disease severity related to progressive pathological changes, most commonly resulting in dysphagia. The pathophysiology of achalasia is still incompletely understood, but recent evidence suggests that degeneration of the postganglionic inhibitory nerves of the myenteric plexus could be due to an infectious or autoimmune mechanism, and nitric oxide is the neurotransmitter affected. Current treatment of achalasia is directed at palliation of symptoms. Therapies include pharmacological therapy, endoscopic injection of botulinum toxin, endoscopic dilation, and surgery. Until the late 1980s, endoscopic dilation was the first line of therapy. The advent of safe and effective minimally invasive surgical techniques in the early 1990s paved the way for the introduction of laparoscopic myotomy. This review will discuss the most up-to-date information regarding the pathophysiology, diagnosis, and treatment of achalasia, including a historical perspective. The laparoscopic Heller myotomy with partial fundoplication performed at an experienced center is currently the first line of therapy because it offers a low complication rate, the most durable symptom relief, and the lowest incidence of postoperative gastroesophageal reflux.


A possible underlying mechanism behind the cardioprotective efficacy of tangeretin on isoproterenol triggered cardiotoxicity via modulating PI3K/Akt signaling pathway in a rat model.
This study was aimed to examine the possible underlying cardioprotective efficacy of tangeretin (TAN) in rats exposed to isoproterenol (ISP). Forty male SD rats were separated into four equal groups as the control group, ISP (myocardial infarction; MI group) group rats which were injected intraperitoneally (ip) with 85 mg/kg of ISP. Treatment TAN groups (TAN 50 and TAN 100) rats were orally pretreated with TAN (50 or 100 mg/kg) for 28 days before ISP exposure. Pretreatment with TAN (50/100) significantly reduced (p < .05/0.01) the infarct size, levels of inflammatory markers, cardiac marker enzymes, apoptotic markers along with improved antioxidants. Histo-morphological results also well-supported the results of the above biochemical parameters by displaying normal myofibrillar arrangement in TAN pretreated rats. Moreover, the protein expressions of pPI3K and pAkt were considerably elevated in rats administered with TAN. Collectively, TAN pretreatment (especially TAN 100) display better cardioprotective activity against ISP-induced MI rats. PRACTICAL APPLICATIONS: Tangeretin (TAN) has been reported to exhibit an array of biological functions including cardioprotective, hepatoprotective, and renoprotective activities. However, the in-depth mechanism is still lacking, which results in this study. Our results indicate that TAN could effectively reduce cardiac infarct size, inflammatory markers, oxidative stress, apoptotic markers, by modulating (upregulating) the protein expressions of the PI3K/Akt signaling pathway. Thus, demonstrating that TAN could be a strong contender for developing a cardioprotective agent and can recommend along with conventional cardioprotective drugs for abolishing MI-related complications/symptoms. Nevertheless, further human studies are needed to confirm the above suggestion.


Divorce in the socially monogamous zebra finch: Hormonal mechanisms and reproductive consequences.
Up to 80% of all bird species are socially monogamous. Divorce (switching partners) or pair disruption (due to the death of a partner) has been associated with decreased reproductive success, suggesting social monogamy is a strategy that may maximize fitness via coordination between partners. Previous studies have demonstrated the effects of divorce and pair disruption on immediate reproductive success. Here, we used a paired experimental design in the zebra finch (Taeniopygia guttata) to examine the hormonal mechanisms that modulate parental behavior and reproductive success in response to a partnership change (hereafter divorce). Specifically, we examined the effects of divorce on the avian stress hormone corticosterone (CORT) in both parents and nestlings, parental behaviors (incubation and nestling provisioning), prolactin (PRL), and reproductive success. We found that divorce resulted in delayed clutch initiation, reduced clutch mass, and an increase in nestling CORT response to a standardized stressor. These effects on reproductive investment and chick CORT response were not clearly determined by parental endocrine responses. Divorce had no effect on the level of parental CORT. PRL levels were highly correlated within a pair regardless of treatment, were negatively related to the investment that males made in incubation, and increased in experimental males as a result of pair disruption. This study demonstrates the fundamental impact which divorce has not only on reproduction, but also the physiological stress responses of offspring and suggests that in socially monogamous animals the maintenance of a stable partnership over time could be advantageous for long term fitness.


Lymphomatoid Papulosis Development in Acute Lymphoblastic Leukemia.
Lymphomatoid papulosis (LyP) is a chronic, recurrent benign skin disease characterized by histological features of a CD 30-positive cutaneous T-cell lymphoproliferative disorder. It is rare, with an annual, worldwide incidence of 1.2 - 1.9 per million, and accounts for 16-47% of pediatric cutaneous lymphoproliferative disorders. It often occurs on the extremities or the trunk and rarely affects the face or genitals. Its onset may be triggered by irradiation therapy, immunomodulating agents, infection or atopic dermatitis. It has a benign course but is associated with certain hematological malignancies. Mycosis fungoides and primary cutaneous anaplastic large cell lymphoma are the most commonly associated hematological malignancies. The incidence of lymphoma in children with LyP has been reported to be 8.5% at most. Most patients who develop lymphomas do so within 4 years of the LyP onset; therefore, patients with LyP should be carefully followed up. Herein, we report a case in which tumors appeared in the left scrotum and under the left lip during maintenance therapy for precursor B-cell acute lymphoblastic leukemia. We needed to distinguish the tumor from extramedullary recurrence of ALL or de novo other cutaneous lymphoma; however, the histological findings of a tumor biopsy resulted in a diagnosis of LyP.


In situ Prokaryotic and Eukaryotic Communities on Microplastic Particles in a Small Headwater Stream in Germany.
The ubiquitous use of plastic products in our daily life is often accompanied by improper disposal. The first interactions of plastics with organisms in the environment occur by overgrowth or biofilm formation on the particle surface, which can facilitate the ingestion by animals. In order to elucidate the colonization of plastic particles by prokaryotic and eukaryotic microorganisms in situ, we investigated microbial communities in biofilms on four different polymer types and on mineral particles in a small headwater stream 500 m downstream of a wastewater treatment plant in Germany. Microplastic and mineral particles were exposed to the free-flowing water for 4 weeks in spring and in summer. The microbial composition of the developing biofilm was analyzed by 16S and 18S amplicon sequencing. Despite the expected seasonal differences in the microbial composition of pro- and eukaryotic communities, we repeatedly observed polymer type-specific differentiation in both seasons. The order of polymer type-specific prokaryotic and eukaryotic community distances calculated by Robust Aitchison principal component analysis (PCA) was the same in spring and summer samples. However, the magnitude of the distance differed considerably between polymer types. Prokaryotic communities on polyethylene particles exhibited the most considerable difference to other particles in summer, while eukaryotic communities on polypropylene particles showed the most considerable difference to other spring samples. The most contributing bacterial taxa to the polyethylene-specific differentiation belong to the Planctomycetales, Saccharimonadales, Bryobacterales, uncultured Acidiomicrobia, and Gemmatimonadales. The most remarkable differences in eukaryotic microorganism abundances could be observed in several distinct groups of Ciliophora (ciliates) and Chlorophytes (green algae). Prediction of community functions from taxonomic abundances revealed differences between spring and summer, and - to a lesser extent - also between polymer types and mineral surfaces. Our results show that different microplastic particles were colonized by different biofilm communities. These findings may be used for advanced experimental designs to investigate the role of microorganisms on the fate of microplastic particles in freshwater ecosystems.


The structure of trimethyltin fluoride.
The solid-state structure of (CH3)3SnF was reinvestigated by X-ray diffraction techniques as well as by multi-nuclear solid-state NMR spectroscopy. Trimethyltin fluoride crystallizes from hot ethanol in the orthorhombic space group Pnma at room temperature and changes to a low-temperature orthorhombic phase (space group: Cmcm) below -70 °C. In both modifications, trimethyltin fluoride adopts a linear chain structure with symmetric fluorine bridges, in contrast to previous reports. During its synthesis, (CH3)3SnF precipitates in another, poorly crystalline modification, as shown by powder X-ray diffraction. Solid-state MAS NMR experiments of both room-temperature phases of (CH3)3SnF (non-recrystallized and recrystallized) were carried out for the (1)H, (13)C, (19)F, and (119)Sn nuclei. The (119)Sn{(19)F, (1)H} and (19)F{(1)H} NMR spectra offer unambiguous determination for the (19)F and (119)Sn shielding tensors. The (119)Sn{(1)H} solid-state NMR spectra are in agreement with pentacoordination of Sn in this compound for the non-recrystallized and the recrystallized modifications. Based on the solid-state NMR results, the non-recrystallized modification of (CH3)3SnF also consists of linear, symmetrically fluorine-bridged chains, and differs from the recrystallized orthorhombic phase only in packing of the chains.


Network meta-analysis with integrated nested Laplace approximations.
Analyzing the collected evidence of a systematic review in form of a network meta-analysis (NMA) enjoys increasing popularity and provides a valuable instrument for decision making. Bayesian inference of NMA models is often propagated, especially if correlated random effects for multiarm trials are included. The standard choice for Bayesian inference is Markov chain Monte Carlo (MCMC) sampling, which is computationally intensive. An alternative to MCMC sampling is the recently suggested approximate Bayesian method of integrated nested Laplace approximations (INLA) that dramatically saves computation time without any substantial loss in accuracy. We show how INLA apply to NMA models for summary level as well as trial-arm level data. Specifically, we outline the modeling of multiarm trials and inference for functional contrasts with INLA. We demonstrate how INLA facilitate the assessment of network inconsistency with node-splitting. Three applications illustrate the use of INLA for a NMA.


