On Your Feet to Earn Your Seat: pilot RCT of a theory-based sedentary behaviour reduction intervention for older adults.
Of all age groups, older adults spend most of the time sitting and are least physically active. This sequential, mixed-methods feasibility study used a randomised controlled trial design to assess methods for trialling a habit-based intervention to displace older adults' sedentary behaviour with light activity and explore impact on behavioural outcomes. Eligibility criteria were age 60-74 years, retired, and ≥6 h/day leisure sitting. Data were collected across four sites in England. The intervention comprised a booklet outlining 15 'tips' for disrupting sedentary habits and integrating activity habits into normally inactive settings, and eight weekly self-monitoring sheets. The control was a non-habit-based factsheet promoting activity and sedentary reduction. A computer-generated 1:1 block-randomisation schedule was used, with participants blinded to allocation. Participants self-reported sedentary behaviour (two indices), sedentary habit, physical activity (walking, moderate, vigorous activity) and activity habit, at pre-treatment baseline, 8- and 12-week follow-ups and were interviewed at 12 weeks. Primary feasibility outcomes were attrition, adverse events and intervention adherence. The secondary outcome was behavioural change. Of 104 participants consented, 103 were randomised (intervention N = 52, control N = 51). Of 98 receiving allocated treatment, 91 (93%; intervention N = 45; control N = 46) completed the trial. One related adverse event was reported in the intervention group. Mean per-tip adherence across 7 weeks was ≥50% for 9/15 tips. Qualitative data suggested acceptability of procedures, and, particularly among intervention recipients, the allocated treatment. Both groups appeared to reduce sedentary behaviour and increase their physical activity, but there were no apparent differences between groups in the extent of change. Trial methods were acceptable and feasible, but the intervention conferred no apparent advantage over control, though it was not trialled among the most sedentary and inactive population for whom it was developed. Further development of the intervention may be necessary prior to a large-scale definitive trial. One possible refinement would combine elements of the intervention with an informational approach to enhance effectiveness. ISRCTN47901994 (registration date: 16th January 2014; trial end date 30th April 2015).


Haemophilus influenzae type b carriage and immunity four years after receiving the Haemophilus influenzae oligosaccharide-CRM197 (HbOC) conjugate vaccine.
Late in 1991, before the implementation of a national immunization program against Haemophilus influenzae type b (Hib) in the United Kingdom, we performed a 4-year follow-up of 120 children who in 1987 had been enrolled in an immunogenicity trial in which 60 of them (vaccinees) received an Hib conjugate vaccine (HbOC) at the same time as diphtheria-tetanus toxoid-pertussis vaccine at the ages of 3, 5 and 9 months. Sixty others (controls) received only diphtheria-tetanus toxoid-pertussis vaccine at the same ages and were not subsequently immunized against Hib. We investigated Hib pharyngeal colonization using the antiserum agar method and the concentrations of serum IgG antibody to the type b capsule by enzyme-linked immunosorbent assay. At 4 years of age the Hib colonization rates in vaccinees and controls were 8% (5 of 60) and 5% (3 of 60), respectively. The children colonized with Hib had greater serum anti-capsular IgG concentrations than did noncolonized children (P < 0.001), and colonized vaccinees tended to have higher concentrations than colonized controls (P = 0.053). Regardless of Hib colonization status vaccinees had greater antibody concentrations than controls (P < 0.001). Forty-nine percent of vaccinees had an antibody concentration > 1 microgram/ml. There was an inverse relationship between the Hib colony count on culture and the serum IgG concentration. These data indicate that the increase in serum antibody concentration after immunization with an Hib conjugate vaccine is sustained and that immunization primes for a booster response on exposure to Hib. There may be a relationship between previous Hib conjugate immunization and the density of Hib colonization in children.