Effects of Resistance Training on Functional Strength and Muscle Mass in 70-Year-Old Individuals With Pre-sarcopenia: A Randomized Controlled Trial.
Sarcopenia has been defined as age-related loss of muscle mass and function. The aim of this randomized controlled trial was to examine the effects of a 10-week instructor-led resistance training program on functional strength and body composition in men and women aged 70 years with pre-sarcopenia. Participants were randomized to either 10 weeks of a physical training regimen including optional nutritional supplementation (n = 36) or to a control group (n = 34) (ClinicalTrials.gov, no. NCT03297632). The main outcome was changes in the Short Physical Performance Battery (SPPB) score. Secondary outcomes included the Timed Up and Go test, chair sit-stand time, lean body mass, and fat mass. The intervention had no significant effect on SPPB in the total cohort (P = .18), when comparing changes in the intervention group with the control group. However, those given the intervention in the male subcohort increased 0.5 ± 0.4 (mean ± standard error for the difference) points in SPPB during follow-up (P = .02) compared to male controls. With respect to secondary outcomes, the intervention group decreased 0.9 ± 0.6 seconds in chair sit-stand time compared to controls (P = .01). Furthermore, the intervention resulted in significantly greater improvements for the training group than control group in all measures of body composition (P ≤ .01 for all). For example, lean body mass increased by a mean of 1147 ± 282 g (P < .001), and total fat mass decreased by a mean of 553 ± 225 g (P = .003), favoring the intervention group. The main finding of this intervention study is that an easy-to-use, functional resistance training program was effective in maintaining functional strength and increasing muscle mass in older adults with pre-sarcopenia.


Late marrow recurrences in childhood acute lymphoblastic leukaemia.
Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival.


Effect of piperlongumine during exposure to cigarette smoke reduces inflammation and lung injury.
Chronic obstructive pulmonary disease (COPD) is related to smoking and anti-inflammatory therapy is indicated. Among the mediators with anti-inflammatory properties, we highlight piperlongumine (PL), an alkaloid/amide of Piper longum. Here we evaluated the PL administration on an experimental model of respiratory inflammation resulting from exposure to cigarette smoke. Male Balb/c mice were exposed to burning of 10 commercial cigarettes, 2x/day, for five weeks on specific equipment. PL efficacy was evaluated in control, exposed to smoke without treatment and PL treated (2.0 mg/kg, 3x/week) groups. Animals were weighed and plethysmographic analyses performed at the end of the exposure protocol. Inflammatory cells were evaluated in the bronchoalveolar lavage (BAL) and hemoglobin and glucose in the blood. Lung fragments were processed for histopathological studies and AnxA1, COX-2, NF-kB and neutrophil elastase expressions. Plethysmography revealed that PL maintained pulmonary frequency, volume and ventilation parameters similar to controls, with respiratory volume reduction compared to untreated animals. Final weight was reduced in both exposed groups. PL decreased hemoglobin concentration, attenuated the reduction of glucose levels and reduced influx of lymphocytes, neutrophils and macrophages in BAL. Histopathologically occured infiltration of inflammatory cells, increase of the interalveolar septa and intra-alveolar spaces in untreated animals. But, PL administration recovered lung tissues and, immunohistochemically, promoted increased expression of AnxA1 and reduction of COX-2, NF-kB and neutrophil elastase. Together the results indicate that PL attenuates systemic and pulmonary inflammatory changes, partially by modulating the expression the endogenous AnxA1, and may represent a promising therapy in preventing the inflammation induced by cigarette smoke.


Street drug use among emergency patients in a Public Hospital in Turkey.
Country-specific numbers of street drug (SD) users are well documented. However, little data exists regarding these patients' clinical presentations and outcomes in the emergency department (ED). Therefore, management of these patients in the emergency setting is still a subject of debate. The aim of this study is to determine the symptoms and signs of SD users presenting to the ED, and to report the substances, treatments, and outcomes. In this single-center study, symptoms, clinical findings, diagnoses, and outcomes of patients who reported to have used SDs or were diagnosed as SD users were investigated within a 1-year study period. Chi-square and Mann-Whitney U tests were performed to compare independent variables. Mean age of the 425 study patients was 25 ± 9 years (range: 12-64 years), and 6.1% (n = 26) of the patients were females. SDs used before presentation to the ED were mostly synthetic cannabinoids and "ecstasy." Overall prevalence of SD user admissions in ED was 0.24%. The most common presenting complaint was weakness/faintness in 21.1% (n = 90). Depressed level of consciousness was the most common physical sign (33.3%, n = 142). Incidences of altered mental status were significantly higher among ecstasy and/or bonsai users (n = 14, 27.5%; P = 0.027 and n = 46, 64.8%; P < 0.001, respectively), compared to other SD users. While 23.1% (n = 98) of the SD users did not warrant any medical intervention, 6.6% of the users (n = 28) underwent advanced life support. Self-reported SD users were mostly young males who were treated symptomatically and discharged. Almost one-third-mostly ecstasy and bonsai users-had depressed level of consciousness and required resuscitation.


Participation in cognitively-stimulating activities is associated with brain structure and cognitive function in preclinical Alzheimer's disease.
This study tested the hypothesis that frequent participation in cognitively-stimulating activities, specifically those related to playing games and puzzles, is beneficial to brain health and cognition among middle-aged adults at increased risk for Alzheimer's disease (AD). Three hundred twenty-nine cognitively normal, middle-aged adults (age range, 43.2-73.8 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP) participated in this study. They reported their current engagement in cognitive activities using a modified version of the Cognitive Activity Scale (CAS), underwent a structural MRI scan, and completed a comprehensive cognitive battery. FreeSurfer was used to derive gray matter (GM) volumes from AD-related regions of interest (ROIs), and composite measures of episodic memory and executive function were obtained from the cognitive tests. Covariate-adjusted least squares analyses were used to examine the association between the Games item on the CAS (CAS-Games) and both GM volumes and cognitive composites. Higher scores on CAS-Games were associated with greater GM volumes in several ROIs including the hippocampus, posterior cingulate, anterior cingulate, and middle frontal gyrus. Similarly, CAS-Games scores were positively associated with scores on the Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility domains. These findings were not modified by known risk factors for AD. In addition, the Total score on the CAS was not as sensitive as CAS-Games to the examined brain and cognitive measures. For some individuals, participation in cognitive activities pertinent to game playing may help prevent AD by preserving brain structures and cognitive functions vulnerable to AD pathophysiology.


Accuracy of bone mapping and guided flapless implant placement in human cadavers using a model-based planning procedure.
The objective of this study was to assess the accuracy of the model-based NobelGuide method in transferring preoperative planning and estimation of bone volume to the surgical situation. Thirteen implant replicas were placed in bounded edentulous spaces in nine human cadavers. Highly restrictive guides were fabricated using preoperative bone mapping data. A stone cast was modified to represent the bone contours at the implant site. Postoperative impressions were taken for comparison with the planning cast that had been used to generate the guides. Mucoperiosteal flaps were raised over each implant site, and the areas were inspected for fenestrations, thread exposures, or dehiscences. A coordinate measuring device was used to obtain positional and angular information from each implant placed in the planned and postsurgical casts. These were compared and analyzed for clinical and statistical significance. The median value for linear accuracy in three dimensions for the model-based NobelGuide was 0.48 mm and the median angular deviation was 2.88 degrees. The greatest measured errors were still within clinically acceptable limits. The bone mapping was of sufficient diagnostic value for implant placement in sites with sufficient bone volume (greater than 5 mm buccolingually). In sites with insufficient bone volume, dehiscences were seen, but the accuracy was independent of bone volume. The use of the model-based NobelGuide encourages adherence to the restorative-driven approach. The accuracy of the method is within acceptable limits for guided surgery described in the literature, and the use of the bone mapping is satisfactory in cases with adequate bone volume. The technique can also be used in sites with insufficient bone volume, but a mucoperiosteal flap procedure is recommended. Int J Oral Maxillofac Implants 2010;25:999-1006.


Two new, near-infrared, fluorescent probes as potential tools for imaging bone repair.
A precise imaging technique to evaluate osteogenesis, osteodifferentiation, and osseointegration following peri-implant surgery is in high clinical demand. Herein, we report the generation of two new, near-infrared (NIR) fluorescent probes for use in the molecular imaging of bone repair. The first probe aims to monitor the in vitro differentiation of human mesenchymal stem cells (MSCs) into osteoblasts. A NIR fluorochrome was conjugated to a cyclic peptide that binds to integrin α5β1, a factor that promotes osteogenesis in MSCs and therefore functioned as an osteoblast-specific marker. The second probe aims to monitor osteogenesis, and was generated by conjugating the drug pamidronate to a NIR fluorescent gold nanocluster. Pamidronate specifically binds to hydroxyapatite (HA), a mineral present in bone that is produced by osteoblasts, and therefore provides a functional marker for new bone formation. Our results show that both probes bind to their specific targets in vitro-differentiated osteoblasts, and not to undifferentiated MSCs, and emit NIR fluorescence for functional detection. This in vitro work demonstrates the ability of these probes to bind to active osteoblasts and their mineral deposits and highlight their potential utility as clinical tools for the imaging of the osseointegration process at the molecular level.


Can telomere length predict bone health? A review of current evidence.
Telomeres are repetitive DNA sequences located at the end of chromosomes that serve as a protective barrier against chromosomal deterioration during cell division. Approximately 50-200 base pairs of nucleotides are lost per cell division, and new repetitive nucleotides are added by the enzyme telomerase, allowing telomere maintenance. Telomere shortening has been proposed as an indicator for biological aging, but its relationship with age-related osteoporosis is ambiguous. We summarize the current evidence on the relationship between telomere length and bone health in experimental and epidemiological studies, which serve as a scientific reference for the development of novel diagnostic markers of osteoporosis or novel therapeutics targeting telomere and telomerase of bone cells to treat osteoporosis.


Knockdown of nuclear Ca2+/calmodulin-dependent protein kinase phosphatase causes developmental abnormalities in zebrafish.
Nuclear Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP-N) is an enzyme that dephosphorylates and concomitantly downregulates multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs) in vitro. However, the functional roles of this enzyme in vivo are not well understood. To investigate the biological significance of CaMKP-N during zebrafish embryogenesis, we cloned and characterized zebrafish CaMKP-N (zCaMKP-N). Based on the nucleotide sequences in the zebrafish whole genome shotgun database, we isolated a cDNA clone for zCaMKP-N, which encoded a protein of 633 amino acid residues. Transiently expressed full-length zCaMKP-N in mouse neuroblastoma, Neuro2a cells, was found to be localized in the nucleus. In contrast, the C-terminal truncated mutant lacking RKKRRLDVLPLRR (residues 575-587) had cytoplasmic staining, suggesting that the nuclear localization signal of zCaMKP-N exists in the C-terminal region. Ionomycin treatment of CaMKIV-transfected Neuro2a cells resulted in a marked increase in the phosphorylated form of CaMKIV. However, cotransfection with zCaMKP-N significantly decreased phospho-CaMKIV in ionomycin-stimulated cells. Whole mount in situ hybridization analysis of zebrafish embryos showed that zCaMKP-N is exclusively expressed in the head and neural tube regions. Gene knockdown of zCaMKP-N using morpholino-based antisense oligonucleotides induced significant morphological abnormalities in zebrafish embryos. A number of apoptotic cells were observed in brain and spinal cord of the abnormal embryos. These results suggest that zCaMKP-N plays a crucial role in the early development of zebrafish.


Global analysis of gene expression in an rpoN mutant of Listeria monocytogenes.
The role of the alternative sigma(54) factor, encoded by the rpoN gene, was investigated in Listeria monocytogenes by comparing the global gene expression of the wild-type EGDe strain and an rpoN mutant. Gene expression, using whole-genome macroarrays, and protein content, using two-dimensional gel electrophoresis, were analysed. Seventy-seven genes and nine proteins, whose expression was modulated in the rpoN mutant as compared to the wild-type strain, were identified. Most of the modifications were related to carbohydrate metabolism and in particular to pyruvate metabolism. However, under the conditions studied, only the mptACD operon was shown to be directly controlled by sigma(54). Therefore, the remaining modifications seem to be due to indirect effects. In parallel, an in silico analysis suggests that sigma(54) may directly control the expression of four different phosphotransferase system (PTS) operons, including mptACD. PTS activity is known to have a direct effect on the pyruvate pool and on catabolite regulation. These results suggest that sigma(54) is mainly involved in the control of carbohydrate metabolism in L. monocytogenes via direct regulation of PTS activity, alteration of the pyruvate pool and modulation of carbon catabolite regulation.


The role of marriage in the causal pathway from economic conditions early in life to mortality.
This paper analyzes the interplay between early-life conditions and marital status, as determinants of adult mortality. We use individual data from Dutch registers (years 1815-2000), combined with business cycle conditions in childhood as indicators of early-life conditions. The empirical analysis estimates bivariate duration models of marriage and mortality, allowing for unobserved heterogeneity. Results show that conditions around birth and school going ages are important for marriage and mortality. Men typically enjoy a protective effect of marriage, whereas women suffer during childbearing ages. However, having been born under favorable economic conditions reduces female mortality during childbearing ages.


Subunit exchange of polydisperse proteins: mass spectrometry reveals consequences of alphaA-crystallin truncation.
The small heat shock protein, alpha-crystallin, plays a key role in maintaining lens transparency by chaperoning structurally compromised proteins. This is of particular importance in the human lens, where proteins are exposed to post-translational modifications over the life-time of an individual. Here, we examine the structural and functional consequences of one particular modification of alphaA-crystallin involving the truncation of 5 C-terminal residues (alphaA(1-168)). Using novel mass spectrometry approaches and established biophysical techniques, we show that alphaA(1-168) forms oligomeric assemblies with a lower average molecular mass than wild-type alphaA-crystallin (alphaA(WT)). Also apparent from the mass spectra of both alphaA(WT) and alphaA(1-168) assemblies is the predominance of oligomers containing even numbers of subunits; interestingly, this preference is more marked for alphaA(1-168). To examine the rate of exchange of subunits between assemblies, we mixed alphaB crystallin with either alphaA(WT) or alphaA(1-168) and monitored in a real-time mass spectrometry experiment the formation of heteroligomers. The results show that there is a significant decrease in the rate of exchange when alphaA(1-168) is involved. These reduced exchange kinetics, however, have no effect upon chaperone efficiency, which is found to be closely similar for both alphaA(WT) and alphaA(1-168). Overall, therefore, our results allow us to conclude that, in contrast to mechanisms established for analogous proteins from plants, yeast, and bacteria, the rate of subunit exchange is not the critical parameter in determining efficient chaperone behavior for mammalian alphaA-crystallin.


First-principles study of silicon nanowire approaching the bulk limit.
First-principles density functional theory calculations on hydrogenated silicon nanowires (SiNWs) with diameters up to 7.3 nm are carried out for comparing to experimentally relevant SiNWs and evaluating its radial doping profiles. We show that the direct band gap nature of both the small diameter (110) and (100) SiNWs fades when the diameter reaches beyond about 4 nm, where the difference of direct and indirect band gaps are close, within the experimental measurement uncertainty of ±0.1 eV, suggesting the diameter size where the gap nature transition starts. In addition, we reveal that core-surface boron (B) codoped SiNW forms more preferably at large diameter than that of the surface-surface codoped one, attributing to the lower energy configuration raised by the core B dopant at large diameter SiNW. More importantly, the diameter for such a preferential transition increases as the doping concentration decreases. Our results rationalize photoluminescent measurements and radial doping distributions of SiNWs.


Beyond the margins: real-time detection of cancer using targeted fluorophores.
Over the past two decades, synergistic innovations in imaging technology have resulted in a revolution in which a range of biomedical applications are now benefiting from fluorescence imaging. Specifically, advances in fluorophore chemistry and imaging hardware, and the identification of targetable biomarkers have now positioned intraoperative fluorescence as a highly specific real-time detection modality for surgeons in oncology. In particular, the deeper tissue penetration and limited autofluorescence of near-infrared (NIR) fluorescence imaging improves the translational potential of this modality over visible-light fluorescence imaging. Rapid developments in fluorophores with improved characteristics, detection instrumentation, and targeting strategies led to the clinical testing in the early 2010s of the first targeted NIR fluorophores for intraoperative cancer detection. The foundations for the advances that underline this technology continue to be nurtured by the multidisciplinary collaboration of chemists, biologists, engineers, and clinicians. In this Review, we highlight the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, and consider the unique challenges associated with their effective application in clinical settings.


An observational study of an employer intervention for children's healthy weight behaviors.
This observational study was undertaken to assess whether changes in healthy weight behaviors could be advanced in a short-term intervention involving parents and children at IBM. IBM's Children's Health Rebate offered a cash incentive for parents to complete a 12-week program of self-selected activities in family food planning and meals, family physical activity, and sedentary time related to electronic entertainment ("screen time"). A preprogram/postprogram comparison of self-reported activities was used to assess behavior change. A total of 22,265 (52.3%) employees elected to participate, 11,631 (52.2%) of whom completed all program requirements and earned a $150 cash rebate. Families completing the program reported significant changes in levels of physical activity, amount of entertainment screen time, and proportion of healthy meals. For example, family physical activity >3 times per week increased by 17.1 percentage points (from 23.2% to 40.3%), eating healthy dinners ≥ 5 days/week increased by 11.8 percentage points (from 74.9% to 86.7%), and entertainment screen time <1 hour/day increased by 8.3 percentage points for children (from 22.4% to 30.7%) and by 6.1 percentage points for adults (from 18.1% to 24.2%). The results of this short-term observational study suggest that healthy weight behaviors in children, adolescents, and parents can be improved by using a Web-based intervention linked with a cash incentive. The results also show that employers can activate parents and support a role for employers in community-based strategies for obesity prevention in children. Experimental designs with biometric data would strengthen the suggestion of positive impact.


Job, family, and gender: determinants of nonstandard work schedules among employed Americans in 1991.
This study provides the most recent national estimates of the prevalence of employment during nonstandard hours (evenings, nights, or rotating hours) and on weekends. It also examines in a multivariate context the relevance of job and family characteristics as determinants of such employment, separately for men and for women. The findings support the contention that the demand for employment during nonstandard hours and weekends is pervasive throughout the occupational hierarchy, but particularly in service occupations and in personal service industries and for both men and women. Gender differences exist, however, in the relevance of family factors. Being married reduces women's but not men's likelihood of employment during nonstandard hours, and the presence of children affects women's but not men's hours and days of employment. (The direction of the effect for women depends on the children's age.) Implications of these findings are discussed.