The HopX (AvrPphE) family of Pseudomonas syringae type III effectors require a catalytic triad and a novel N-terminal domain for function.
Many gram-negative plant pathogenic bacteria employ type III secretion systems to deliver effector proteins directly into the host cell during infection. On susceptible hosts, type III effectors aid pathogen growth by manipulating host defense pathways. On resistant hosts, some effectors can activate specific host disease resistance (R) genes, leading to generation of rapid and effective immune responses. The biochemical basis of these processes is poorly understood. The HopX (AvrPphE) family is a widespread type III effector among phytopathogenic bacteria. We determined that HopX family members are modular proteins composed of a conserved putative cysteine-based catalytic triad and a conserved potential target/cofactor interaction domain. HopX is soluble in host cells. Putative catalytic triad residues are required for avirulence activity on resistant bean hosts and for the generation of a cell-death response in specific Arabidopsis genotypes. The putative target/cofactor interaction domain is also required for these activities. Our data suggest that specific interaction with and modification of a cytosolic host target drives HopX recognition in resistant hosts and may contribute to virulence in susceptible hosts. Surprisingly, the Legionella pneumophila genome was found to contain a protein with similarity to HopX in sequence and domain arrangement, suggesting that these proteins might also contribute to animal pathogenesis and could be delivered to plant and animal hosts by diverse secretion systems.


Discontinuous electromagnetic fields using orthogonal electric and magnetic currents for wavefront manipulation.
We introduce the idea of discontinuous electric and magnetic fields at a boundary to design and shape wavefronts in an arbitrary manner. To create this discontinuity in the field we use orthogonal electric and magnetic currents which act like Huygens source to radiate the desired wavefront. These currents can be synthesized either by an array of electric and magnetic dipoles or by a combined impedance and admittance surface. A dipole array is an active implementation to impose discontinuous fields while the impedance/admittance surface acts as a passive one. We then expand on our previous work showing how electric and magnetic dipole arrays can be used to cloak an object demonstrating novel cloaking and anti-cloaking schemes. We also show how to arbitrarily refract a beam using a set of impedance and admittance surfaces. Refraction using the idea of discontinuous fields is shown to be a more general case of refraction than using simple phase discontinuities.


Chemical evidence of inter-hemispheric air mass intrusion into the Northern Hemisphere mid-latitudes.
The East Asian Summer Monsoon driven by temperature and moisture gradients between the Asian continent and the Pacific Ocean, leads to approximately 50% of the annual rainfall in the region across 20-40°N. Due to its increasing scientific and social importance, there have been several previous studies on identification of moisture sources for summer monsoon rainfall over East Asia mainly using Lagrangian or Eulerian atmospheric water vapor models. The major source regions for EASM previously proposed include the North Indian Ocean, South China Sea and North western Pacific. Based on high-precision and high-frequency 6-year measurement records of hydrofluorocarbons (HFCs), here we report a direct evidence of rapid intrusion of warm and moist tropical air mass from the Southern Hemisphere (SH) reaching within a couple of days up to 33°N into East Asia. We further suggest that the combination of direct chemical tracer record and a back-trajectory model with physical meteorological variables helps pave the way to identify moisture sources for monsoon rainfall. A case study for Gosan station (33.25°N, 126.19°E) indicates that the meridional transport of precipitable water from the SH accompanying the southerly/southwesterly flow contributes most significantly to its summer rainfall.


The state of global health in 2014.
The global health landscape looks more promising than ever, although progress has been uneven. Here, we describe the current global burden of disease throughout the life cycle, highlighting regional differences in the unfinished agenda of communicable diseases and reproductive, maternal, and child health and the additive burden of emerging noncommunicable diseases and injuries. Understanding this changing landscape is an essential starting point for effective allocation of both domestic and international resources for health.


Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.
Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.


Cilostazol administered to female mice induces ovulation of immature oocytes: a contraceptive animal model.
Both Cilostamide and Org 9935 are phosphodiesterase 3A (PDE3A) inhibitors that were evaluated in rodents and monkeys for their non-steroidal contraceptive properties. Although both compounds inhibited oocyte maturation, an adverse effect on heart rate was observed. Cilostazol (CLZ, Pletal) is a safe PDE3A inhibitor that was recently reported to block pregnancy in naturally cycling mice. In this study, the dose, frequency, time of administration, and reversibility effects of CLZ on oocyte maturation were defined using superovulated mice. Superovulated mice were gavaged once or twice with 0, 7.5, or 15 mg CLZ at various times around the ovulatory stimulus. Ovulated oocytes were then evaluated for maturational stages. CLZ resulted in mice ovulating significant numbers of immature oocytes when administered anytime between 9h before the ovulatory stimulus and 2 h after the stimulus. This inhibitory effect was greater when CLZ dose was increased, administered twice or closer to the time of the ovulatory stimulus. Conversely, ovulated immature oocytes resumed maturation in oviducts when CLZ dose was reduced, administered once and away from the time of the stimulus. Controlling CLZ dose, frequency, and time of administration produced mice ovulating immature oocytes at different stages, which may be an advantage over the conventional collection of immature oocytes from ovaries. More importantly, the capability of a clinically approved PDE3A inhibitor, with a reasonable margin of safety, to arrest oocyte maturation over a wide range of administration times and at doses extrapolated from human therapeutic doses demonstrates the contraceptive capacity of CLZ.


Treatments for Adolescents With Comorbid ADHD and Substance Use Disorder: A Systematic Review.
Objective: Comorbid ADHD and substance use disorder (SUD) presents frequently in adolescence, a developmental period that may promote the emergence of substance misuse among individuals with ADHD. Comorbid ADHD and SUD in adolescence results in significant and unique treatment challenges, necessitating examination into effective interventions. Method: This systematic review examined existing research into the treatment of comorbid adolescent ADHD and SUD. Results: Findings from a small number of pharmacological intervention studies suggest potential efficacy of extended-release stimulant and nonstimulant medications. Efficacy of psychotherapeutic interventions has not been systematically examined. Conclusion: Current research on treatments for comorbid ADHD and SUD in adolescence is limited. Future placebo-controlled clinical trials using large samples are needed to examine the efficacy of psychotherapeutic interventions, the heightened risk of prescription stimulant misuse, and the long-term maintenance of treatment gains in this population. Clinical guidelines for the treatment of comorbid ADHD and SUD are discussed.


Data integrity of the Pediatric Cardiac Critical Care Consortium (PC4) clinical registry.
Clinical databases in congenital and paediatric cardiac care provide a foundation for quality improvement, research, policy evaluations and public reporting. Structured audits verifying data integrity allow database users to be confident in these endeavours. We report on the initial audit of the Pediatric Cardiac Critical Care Consortium (PC4) clinical registry. Materials and methods Participants reviewed the entire registry to determine key fields for audit, and defined major and minor discrepancies for the audited variables. In-person audits at the eight initial participating centres were conducted during a 12-month period. The data coordinating centre randomly selected intensive care encounters for review at each site. The audit consisted of source data verification and blinded chart abstraction, comparing findings by the auditors with those entered in the database. We also assessed completeness and timeliness of case submission. Quantitative evaluation of completeness, accuracy, and timeliness of case submission is reported. We audited 434 encounters and 29,476 data fields. The aggregate overall accuracy was 99.1%, and the major discrepancy rate was 0.62%. Across hospitals, the overall accuracy ranged from 96.3 to 99.5%, and the major discrepancy rate ranged from 0.3 to 0.9%; seven of the eight hospitals submitted >90% of cases within 1 month of hospital discharge. There was no evidence for selective case omission. Based on a rigorous audit process, data submitted to the PC4 clinical registry appear complete, accurate, and timely. The collaborative will maintain ongoing efforts to verify the integrity of the data to promote science that advances quality improvement efforts.


Traditional Chinese medicine in the treatment of symptoms in patients with advanced cancer.
Patients with advanced malignancies are often suffered from deficient vital qi, which is clinically presented as cancer-related pain, anorexia, nausea/vomiting, fatigue, fever, indigestion, and constipation, which severely lower the quality of life and even shorten the survival of these patients. Traditional Chinese medicine (TCM) has a long history and rich experiences in treating malignancies. In addition to surgery, radiotherapy, chemotherapy, and other modern therapies, the TCM-based treatment can dramatically alleviate the clinical symptoms and improve the quality of life. This article analyzes the TCM treatment for the cancer pain, nausea/vomiting and cancer-related fatigue in patients with advanced malignancies, and the TCM-based emotional care for these patients are also discussed.