Celecoxib and radioresistant glioblastoma-derived CD133+ cells: improvement in radiotherapeutic effects. Laboratory investigation.
Glioblastoma, the most common primary brain tumor, has a poor prognosis, even with aggressive resection and chemoradiotherapy. Recent studies indicate that CD133(+) cells play a key role in radioresistance and recurrence of glioblastoma. Cyclooxygenase-2 (COX-2), which converts arachidonic acid to prostaglandins, is over-expressed in a variety of tumors, including CD133(+) glioblastomas. The COX-2-derived prostaglandins promote neovascularization during tumor development, and conventional radiotherapy increases the proportion of CD133(+) cells rather than eradicating them. The aim of the present study was to investigate the role of celecoxib, a selective COX-2 inhibitor, in enhancing the therapeutic effects of radiation on CD133(+) glioblastomas. Cells positive for CD133 were isolated from glioblastoma specimens and characterized by flow cytometry, then treated with celecoxib and/or ionizing radiation (IR). Clonogenic assay, cell irradiation, cell cycle analysis, Western blot, and xenotransplantation were used to assess the effects of celecoxib alone, IR alone, and IR with celecoxib on CD133(+) and CD133(-) glioblastoma cells. Three separate xenotransplantation experiments were carried out using 310 severe combined immunodeficient (SCID) mice: 1) an initial tumorigenicity evaluation in which 3 different quantities of untreated CD133(-) cells or untreated or pretreated CD133(+) cells (5 treatment conditions) from 7 different tumors were injected into the striatum of 2 mice (210 mice total); 2) a tumor growth study (50 mice); and 3) a survival study (50 mice). For these last 2 studies the same 5 categories of cells were used as in the tumorigenicity (untreated CD133(-) cells, untreated or pretreated CD133(+) cells, with pretreatment consisting of celecoxib alone, IR alone, or IR and celecoxib), but only 1 cell source (Case 2) and quantity (5 × 10(4) cells) were used. High levels of COX-2 protein were detected in the CD133(+) but not the CD133(-) glioblastoma cells. The authors further demonstrated that 30 μM celecoxib was able to effectively enhance the IR effect in inhibiting colony formation and increasing IR-mediated apoptosis in celecoxib-treated CD133(+) glioblastoma cells. Furthermore, reduction in radioresistance was correlated with the induction of G2/M arrest, which was partially mediated through the increase in the level of phosphorylated-cdc2. In vivo xenotransplant analysis further confirmed that CD133(+)-associated tumorigenicity was significantly suppressed by celecoxib treatment. Importantly, pretreatment of CD133(+) glioblastoma cells with a combination of celecoxib and IR before injection into the striatum of SCID mice resulted in a statistically significant reduction in tumor growth and a statistically significant increase in the mean survival rate of the mice. Celecoxib combined with radiation plays a critical role in the suppression of growth of CD133(+) glioblastoma stemlike cells. Celecoxib is therefore a radiosensitizing drug for clinical application in glioblastoma.


Effect of hydroxyapatite concentration and size on morpho-mechanical properties of PLA-based randomly oriented and aligned electrospun nanofibrous mats.
The growing demand for nanofibrous biocomposites able to provide peculiar properties requires systematic investigations of processing-structure-property relationships. Understanding the morpho-mechanical properties of an electrospun scaffold as a function of the filler features and mat microstructure can aid in designing these systems. In this work, the reinforcing effect of micrometric and nanometric hydroxyapatite particles in polylactic acid-based electrospun scaffold presenting random and aligned fibers orientation, was evaluated. The particles incorporation was investigated trough Fourier transform infrared spectroscopy in attenuated total reflectance. The morphology of the nanofibers was analyzed through scanning electron microscopy and it was correlated with the viscosity of polymeric solutions studied by rheological measurements. Scaffolds were mechanical characterized with tensile tests in order to find a correlation between the preparation method and the strength of the mats. The influence of hydroxyapatite particles on the crystallinity of the composites was investigated by differential scanning calorimetry. Finally, cell culture assays with pre-osteoblatic cells were conducted on a selected composite scaffold in order to compare the cell proliferation and morphology with that of polylactic acid scaffolds. Based on the results, we can prove that polylactic acid/hydroxyapatite composites can be one of the biomaterials with the greatest potential for bone tissue regeneration.


Magnetic-resonance studies of the geometry of bound substrate, coenzyme and activator on bovine-liver glutamate dehydrogenase.
ADP and ATP with a spin-label linked to the terminal phosphate are activators of glutamate dehydrogenase and bind to the same site as the activator ADP. There is hardly any interaction with the coenzyme site. Glutamate dehydrogenase can be modified with a ketone spin-label at a site in the active centre[Andree and Zantema, (1978) Biochemistry, 17, 778--783]. The spin-labelled activators interact with ketone spin-labelled glutamate dehydrogenase in the same way as with native glutamate dehydrogenase relative to the activator site, but show a stronger binding to the coenzyme site. Upon binding to the coenzyme site a spin-spin interaction between the ketone spin-label and the spin-labelled activators is observed. Nuclear magnetic resonance studies of the linewidth of 2-oxoglutarate and NADP+ bound to their functional sites on glutamate dehydrogenase without and with spin-labels result in distances between the ligand nuclei and the spin-labels. The results show that NADP+ binds in an open conformation consistent with the conformation in other dehydrogenases. The activator ADP binds in the neighbourhood of the active centre, but with very little or no overlap with the coenzyme site.


Associations Between Extracurricular Activity and Self-Regulation: A Longitudinal Study From 5 to 10 Years of Age.
Health promotion in youth is likely to benefit from enhancing academic achievement and physical activity. The present study examines how kindergarten childhood self-regulation skills and behaviors predict involvement in both structured and unstructured physical and nonphysical extracurricular activities in the fourth grade. As a second objective this study also investigated how kindergarten childhood participation in extracurricular activities predicts classroom engagement, reflective of self-regulation, by the fourth grade. Secondary analyses were conducted using prospective-longitudinal data. The Quebec Longitudinal Study of Child Development, Quebec, Canada. Participants were randomly selected at birth from a stratified sample of 2694 born in Québec, Canada, between 1997 and 1998. Participants were included if they had complete data on teacher ratings of child self-regulation as measured by classroom engagement and parent ratings of sports participation (n = 935). Teachers reported self-regulation skills in children through a measure of classroom engagement. Parents provided reports of child participation extracurricular activities. Ordinary least-squares regressions were conducted. A higher-frequency kindergarten involvement with structured physical activities was associated with fourth-grade classroom engagement (β = .061, 95% confidence interval [CI]: .017, .104). Better kindergarten classroom engagement predicted more frequent participation in fourth-grade structured physical activities (β = .799, 95% CI: .405, 1.192) and team sports (β = .408, 95% CI: .207, .608). Results suggest mutual relations between physical activity and self-regulation from kindergarten to grade four. This suggests strong learning skills indicative of self-regulation and opportunities to participate in supervised physical activities or sports teams may help children develop healthy dispositions and behaviors in emerging adolescence.


Convergent validity of ActiGraph and Actical accelerometers for estimating physical activity in adults.
The aim of the present study was to examine the convergent validity of two commonly-used accelerometers for estimating time spent in various physical activity intensities in adults. The sample comprised 37 adults (26 males) with a mean (SD) age of 37.6 (12.2) years from San Diego, USA. Participants wore ActiGraph GT3X+ and Actical accelerometers for three consecutive days. Percent agreement was used to compare time spent within four physical activity intensity categories under three counts per minute (CPM) threshold protocols: (1) using thresholds developed specifically for each accelerometer, (2) applying ActiGraph thresholds to regression-rectified Actical CPM data, and (3) developing new 'optimal' Actical thresholds. Using Protocol 1, the Actical estimated significantly less time spent in light (-16.3%), moderate (-2.8%), and vigorous (-0.4%) activity than the ActiGraph, but greater time spent sedentary (+20.5%). Differences were slightly more pronounced when the low frequency extension filter on the ActiGraph was enabled. The two adjustment methods (Protocols 2 and 3) improved agreement in this sample. Our findings show that ActiGraph and Actical accelerometers provide significantly different estimates of time spent in various physical activity intensities. Regression and threshold adjustment were able to reduce these differences, although some level of non-agreement persisted. Researchers should be aware of the inherent limitations of count-based physical activity assessment when reporting and interpreting study findings.


Are all perpetrators alike? Comparing risk factors for sexual coercion and aggression.
The present study developed and contrasted predictive models of male nonphysical sexual coercion (e.g., verbal pressure or manipulation) and physical sexual aggression (e.g., incapacitation, physical force, or threats) using a sample of 369 incarcerated males to identify shared and unique risk factors for each form of sexual perpetration. Results revealed a set of shared risk characteristics that predisposed individuals to both sexual coercion and aggression (i.e., belief in rape myths, sexual promiscuity, aggressive tendencies, and empathic deficits). In addition, findings indicated that whether the offenders engaged in only sexual coercion or also used more violent sexually aggressive tactics depended on the presence of two sets of traits unique to these forms of perpetration. Specifically, sexual coercers tended to possess traits that facilitated the use of verbal tactics (i.e., ability to manipulate others and to imagine others' emotional reactions). In contrast, sexual aggressors had characteristics that could increase their willingness to "cross the line" and resort to more violent means to obtain sex from an unwilling partner (i.e., hostility toward women, egocentricity, an impulsive disregard for sociolegal proscriptions, and childhood emotional abuse). A model of general sexual perpetration that directly contrasted sexually coercive and aggressive men was also developed, and hostility toward women was identified as the only predictor capable of predicting perpetrator group membership. Together, these findings suggest that although sexual coercers and aggressors share some underlying risk factors, the etiological patterns of these behaviors are distinct and necessitate individual attention by researchers and prevention programs.


Effect of antioxidants on polyunsaturated fatty acids - review.
This paper aims to review the available literature data and provide an overview regarding the efficiency of antioxidants to prevent peroxidation of polyunsaturated fatty acids. Lipid peroxidation is a serious problem that often leads to a loss of shelf-life, reduced consumer acceptability, poorer functionality, lower nutritional value, and poorer safety. It represents an oxidative degradation of polyunsaturated fatty acids incorporated in cell membrane lipids or in lipoproteins, but also in vegetables and food oils rich in PUFA n-3. It is a complex process that leads to the production of numerous highly reactive metabolites with consequences for food preservation and for the development of various diseases. The targets of lipid oxidation are polyunsaturated fatty acids. Lipid peroxidation can proceed by means of two different reactions that lead to the formation of hydroperoxides as primary products. Hydroperoxides decompose rapidly to give many secondary products, such as lipid free radicals, which contribute to increased oxidation of other molecules, such as proteins, nucleic acids and other lipids. Lipid peroxidation is a major problem for the food industry, as well as for human health, since it is associated with many diseases. The use of antioxidants reduces oxidative damage.