Human, Nature, Dynamism: The Effects of Content and Movement Perception on Brain Activations during the Aesthetic Judgment of Representational Paintings.
Movement perception and its role in aesthetic experience have been often studied, within empirical aesthetics, in relation to the human body. No such specificity has been defined in neuroimaging studies with respect to contents lacking a human form. The aim of this work was to explore, through functional magnetic imaging (f MRI), how perceived movement is processed during the aesthetic judgment of paintings using two types of content: human subjects and scenes of nature. Participants, untutored in the arts, were shown the stimuli and asked to make aesthetic judgments. Additionally, they were instructed to observe the paintings and to rate their perceived movement in separate blocks. Observation highlighted spontaneous processes associated with aesthetic experience, whereas movement judgment outlined activations specifically related to movement processing. The ratings recorded during aesthetic judgment revealed that nature scenes received higher scored than human content paintings. The imaging data showed similar activation, relative to baseline, for all stimuli in the three tasks, including activation of occipito-temporal areas, posterior parietal, and premotor cortices. Contrast analyses within aesthetic judgment task showed that human content activated, relative to nature, precuneus, fusiform gyrus, and posterior temporal areas, whose activation was prominent for dynamic human paintings. In contrast, nature scenes activated, relative to human stimuli, occipital and posterior parietal cortex/precuneus, involved in visuospatial exploration and pragmatic coding of movement, as well as central insula. Static nature paintings further activated, relative to dynamic nature stimuli, central and posterior insula. Besides insular activation, which was specific for aesthetic judgment, we found a large overlap in the activation pattern characterizing each stimulus dimension (content and dynamism) across observation, aesthetic judgment, and movement judgment tasks. These findings support the idea that the aesthetic evaluation of artworks depicting both human subjects and nature scenes involves a motor component, and that the associated neural processes occur quite spontaneously in the viewer. Furthermore, considering the functional roles of posterior and central insula, we suggest that nature paintings may evoke aesthetic processes requiring an additional proprioceptive and sensori-motor component implemented by "motor accessibility" to the represented scenario, which is needed to judge the aesthetic value of the observed painting.


Actor-specific contributions to the deforestation slowdown in the Brazilian Amazon.
Annual deforestation rates in the Brazilian Amazon fell by 77% between 2004 and 2011, yet have stabilized since 2009 at 5,000-7,000 km(2). We provide the first submunicipality assessment, to our knowledge, of actor-specific contributions to the deforestation slowdown by linking agricultural census and remote-sensing data on deforestation and forest degradation. Almost half (36,158 km(2)) of the deforestation between 2004 and 2011 occurred in areas dominated by larger properties (>500 ha), whereas only 12% (9,720 km(2)) occurred in areas dominated by smallholder properties (<100 ha). In addition, forests in areas dominated by smallholders tend to be less fragmented and less degraded. However, although annual deforestation rates fell during this period by 68-85% for all actors, the contribution of the largest landholders (>2,500 ha) to annual deforestation decreased over time (63% decrease between 2005 and 2011), whereas that of smallholders went up by a similar amount (69%) during the same period. In addition, the deforestation share attributable to remote areas increased by 88% between 2009 and 2011. These observations are consistent across the Brazilian Amazon, regardless of geographical differences in actor dominance or socioenvironmental context. Our findings suggest that deforestation policies to date, which have been particularly focused on command and control measures on larger properties in deforestation hotspots, may be increasingly limited in their effectiveness and fail to address all actors equally. Further reductions in deforestation are likely to be increasingly costly and require actor-tailored approaches, including better monitoring to detect small-scale deforestation and a shift toward more incentive-based conservation policies.


Feasibility of using volunteer research staff to deliver and evaluate a low-fat dietary intervention: the American Cancer Society Breast Cancer Dietary Intervention Project.
This report presents the results of a study to examine the feasibility of using volunteers as research staff for a randomized trial of whether reduction in dietary fat intake could prevent or delay breast cancer recurrence. We examined whether volunteers could be trained to recruit study participants, deliver a complex and intensive dietary intervention, and monitor intervention effectiveness. Volunteers, who were mostly employed nurses and dietitians, screened 521 women, of whom 293 were eligible and 144 were randomized. Participants were postmenopausal women under age 75, who had recently been diagnosed with breast cancer and treated with either mastectomy or lumpectomy. At 1 year postrandomization, 77% of intervention and 75% of control participants remained active in the study. Intervention effects (change in intervention group minus change in control group) at 3, 6, and 12 months postrandomization were 5.9, 8.4, and 7.2% energy from fat and 1.7, 3.0, and 3.5 kg body weight (all P < 0.001). These results were similar to those from other studies that used paid, professional staff to deliver and monitor interventions. Results from this feasibility study suggest that volunteer-based health organizations can provide research opportunities for health practitioners and can conduct high-quality research at lower costs.


Measurement of radiation-induced DNA double-strand breaks in human diploid fibroblasts from keloid and normal skin by single-cell gel electrophoresis.
Cell culture experiments recently have shown that different populations of fibroblasts may exist in keloid patients. Moreover, several studies have strongly suggested heterogeneity in cell response of skin fibroblasts in the same individual. The purpose of this study was to evaluate the radiation sensitivity of skin fibroblasts from keloid and normal skin. Single-cell gel electrophoresis was employed in detecting amounts of DNA double-strand breaks generated in individual fibroblasts primarily cultured from normal skin and from keloid tissue after various doses of gamma-irradiation (0, 25, 50, and 100 Gy aerobically) from a 137Cs radiation generator. For the repair study, cells were incubated at 37 degrees C for 0 and 15 minutes and 1 and 2 hours after irradiation. Following neutral lysis and electrophoresis, DNA double-strand breaks were then detected by propidium iodide staining and determined by fluorescence microscope and quantitative image analysis. No significant difference in the extent of DNA double strand breaks in fibroblasts from normal skin or keloid after various doses of irradiation was observed. However, the residual DNA double-strand breaks remaining after various periods of incubation were demonstrated to be significantly increased in fibroblasts from keloid (p < 0.01). In conclusion, different repair capacities were found in fibroblasts from normal skin and keloid scar; this finding may play a role in the treatment of the disease entity.


Health Literate Organizations: Are Clinical Trial Sites Equipped to Recruit Minority and Limited Health Literacy Patients?
Racial/ethnic minority patients are less likely than non-Latino white patients to participate in cancer clinical trials. A key barrier to participation is limited health literacy which is more common among minorities. At the organizational level, it is important that clinical trials sites become better equipped to recruit minority patients by expanding their organizational health literacy including language competency and outreach efforts. We explored the characteristics of clinical trial sites that are associated with these health literate behaviors. We identified 353 breast clinical trials recruiting participants in 2006 from four states (California, Florida, Illinois, and New York) through the National Cancer Institute Physician Data Query system. From October 2008 to November 2009, we contacted one research team member (RTM) from each site for a telephone survey to assess the site's health literate characteristics. Of 233 RTMs who responded, 93% were female and 89% were US-born. Overall, 48% of sites offered supplementary trial information, 80% offered materials to assist with patient navigation and 45% reported outreach efforts. Lower percentages offered information in other languages while 65% offered professional interpretation services. Sites with >10% limited English proficiency (LEP) patients were more likely than their counterparts to offer consent forms (OR=3.13, 1.36-7.19) and supplementary information about trials in other languages (OR=2.52, 1.15-5.52). Sites with diverse patient populations (>10% Latino) were also more likely than less diverse sites to engage in outreach (OR=1.97, 1.07-3.60), to offer consent forms (OR=2.72, 1.38-5.36), supplementary information about trials (OR=2.58, 1.24-5.36), and materials to improve patient navigation (OR=2.50, 1.22-5.13) in other languages. Efforts to recruit diverse participants were limited. Practice type and diversity of patient population were associated with sites' efforts to accommodate these characteristics, suggesting that sites were responsive to the needs of their patients when diversity was prevalent.


Processing and Structure of the Lantibiotic Peptide Nso From the Human Gut Bacterium Blautia obeum A2-162 analysed by Mass Spectrometry.
A previously reported gene cluster encoding four nisin-like peptides, three with the same sequence (NsoA1-3) and the unique NsoA4, produced antimicrobial activity in the presence of trypsin after heterologous expression in Lactococcus lactis. Protein extracts were separated by SDS gel electrophoresis or immunoprecipitation using an antibody to the NsoA2 leader. Tryptic peptides observed by LC-MS/MS covered the complete sequence of preNsoA1-3 and part of the leader sequence of preNsoA4 and confirmed the expression and the predicted sequences of the preNsoA peptides. Further, the data revealed that the preNsoA1-3 peptides were partly modified with dehydrations and formation of lanthionine rings. A certain amount of fully modified preNsoA1-3 was observed. Details of modifications of the core peptide and the C-terminal tryptic peptide TATCGCHITGK covering rings D and E indicated that 22% of these preNsoA1-3 peptides were completely modified. A lower amount of ring formation is estimated for rings A-C. Intact masses of immunoprecipitation-derived peptides determined by LC-MS accurately matched the expected preNsoA precursor peptides. The most abundant peptides detected were preNsoA2-3-8H2O followed by preNsoA1-8H2O and other states of dehydration. The results confirm incomplete processing of preNsoA peptides in the heterologous system, with the formation of a certain amount of fully modified peptides.