Cellular immune response to phogrin in the NOD mouse: cloned T-cells cause destruction of islet transplants.
The ability of nonobese diabetic (NOD) mice to mount a cellular immune response to the secretory granule protein tyrosine phosphatase (PTP), phogrin was evaluated by immunization of 8- to 12-week-old animals with recombinant phogrin in complete Freund's adjuvant. Draining lymph nodes displayed a robust proliferative response to the protein, as did derived T-cell lines and clones. Ten clones obtained by limiting dilution were all CD4+ and of a T-helper-1-like phenotype, but showed variation in their Vbeta usage. Of the 10 clones, 3 responded to endogenous antigens in rat islets. Two of these caused the destruction of rat islets that had been transplanted under the kidney capsule of streptozotocin-treated NOD scid mice without affecting adjacent thyroid implants. The results demonstrate the feasibility of generating antigen-specific diabetes-inducing CD4+ cells by direct immunization of NOD mice and their potential use for further studies of the antigenic epitopes in the PTP family members. The conclusion, based on serological studies, that PTP members do not play a role in the pathogenesis of type 1 diabetes in rodent models needs reevaluation in light of these findings.


Identification of extracellular glycerophosphodiesterases in Pseudomonas and their role in soil organic phosphorus remineralisation.
In soils, phosphorus (P) exists in numerous organic and inorganic forms. However, plants can only acquire inorganic orthophosphate (Pi), meaning global crop production is frequently limited by P availability. To overcome this problem, rock phosphate fertilisers are heavily applied, often with negative environmental and socio-economic consequences. The organic P fraction of soil contains phospholipids that are rapidly degraded resulting in the release of bioavailable Pi. However, the mechanisms behind this process remain unknown. We identified and experimentally confirmed the function of two secreted glycerolphosphodiesterases, GlpQI and GlpQII, found in Pseudomonas stutzeri DSM4166 and Pseudomonas fluorescens SBW25, respectively. A series of co-cultivation experiments revealed that in these Pseudomonas strains, cleavage of glycerolphosphorylcholine and its breakdown product G3P occurs extracellularly allowing other bacteria to benefit from this metabolism. Analyses of metagenomic and metatranscriptomic datasets revealed that this trait is widespread among soil bacteria with Actinobacteria and Proteobacteria, specifically Betaproteobacteria and Gammaproteobacteria, the likely major players.


A Comparison of Body Composition Across Two Phases of the Menstrual Cycle Utilizing Dual-Energy X-Ray Absorptiometry, Air Displacement Plethysmography, and Bioelectrical Impedance Analysis.
The purpose of this investigation was to utilize several different technologies to compare body composition results across two phases of the menstrual cycle, and to investigate whether being on hormonal birth control or not has any effect on results. The secondary purpose was to determine if body satisfaction or perception of fluid retention differed across phases or between groups. A total of 39 females with a mean age of 26 ± 7 yrs were included in the study, 15 were on hormonal birth control (BC) and 24 were not (non-BC). Participants came into the lab for two trials: once while menstruating and another during the estimated pre-ovulation phase of the menstrual cycle. Demographic and body satisfaction questionnaires were completed prior to body composition testing. This testing included dual-energy x-ray absorptiometry, BOD POD®, and three separate bioelectrical impedance analyses. Participants completed the body satisfaction questionnaire and all body composition tests on each trial. No significant differences (P > 0.05) were found between body fat percentage or total body water estimates taken during menses and pre-ovulation for the BC or non-BC group. There was no significant difference (P > 0.05) in overall body satisfaction across the two phases for the non-BC group, though the BC group had significantly lower body satisfaction during menses (P < 0.01). Participants in both groups identified feeling more bloated during menses (P < 0.001). Results suggest that menses should not affect the reliability of body composition estimates regardless of whether or not females are on hormonal BC.


Optimizing acupuncture treatment for dry eye syndrome: a systematic review.
In a former meta-analysis review, acupuncture was considered a potentially effective treatment for dry eye syndrome (DES), but there were heterogeneities among the outcomes. We updated the meta-analysis and conducted subgroup analysis to reduce the heterogeneity and suggest the most effective acupuncture method based on clinical trials. We searched for randomized controlled trials (RCTs) in 10 databases (MEDLINE, EMBASE, CENTAL, AMED, SCOPUS, CNKI, Wangfang database, Oriental Medicine Advanced Searching Integrated System (OASIS), Koreamed, J-stage) and searched by hand to compare the effects of acupuncture and artificial tears (AT). We also conducted subgroup analysis by (1) method of intervention (acupuncture only or acupuncture plus AT), (2) intervention frequency (less than 3 times a week or more than 3 times a week), (3) period of treatment (less than 4 weeks or more than 4 weeks), and (4) acupoints (BL1, BL2, ST1, ST2, TE23, Ex-HN5). The Bucher method was used for subgroup comparisons. Nineteen studies with 1126 patients were included. Significant improvements on the Schirmer test (weighted mean difference[WMD], 2.14; 95% confidence interval[CI], 0.93 to 3.34; p = 0.0005) and break up time (BUT) (WMD, 0.98; 95% CI, 0.79 to 1.18; p < 0.00001) were reported. In the subgroup analysis, acupuncture plus AT treatment had a weaker effect in BUT but a stronger effect on the Schirmer test and a better overall effect than acupuncture alone. For treatment duration, treatment longer than 1 month was more effective than shorter treatment. With regard to treatment frequency, treatment less than three times a week was more effective than more frequent treatment. In the acupoint analysis, acupuncture treatment including the BL2 and ST1 acupoints was less effective than treatment that did not include them. None of those factors reduced the heterogeneity. Acupuncture was more effective than AT in treating DES but showed high heterogeneity. Intervention differences did not influence the heterogeneity.


Cloning and expression of the mouse serotonin transporter.
A mouse brain cDNA encoding the high-affinity serotonin transporter (SERT) has been identified and characterized. The mouse transporter sequence (mSERT) encodes a protein of 630 amino acids which contains twelve potential transmembrane domains (TMDs), N-linked glycosylation and kinase-mediated phosphorylation sites, and high levels of homology with rat and human SERTs. Heterologous expression of mSERT in COS-I cells resulted in a [3H]serotonin transport activity characterized by kinetic saturability (Km = 403 +/- 42 nM. Vmax = 1.02 +/- 0.10 pmol/mg/min), Na1 and Cl- dependences (5HT:Na+:Cl- coupling ratio of 1:1:1), and sensitivity to known inhibitors of serotonin transport (including antidepressant and psychostimulant agents). Northern analysis using mSERT cDNA as probe revealed a single 3.4 kb mRNA species expressed in mouse lung, midbrain and brainstem regions, and absent from heart and liver. In situ hybridization studies further established the specific localization of mSERT gene expression to the raphe nuclei of the mouse midbrain. The identified mSERT cDNA sequence provides a new tool for the evaluation of serotonin transport pharmacology in heterologous expression systems and provides an opportunity for the evaluation of mSERT gene expression in a well-characterized model of mammalian development.


CRISPR-Cas12a/Cpf1-assisted precise, efficient and multiplexed genome-editing in Yarrowia lipolytica.
CRISPR-Cas9 has been widely adopted as the basic toolkit for precise genome-editing and engineering in various organisms. Alternative to Cas9, Cas12 or Cpf1 uses a simple crRNA as a guide and expands the protospacer adjacent motif (PAM) sequence to TTTN. This unique PAM sequence of Cpf1 may significantly increase the on-target editing efficiency due to lower chance of Cpf1 misreading the PAMs on a high GC genome. To demonstrate the utility of CRISPR-Cpf1, we have optimized the CRISPR-Cpf1 system and achieved high-editing efficiency for two counter-selectable markers in the industrially-relevant oleaginous yeast Yarrowia lipolytica: arginine permease (93% for CAN1) and orotidine 5'-phosphate decarboxylase (~96% for URA3). Both mutations were validated by indel mutation sequencing. For the first time, we further expanded this toolkit to edit three sulfur house-keeping genetic markers (40%-75% for MET2, MET6 and MET25), which confers yeast distinct colony color changes due to the formation of PbS (lead sulfide) precipitates. Different from Cas9, we demonstrated that the crRNA transcribed from a standard type II RNA promoter was sufficient to guide Cpf1 endonuclease activity. Furthermore, modification of the crRNA with 3' polyUs facilitates the faster maturation and folding of crRNA and improve the genome editing efficiency. We also achieved multiplexed genome editing, and the editing efficiency reached 75%-83% for duplex genomic targets (CAN1-URA3 and CAN1-MET25) and 41.7% for triplex genomic targets (CAN1-URA3-MET25). Taken together, this work expands the genome-editing toolbox for oleaginous yeast species and may accelerate our ability to engineer oleaginous yeast for both biotechnological and biomedical applications.


JNK-dependent cell cycle stalling in G2 promotes survival and senescence-like phenotypes in tissue stress.
The restoration of homeostasis after tissue damage relies on proper spatial-temporal control of damage-induced apoptosis and compensatory proliferation. In Drosophila imaginal discs these processes are coordinated by the stress response pathway JNK. We demonstrate that JNK signaling induces a dose-dependent extension of G2 in tissue damage and tumors, resulting in either transient stalling or a prolonged but reversible cell cycle arrest. G2-stalling is mediated by downregulation of the G2/M-specific phosphatase String(Stg)/Cdc25. Ectopic expression of stg is sufficient to suppress G2-stalling and reveals roles for stalling in survival, proliferation and paracrine signaling. G2-stalling protects cells from JNK-induced apoptosis, but under chronic conditions, reduces proliferative potential of JNK-signaling cells while promoting non-autonomous proliferation. Thus, transient cell cycle stalling in G2 has key roles in wound healing but becomes detrimental upon chronic JNK overstimulation, with important implications for chronic wound healing pathologies or tumorigenic transformation.