Transforming growth factor beta 1: three-dimensional structure in solution and comparison with the X-ray structure of transforming growth factor beta 2.
The three-dimensional solution structure of human transforming growth factor beta 1 (TGF-beta 1) has been determined using multinuclear magnetic resonance spectroscopy and a hybrid distance geometry/ simulated annealing algorithm. It represents one of the first examples of a mammalian protein structure that has been solved by isotopic labeling of the protein in a eukaryotic cell line and multinuclear NMR spectroscopy. The solution structure of the 25 kDa disulfide-linked TGF-beta 1 homodimer was calculated from over 3200 distance and dihedral angle restraints. The final ensemble of 33 accepted structures had no NOE or dihedral angle violations greater than 0.30 A and 5.0 degrees, respectively. The RMSD of backbone atoms for the ensemble of 33 structures relative to their mean structure was 1.1 A when all residues were used in the alignment and 0.7 A when loop regions were omitted. The solution structure of TGF-beta 1 follows two independently determined crystal structures of TGF-beta 2 (Daopin et al., 1992, 1993; Schlunegger & Grütter, 1992, 1993), providing the first opportunity to examine structural differences between the two isoforms at the molecular level. Although the structures are very similar, with an RMSD in backbone atom positions of 1.4 A when loop regions are omitted in the alignment and 1.9 A when all residues are considered, there are several notable differences in structure and flexibility which may be related to function. The clearest example of these is in the beta-turn from residues 69-72: the turn type found in the solution structure of TGF-beta 1 falls into the category of type II, whereas that present in the X-ray crystal structure of TGF-beta 2 is more consistent with a type I turn conformation. This may be of functional significance as studies using TGF-beta chimeras and deletion mutants indicate that this portion of the molecule may be important in receptor binding.


Developing collaborative works for faster progress on fungal respiratory infections in cystic fibrosis.
Cystic fibrosis (CF) is the major genetic inherited disease in Caucasian populations. The respiratory tract of CF patients displays a sticky viscous mucus, which allows for the entrapment of airborne bacteria and fungal spores and provides a suitable environment for growth of microorganisms, including numerous yeast and filamentous fungal species. As a consequence, respiratory infections are the major cause of morbidity and mortality in this clinical context. Although bacteria remain the most common agents of these infections, fungal respiratory infections have emerged as an important cause of disease. Therefore, the International Society for Human and Animal Mycology (ISHAM) has launched a working group on Fungal respiratory infections in Cystic Fibrosis (Fri-CF) in October 2006, which was subsequently approved by the European Confederation of Medical Mycology (ECMM). Meetings of this working group, comprising both clinicians and mycologists involved in the follow-up of CF patients, as well as basic scientists interested in the fungal species involved, provided the opportunity to initiate collaborative works aimed to improve our knowledge on these infections to assist clinicians in patient management. The current review highlights the outcomes of some of these collaborative works in clinical surveillance, pathogenesis and treatment, giving special emphasis to standardization of culture procedures, improvement of species identification methods including the development of nonculture-based diagnostic methods, microbiome studies and identification of new biological markers, and the description of genotyping studies aiming to differentiate transient carriage and chronic colonization of the airways. The review also reports on the breakthrough in sequencing the genomes of the main Scedosporium species as basis for a better understanding of the pathogenic mechanisms of these fungi, and discusses treatment options of infections caused by multidrug resistant microorganisms, such as Scedosporium and Lomentospora species and members of the Rasamsonia argillacea species complex.