The impact of common co-morbidities (as measured using the Charlson index) on hip fracture risk in elderly men: a population-based cohort study.
We used a large population-based health care database to determine the impact of common co-morbidities on hip fracture risk amongst elderly men. We demonstrated that diabetes, chronic obstructive pulmonary disease, renal failure, HIV infection, dementia, and cerebrovascular disease are independent predictors of hip fracture, as is a Charlson score of ≥ 3. Risk factors for hip fractures in men are still unclear. We aimed to identify common co-morbidities (amongst those in the Charlson index) that confer an increased risk of hip fracture amongst elderly men. We conducted a population-based cohort study using data from the SIDIAP (Q) database. SIDIAP(Q) contains primary care and hospital inpatient records of a representative 30% of the population of Catalonia, Spain (>2 million people). All men aged ≥ 65 years registered on 1 January 2007 were followed up until 31 December 2009. Both exposure (co-morbidities in the Charlson index) and outcome (incident hip fractures) were ascertained using ICD codes. Poisson regression models were fitted to estimate the effect of (1) each individual co-morbidity and (2) the composite Charlson index score, on hip fracture risk, after adjustment for age, body mass index, smoking, alcohol drinking, and use of oral glucocorticoids. We observed 186,171 men for a median (inter-quartile range) of 2.99 (2.37-2.99) years. In this time, 1,718 (0.92%) participants had a hip fracture. The following co-morbidities were independently associated with hip fractures: diabetes mellitus, chronic obstructive pulmonary disease (COPD), renal failure, HIV infection, dementia, and cerebrovascular disease. A Charlson score of ≥ 3 conferred an increased hip fracture risk. Common co-morbidities including diabetes, COPD, cerebrovascular disease, renal failure, and HIV infection are independently associated with an increased risk of hip fracture in elderly men. A Charlson score of 3 or more is associated with a 50% higher risk of hip fracture in this population.


Elicitation of Protective Antibodies against 20 Years of Future H3N2 Cocirculating Influenza Virus Variants in Ferrets Preimmune to Historical H3N2 Influenza Viruses.
The vast majority of people already have preexisting immune responses to influenza viruses from one or more subtypes. However, almost all preclinical studies evaluate new influenza vaccine candidates in immunologically naive animals. Recently, our group demonstrated that priming naive ferrets with broadly reactive H1 COBRA HA-based vaccines boosted preexisting antibodies induced by wild-type H1N1 virus infections. These H1 COBRA hemagglutinin (HA) antigens induced antibodies with HAI activity against multiple antigenically different H1N1 viral variants. In this study, ferrets, preimmune to historical H3N2 viruses, were vaccinated with virus-like particle (VLP) vaccines expressing either an HA from a wild-type H3 influenza virus or a COBRA H3 HA antigen (T6, T7, T10, or T11). The elicited antisera had the ability to neutralize virus infection against either a panel of viruses representing vaccine strains selected by the World Health Organization or a set of viral variants that cocirculated during the same time period. Preimmune animals vaccinated with H3 COBRA T10 HA antigen elicited sera with higher hemagglutination inhibition (HAI) antibody titers than antisera elicited by VLP vaccines with wild-type HA VLPs in preimmune ferrets. However, while the T11 COBRA vaccine did not elicit HAI activity, the elicited antibodies did neutralize antigenically distinct H3N2 influenza viruses. Overall, H3 COBRA-based HA vaccines were able to neutralize both historical H3 and contemporary, as well as future, H3N2 viruses with higher titers than vaccines with wild-type H3 HA antigens. This is the first report demonstrating the effectiveness of a broadly reactive H3N3 vaccine in a preimmune ferret model.IMPORTANCE After exposure to influenza virus, the host generates neutralizing anti-hemagglutinin (anti-HA) antibodies against that specific infecting influenza strain. These antibodies can also neutralize some, but not all, cocirculating strains. The goal of next-generation influenza vaccines, such as HA head-based COBRA, is to stimulate broadly protective neutralizing antibodies against all strains circulating within a subtype, in particular those that persist over multiple influenza seasons, without requiring an update to the vaccine. To mimic the human condition, COBRA HA virus-like particle vaccines were tested in ferrets that were previously exposed to historical H3N2 influenza viruses. In this model, these vaccines elicited broadly protective antibodies that neutralized cocirculating H3N2 influenza viruses isolated over a 20-year period. This is the first study to show the effectiveness of H3N3 COBRA HA vaccines in a host with preexisting immunity to influenza.


Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin.
Arginine, phenylalanine, and tryptophan have been previously shown to improve the solid-state stability of amorphous indomethacin. The present study investigates the ability of these amino acids to prolong the supersaturation of indomethacin in both aqueous and biorelevant conditions either when freely in solution or when formulated as co-amorphous mixtures. The co-amorphous amino acid-indomethacin mixtures (molar ratio 1:1) and amorphous indomethacin were prepared by cryomilling. Dissolution and precipitation tests were performed in buffer solutions (pH 5 and 6.5) and in Fed and Fasted State Simulated Intestinal Fluids (FeSSIF and FaSSIF, respectively). Precipitation tests were conducted with the solvent shift method. The supersaturation stability of indomethacin and the precipitation inhibitory effect of amino acids were evaluated by calculating the supersaturation factor and the excipient gain factor, respectively. Biorelevant media exerted a significant effect on indomethacin solubility but had little effect on the supersaturation stability. Arginine had the most significant impact on the dissolution properties of indomethacin, but also phenylalanine and tryptophan stabilized supersaturation in some media when formulated as co-amorphous mixtures with indomethacin. Only arginine stabilized supersaturation without co-amorphization, an effect only observed in media of pH 6.5. The unique behavior of the arginine-indomethacin mixture was further demonstrated by the abrupt formation of a precipitate, when an excess physical mixture of arginine and indomethacin was added to FeSSIF (pH 6.5). The solid-state investigation of this precipitate indicated that it probably consisted of crystalline arginine-indomethacin salt with possibly some residual crystalline starting materials.


Model specification and the reliability of fMRI results: implications for longitudinal neuroimaging studies in psychiatry.
Functional Magnetic Resonance Imagine (fMRI) is an important assessment tool in longitudinal studies of mental illness and its treatment. Understanding the psychometric properties of fMRI-based metrics, and the factors that influence them, will be critical for properly interpreting the results of these efforts. The current study examined whether the choice among alternative model specifications affects estimates of test-retest reliability in key emotion processing regions across a 6-month interval. Subjects (N = 46) performed an emotional-faces paradigm during fMRI in which neutral faces dynamically morphed into one of four emotional faces. Median voxelwise intraclass correlation coefficients (mvICCs) were calculated to examine stability over time in regions showing task-related activity as well as in bilateral amygdala. Four modeling choices were evaluated: a default model that used the canonical hemodynamic response function (HRF), a flexible HRF model that included additional basis functions, a modified CompCor (mCompCor) model that added corrections for physiological noise in the global signal, and a final model that combined the flexible HRF and mCompCor models. Model residuals were examined to determine the degree to which each pipeline met modeling assumptions. Results indicated that the choice of modeling approaches impacts both the degree to which model assumptions are met and estimates of test-retest reliability. ICC estimates in the visual cortex increased from poor (mvICC = 0.31) in the default pipeline to fair (mvICC = 0.45) in the full alternative pipeline - an increase of 45%. In nearly all tests, the models with the fewest assumption violations generated the highest ICC estimates. Implications for longitudinal treatment studies that utilize fMRI are discussed.


Retinoic acid signaling restricts the cardiac progenitor pool.
Organogenesis begins with specification of a progenitor cell population, the size of which provides a foundation for the organ's final dimensions. Here, we present a new mechanism for regulating the number of progenitor cells by limiting their density within a competent region. We demonstrate that retinoic acid signaling restricts cardiac specification in the zebrafish embryo. Reduction of retinoic acid signaling causes formation of an excess of cardiomyocytes, via fate transformations that increase cardiac progenitor density within a multipotential zone. Thus, retinoic acid signaling creates a balance between cardiac and noncardiac identities, thereby refining the dimensions of the cardiac progenitor pool.


Elevation of cyclic adenosine 3',5'-monophosphate potentiates activation of mitogen-activated protein kinase by growth factors in LNCaP prostate cancer cells.
Prostate cells are simultaneously exposed to a variety of peptide growth factors and neuropeptides that elevate cAMP. Both the growth factors and cAMP have large effects on the growth, differentiation, and movement of many cell types. Because mitogen-activated protein kinase (MAPK) is central to these effects, we analyzed the ways in which these agonists interact in regulating MAPK in prostate cancer cells. We show that, in LNCaP prostate cancer cells, elevation of intracellular cAMP can potentiate the ability of epidermal growth factor (EGF), interleukin 6, and serum to activate MAPK and that this potentiation depends on protein kinase A and Rap1. The response to cAMP is different in the androgen-independent prostate cancer cell line PC-3, where elevation of cAMP slightly inhibits MAPK activation by EGF. We also show that treatment of LNCaP with the calcium ionophore A23187 or the phorbol ester phorbol 12-myristate 13-acetate activates MAPK, but the activation of MAPK by these agonists is inhibited rather than potentiated by increasing cAMP. Finally, we show that phorbol 12-myristate 13-acetate and interleukin 6 can potentiate the signaling activity of EGF. We conclude that neuroendocrine factors that elevate cAMP sensitize LNCaP prostate cancer cells to signaling by peptide growth factors and that low levels of mixtures of growth factors can activate intracellular signaling to a greater degree than would be predicted from the activity of the individual agonists.


Caring for Families Separated by Changing Immigration Policies and Enforcement: A Cultural Psychiatry Perspective.
Recent changes in U.S. immigration policies and enforcement have precipitated a 300% rise in arrests and planned deportations. Although some family members face deportation, other family members may have state-sanctioned status. Such mixed status puts hundreds of thousands of families at risk of forced separation and associated mental health problems. Building on cross-cultural work with refugee families and other groups and on work with families separated by parental incarceration, the authors provide recommendations to guide clinicians working with families who are separated or who fear separation. Mental health problems among separated families can in part be addressed through identifying the origins of distress, elucidating family structures and roles, strengthening communication practices, linking with legal and economic resources, and facilitating decision making through distress reduction.


Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice.
Acute pancreatitis has long been considered a disorder of pancreatic self-digestion, in which intracellular activation of digestive proteases induces tissue injury. Chemokines, released from damaged pancreatic cells then attract inflammatory cells, whose systemic action ultimately determines the disease severity. In the present work the opposite mechanism is investigated; that is, whether and how inflammatory cells can activate intracellular proteases. Using mice either deficient for the CD18-α subunit of the membrane attack complex-1 (MAC-1) complex or tumour necrosis factor (TNF)α, as well as after depletion of leucocyte subpopulations, pancreatitis was induced by 7-hourly caerulein injections (50 μg/kg, intraperitoneally). Pancreatic acini were coincubated in vitro from wild-type and cathepsin-B-deficient animals with phorbol-12-myristate-13-acetate (PMA)-activated neutrophils and macrophages, caerulein or TNFα, and activities of trypsin, cathepsin-B and caspase-3 were measured, as well as necrosis using fluorogenic substrates. TNFα was inhibited with monospecific antibodies. Deletion of CD18 prevented transmigration of leucocytes into the pancreas during pancreatitis, greatly reduced disease severity and abolished digestive protease activation. Depletion of neutrophils and macrophages equally reduced premature trypsinogen activation and disease severity. In vitro activated neutrophils and macrophages directly induced premature protease activation and cell death in pancreatic acini and stimulation of acini with TNFα induced caspase-3 activation and necrosis via a cathepsin-B and calcium-dependent mechanism. Neutralising antibodies against TNFα and genetic deletion of TNFα prevented leucocyte-induced trypsin activity and necrosis in isolated acini. The soluble inflammatory cell mediator TNFα directly induces premature protease activation and necrosis in pancreatic acinar cells. This activation depends on calcium and cathepsin-B activity. The findings from the present work further suggest that targeting TNFα, for which pharmaceutical agents are readily available, could be an effective treatment strategy that directly addresses the cellular causes of pancreatitis.


Spatial and temporal distribution of proopiomelanotropin and proopiocortin mRNA during the life cycle of the sea lamprey: a qualitative and quantitative in situ hybridization study.
Two POMC-like pituitary prohormones proopiocortin (POC) and proopiomelanotropin (POM) have been characterized from adult sea lampreys (Petromyzon marinus). POC encodes a nasohypophysial factor (NHF), ACTH, an MSH, and beta-END; and POM encodes MSH-A, MSH-B, and beta-END. Two radiolabeled riboprobes, one encoding a unique portion of POC mRNA and the other encoding the MSH-B domain unique to POM mRNA, were generated in order to examine the expression of POC and POM during the life cycle of the sea lamprey by in situ hybridization. POC expression appears evenly distributed throughout most cells of the rostral pars distalis (RPD) during the entire life cycle. POC expression also occurs in scattered cells of the caudal (proximal) pars distalis (CPD) at stage 5 of metamorphosis. By the prespawner period, POC expression is mainly distributed in the dorsal aspect of this region. POM expression was completely confined to most cells of the pars intermedia (PI) at all periods examined. Quantitative, computer-assisted, image analysis of POM expression revealed high signal densities in all larvae which decreased by early metamorphosis, steadily increased and reached high levels by late metamorphosis (stages 6 and 7), and attained even higher levels in prespawners. Volumetric analysis revealed that the net volume of POM expressing cells is at its lowest in larvae and increases during subsequent development. Analysis of signal density and volumetric measurements of POC expression revealed that POC expression in the RPD is low in larvae and steadily increases during subsequent intervals of the life cycle reaching very high levels by the prespawning period. POC expression in the CPD, first visible at stage 5, increases steadily throughout the remainder of metamorphosis and reaches the highest levels of expression in prespawning animals. These results would implicate the role of POM and POC in some developmental processes but not in the initiation of metamorphosis. The very high levels of POM and POC expression in prespawner animals suggest that the two genes may have important roles at this time in the life cycle of lampreys.


Lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species.
Acute cessation of flow (ischemia) leads to depolarization of the endothelial cell (EC) membrane mediated by K(ATP) channels and followed by production of reactive oxygen species (ROS) from NADPH oxidase. We postulated that ROS are a signal for initiating EC proliferation associated with the loss of shear stress. Flow cytometry was used to identify proliferating CD31-positive pulmonary microvascular endothelial cells (mPMVECs) from wild-type, Kir6.2-/-, and gp91phox-/- mice. mPMVECs were labeled with PKH26 and cultured in artificial capillaries for 72 h at 5 dyn/cm2 (flow adaptation), followed by 24 h of stop flow or continued flow. ROS production during the first hour of ischemia was markedly diminished compared with wild-type mice in both types of gene-targeted mPMVECs. Cell proliferation was defined as the proliferation index (PI). After 72 h of flow, >98% of PKH26-labeled wild-type mPMVECs were at a single peak (PI 1.0) and the proportion of cells in the S+G2/M phases were at 5.8% on the basis of cell cycle analysis. With ischemia (24 h), PI increased to 2.5 and the ratio of cells in S+G2/M phases were at 35%. Catalase, diphenyleneiodonium, and cromakalim markedly inhibited ROS production and cell proliferation in flow-adapted wild-type mPMVECs. Significant effects of ischemia were not observed in Kir6.2-/- and gp91phox-/- cells. ANG II activation of NADPH oxidase was unaffected by KATP gene deletion. Thus loss of shear stress in flow-adapted mPMVECs results in cell division associated with ROS generated by NADPH oxidase. This effect requires a functioning cell membrane KATP channel.


Differences in level of care at the end of life according to race.
Tailoring care for patients and their families at the end of life is important. To examine factors associated with patients' choices for level of care at the end of life. Data on demographics and level of care (full code, do not resuscitate, or withdrawal of life support) were collected on 1072 patients who died between January 1998 and June 2006 on a cardiac care unit. Logistic regression was used to identify factors associated with level of care. Median (interquartile range) age of blacks was 64 (50-74) years and of whites was 70 (62-78) years. At the time of death, the level of care differed significantly between blacks and whites: 41.8% (n = 112) of blacks versus 26.7% (n = 194) of whites chose full code (P <.001), 37.3% (n = 96) of blacks versus 43.9% (n = 317) of whites chose do not resuscitate (P = .03), and 20.9% (n = 54) of blacks versus 29.3% (n = 210) of whites chose withdrawal of life support (P = .005). After age, sex, diagnosis, and lengths of stay in intensive care unit and hospital were controlled for, blacks were more likely than whites to choose full code status at the time of death (odds ratio 1.91 [95% confidence interval, 2.63-1.39], P < .001). Blacks are 1.9 times as likely as others to choose full code at time of death. Cultural differences should be acknowledged when providing end-of-life care.


Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors.
Exosomes are nano-sized (40 - 100 nm), extracellular vesicles, of endosomal origin. They are released by cells and found in many body fluids, including plasma. Exosomes contain proteins, microRNAs (miRNAs), and messenger RNAs (mRNAs) that can be transferred between cells. The discovery that exosomes contain RNA, and that this encapsulated RNA could potentially be transferred over distances in vivo, reinforced the importance of exosomes in cell-to-cell communication. The existence of exosomes, as a naturally occurring delivery system of RNA, enables their use as both biomarkers and vectors in gene therapy. This review provides an overview of studies reporting that exosomal miRNA and mRNA in plasma can serve as a diagnostic marker in various types of cancers. In addition, the recent finding that exosomes can be used as vectors for delivery of small interfering RNA (siRNA) in mice, with therapeutic effects, is also reviewed. The data reviewed here suggest that exosomal RNA has the potential to play an important role in the diagnosis, prognosis, and treatment of diseases in the future.


Do Medical Homes Improve Quality of Care for Persons with Multiple Chronic Conditions?
To examine the association between medical home enrollment and receipt of recommended care for Medicaid beneficiaries with multiple chronic conditions (MCC). Secondary claims data from fiscal years 2008-2010. The sample included nonelderly Medicaid beneficiaries with at least two of eight target conditions (asthma, chronic obstructive pulmonary disease, diabetes, hypertension, hyperlipidemia, seizure disorder, major depressive disorder, and schizophrenia). We used linear probability models with person- and year-level fixed effects to examine the association between patient-centered medical home (PCMH) enrollment and nine disease-specific quality-of-care metrics, controlling for selection bias and time-invariant differences between enrollees. This study uses a dataset that links Medicaid claims with other administrative data sources. Patient-centered medical home enrollment was associated with an increased likelihood of receiving eight recommended mental and physical health services, including A1C testing for persons with diabetes, lipid profiles for persons with diabetes and/or hyperlipidemia, and psychotherapy for persons with major depression and persons with schizophrenia. PCMH enrollment was associated with overuse of short-acting β-agonists among beneficiaries with asthma. The PCMH model can improve quality of care for patients with multiple chronic conditions.


Temozolomide and 13-cis retinoic acid in patients with anaplastic gliomas: a prospective single-arm monocentric phase-II study (RNOP-05).
The objective of this prospective, monocentric phase-II pilot study was to evaluate toxicity and efficacy of neoadjuvant temozolomide (TMZ) and 13-cis retinoic acid (13-cRA) treatment in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection. The primary endpoint of the study was median progression-free survival (PFS). Secondary endpoints were toxicity and PFS rates at 6, 12 and 24 months. Thirty-two adult patients were included in the study and treated with a median number of 10 TMZ and 13-cRA cycles (range 1-26). The majority of patients had favorable prognostic factors characterized by young age, complete resection, oligodendroglial histology, 1p/19q co-deletion, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase 1 (IDH1) mutation. Grade 3/4 myelotoxicity occurred in 5/32 patients, and about 90% of patients suffered from grade 2/3 adverse events attributable to 13-cRA. The median PFS was 37.8 months (95% CI 22.2-53.4). The 6-, 12- and 24-month PFS rates were 84.4, 75 and 42.4%. The extent of tumor resection was the only prognostic factor associated with better PFS. TMZ and 13-cRA treatment did not improve PFS when retrospectively compared to the TMZ-treated group within the randomized NOA-04 phase-III trial. In conclusion, 13-cRA addition to TMZ in a neoadjuvant setting showed acceptable toxicity, but did not yield an advantage in PFS in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection.


Endocrine disruptors and dental materials: health implications associated with their use in Brazil.
This study analyzes international historical trends in the use of different types of materials in dental practice. The author describes the chemical properties of their ingredients and the potential and observed adverse effects in patients and dental technicians resulting from clinical or occupational exposure to various metals like beryllium, used to produce metal alloys. The growing use of various products (resin cements, ionomer cements, aesthetic restorative materials, resins, endodontal cements, and others) based on the compound bisphenol-A, whose chemical structure is similar to that of estrogen. Considering the demographic and contemporary work force characteristics of those involved in dental practice in the Brazil, the study highlights the possible effect of the use of these materials in both male and female patients and all age strata, as well as in health professionals with occupational exposure to products containing bisphenol-A.


Freeze Granulated Zeolites X and A for Biogas Upgrading.
Biogas is a potential renewable energy resource that can reduce the current energy dependency on fossil fuels. The major limitation of utilizing biogas fully in the various applications is the presence of a significant volume fraction of carbon dioxide in biogas. Here, we used adsorption-driven CO2 separation using the most prominent adsorbents, NaX (faujasite) and CaA (Linde Type A) zeolites. The NaX and CaA zeolites were structured into hierarchically porous granules using a low-cost freeze granulation technique to achieve better mass transfer kinetics. The freeze granulation processing parameters and the rheological properties of suspensions were optimized to obtain homogenous granules of NaX and CaA zeolites 2-3 mm in diameter with macroporosity of 77.9% and 68.6%, respectively. The NaX and CaA granules kept their individual morphologies, crystallinities with a CO2 uptake of 5.8 mmol/g and 4 mmol/g, respectively. The CO2 separation performance and the kinetic behavior were estimated by breakthrough experiments, where the NaX zeolite showed a 16% higher CO2 uptake rate than CaA granules with a high mass transfer coefficient, 1.3 m/s, compared to commercial granules, suggesting that freeze-granulated zeolites could be used to improve adsorption kinetics and reduce cycle time for biogas upgrading in the adsorption swing technology.


The Cancer Loneliness Scale and Cancer-related Negative Social Expectations Scale: development and validation.
Loneliness is a known risk factor for poor mental and physical health outcomes and quality of life in the general population, and preliminary research suggests that loneliness is linked to poorer health outcomes in cancer patients as well. Various aspects of the cancer experience contribute to patients feeling alone and misunderstood. Furthermore, loneliness theory suggests that negative social expectations, which may specifically relate to the cancer experience, precipitate and sustain loneliness. Cancer-specific tools are needed to assess key constructs of this theory. In the current study, we developed and tested measures of (1) loneliness attributed to cancer (i.e., cancer-related loneliness) and (2) negative social expectations related to cancer. First, we developed the items for the measures based on theory, prior research, and expert feedback. Next, we assessed the measures' psychometric properties (i.e., internal consistency and construct validity) in a diverse sample of cancer patients. The final products included a 7-item unidimensional Cancer Loneliness Scale and a 5-item unidimensional Cancer-related Negative Social Expectations Scale. Evidence of excellent reliability and validity was found for both measures. The resulting measures have both clinical and research utility.


Women Veterans' Perspectives on How to Make Veterans Affairs Healthcare Settings More Welcoming to Women.
Women veterans are a rapidly increasing subset of the Veterans Affairs (VA) patient population but remain a numerical minority. Men veteran-dominated health care settings pose unique considerations for providing care to women veterans in a comfortable and welcoming environment. We analyzed patient suggestions on how to make the VA more welcoming to women. We surveyed a convenience sample of women veteran patients who visited 1 of 26 VA locations in August and September of 2017. Women veterans were invited to complete brief anonymous questionnaires that included questions about harassment experiences and feeling welcome at the VA, and an open-ended question about suggestions to make the VA more welcoming to women. We analyzed data from the open-ended question using the constant comparison method. Among respondents (N = 1,303), 85% felt welcome at the VA. Overall, 29% answered the open-ended prompt for a total of 490 distinct responses: 260 comments and 230 suggestions. Comments included praise for the VA (67%) and stories about feeling uncomfortable or harassed in the VA (26%). Suggestions included those related to VA staff (31%), the environment of care (18%), additional resources for women veterans (18%), clinical services for women veterans (15%), changing men veterans' behavior toward women veterans at the VA (5%), and making the treatment of women and men the same (5%). Although most women veterans felt welcome in the VA, patient-centered suggestions offer opportunities for making the VA more welcoming to women. Soliciting patient suggestions and increasing awareness of how feeling welcome is experienced by patients are first steps to health care settings becoming more inclusive.


Natural selection among Eurasians at genomic regions associated with HIV-1 control.
HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome. We find that the Europe-Middle East and Europe-South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians. These findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control.


Effects of pulmonary exposure to chemically-distinct welding fumes on neuroendocrine markers of toxicity.
Exposure to welding fumes may result in disorders of the pulmonary, cardiovascular, and reproductive systems. Welders are also at a greater risk of developing symptoms similar to those seen in individuals with idiopathic Parkinson's disease. In welders, there are studies that suggest that alterations in circulating prolactin concentrations may be indicative of injury to the dopamine (DA) neurons in the substantia nigra. The goal of these studies was to use an established model of welding particulate exposure to mimic the effects of welding fume inhalation on reproductive functions. Since previous investigators suggested that changes in circulating prolactin may be an early marker of DA neuron injury, movement disorders, and reproductive dysfunction, prolactin, hypothalamic tyrosine hydroxylase (TH) levels (a marker of DA synthesis), and other measures of hypothalamic-pituitary-gonadal (HPG) function were measured after repetitive instillation of welding fume particulates generated by flux core arc-hard surfacing (FCA-HS), manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) welding, or manganese chloride (MnCl2). Exposure to welding fume particulate resulted in the accumulation of various metals in the pituitary and testes of rats, along with changes in hypothalamic TH and serum prolactin levels. Exposure to particulates with high concentrations of soluble manganese (Mn) appeared to exert the greatest influence on TH activity levels and serum prolactin concentrations. Thus, circulating prolactin levels may serve as a biomarker for welding fume/Mn-induced neurotoxicity. Other reproductive measures were collected, and these data were consistent with epidemiological findings that prolactin and testosterone may serve as biomarkers of welding particulate induced DA neuron and reproductive dysfunction.


Programme characteristics and everyday occupations in day centres and clubhouses in Sweden.
Meaningful everyday occupations are important for mental health and recovery and are provided by both community-based day centres (DCs) and clubhouses. It is unknown, however, if any of the two has more recovery-promoting features. This nine-month longitudinal study compared DC and clubhouses, concerning the users' perceptions of unit and programme characteristics, and aspects of everyday occupations in terms of engagement and satisfaction. Stability over time in these respects, as well as motivation for participation and relationships with occupational engagement and satisfaction, were explored. Participants from 10 DCs (n = 128) and 5 clubhouses (n = 57) completed self-report instruments. DC attendees rated lower levels on two organizational factors; choice and ability to influence decisions, and the unit's social network. Motivation showed to be an important factor for perceived occupational engagement, which did not differ between the two groups. DC attendees were more satisfied with their everyday occupations at baseline, but that factor increased more in the clubhouse group and there was no group difference at follow-up. The unit and programme characteristics and occupational engagement showed stability over time. Clubhouses seemed more advantageous and DC services may consider developing users' opportunities for choice and decision-making, and peer support.


Aldosterone-to-renin ratio and nocturnal blood pressure decline in a general population: the Ohasama study.
Aldosterone-to-renin ratio (ARR) is an index for inappropriate aldosterone activity and salt sensitivity. We previously reported that elevated ARR might be associated with salt-sensitive hypertension. Because salt-sensitive hypertensive patients are reported to show a diminished nocturnal decline in blood pressure, we hypothesized that high ARR may be associated with diminished nocturnal decline in blood pressure (generally referred to as a 'nondipping' pattern), especially in individuals with high sodium intake. This study tested this hypothesis in 184 participants aged at least 55 years not receiving antihypertensive treatment in a general Japanese population (age: 67.6 ± 6.9 years; 71.7% women). Ambulatory blood pressure monitoring identified 63 (34.2%) participants with a nondipping pattern (nocturnal decline of SBP <10%). The median plasma renin activity (PRA), plasma aldosterone concentration (PAC), and ARR were 0.8 ng/ml per h, 8.3 ng/dl, and 8.7 ng/dl per (ng/ml per h), respectively. After adjustment for possible confounding factors, each 1 SD increase in logARR was associated with the prevalence of nondipping pattern (odds ratio, 1.95; P = 0.002). This association was observed in individuals in the highest tertile of 24-h urinary sodium excretion estimated from spot urine data (e24-hUNa; ≥179.6 mEq/day; P = 0.01) but disappeared in those in the lowest tertile of e24-hUNa (<147.9 mEq/day; P = 0.6). In those in the highest tertile of e24-hUNa, PRA was significantly lower in nondippers than in dippers (0.49 vs. 0.85 ng/ml per h) despite no differences in PAC. These results suggest that relative aldosterone excess might be related to a nondipping pattern of blood pressure, especially in individuals with high sodium intake.