Fructose-1,6-bisphosphatase deficiency presented with complex febrile convulsion.
Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inborn error of metabolism affecting gluconeogenesis caused by FBP1 gene mutations. It could be more fatal to infants and children when glycogen reserves are insufficient. A 4-year-old girl was admitted with complex febrile convulsion. Initial laboratory results showed hypoglycemia, metabolic acidosis, and hyperlactatemia. Plasma amino acid and urine organic acid analyses showed increased levels of alanine and tricarboxylic acid cycle intermediates. However, she had similar clinical features, including confusion under severe hypoglycemia, two additional times over 6 months. Correct diagnosis could not be made because of nonspecific symptoms, and mitochondrial disorder was initially suspected. Clinical exome sequencing was performed, and compound heterozygous mutations of c.960_961insG and c.490G>A (p. Ser321ValfsTer13 and p. Gly164Ser) in the FBP1 gene were identified. This is the first Korean pediatric case of FBPase deficiency that initially presented with neurologic clinical features. Despite its very low prevalence in Far-East Asian countries, FBPase deficiency should be considered in children with repeated clinical features of metabolic acidosis with hypoglycemia.


Oxidation of Hindered Allylic C-H Bonds with Applications to the Functionalization of Complex Molecules.
We report the palladium-catalyzed oxidation of hindered alkenes to form linear allylic esters. The combination of palladium(II) benzoate, 4,5-diazafluoren-9-one, and benzoquinone catalyzes the mild oxidation of terminal alkenes with tert-butyl benzoyl peroxide as an oxidant in the presence of diverse functional groups. Selective oxidation of terminal alkenes in the presence of trisubstituted and disubstituted alkenes has been achieved, and the ability to conduct the reaction on a gram scale has been demonstrated. The mild conditions and high tolerance for auxiliary functionality make this method suitable for the synthesis and derivatization of complex molecules.


Toxic megacolon associated with anticancer chemotherapy.
The majority of gastrointestinal side effects associated with anticancer chemotherapy are relatively mild and self-limiting and can be managed empirically. However, severe side effects, such as necrotizing enterocolitis and ischemic colitis, sometimes do occur after chemotherapy. The authors present a case of toxic megacolon associated with anticancer chemotherapy. This is a relatively uncommon but potentially lethal complication of ulcerative colitis.


Transcriptional and post-translational regulation of insulin-like growth factor-binding protein-5 in rat articular chondrocytes.
The aim of this study was to assess the regulation of insulin-like growth factor-binding proteins (IGFBPs) by IGFs in primary cultures of rat articular chondrocytes (RAC). Employing Western ligand blotting, immunoprecipitation and Northern blot analysis, RAC were found to secrete IGFBP-5 (29 kDa) and IGFBP-4 (24 kDa) as the predominant IGFBPs, as well as IGFBP-2 (32-30 kDa) and IGFBP-3 (43-39 kDa) as the minor species. Treatment of cells with IGF-I and IGF-II resulted in a dose-dependent increase of IGFBP-5 and a small increase in IGFBP-4 in conditioned media (CM). Des(1-3) IGF-I and [Gln6, Ala7, Tyr18, Leu19] IGF-II ([QAYL] IGF-II), which bind to the type 1 IGF receptor but not to IGFBPs, also induced IGFBP-5 peptide, although the increase was less than with IGF-I or IGF-II treatment of RAC. [Leu27] IGF-II, which does not bind to the type 1 IGF receptor but binds to IGFBPs, resulted in little induction of IGFBP-5, while [QAYL-Leu27] IGF-II, which has reduced affinity for both the type 1 IGF receptor and IGFBPs, did not increase IGFBP-5. These data suggest that the increase in IGFBP-5 in CM is modulated by both the type 1 IGF receptor and the interaction between IGFs and IGFBPs. Northern blotting analysis showed that IGF-I, IGF-II and des(1-3) IGF-I treatment of RAC increased steady state levels of IGFBP-5 mRNA, suggesting that the IGF-mediated increase in IGFBP-5 is transcriptionally modulated. Interestingly, the increase in IGFBP-5 peptide levels and mRNA were not parallel, suggesting the possibility of post-translational modifications of IGFBP-5, such as those seen with IGFBP-5 protease. IGFBP-5 protease activity was detectable in untreated CM, whereas treatment with IGF-I and IGF-II partially protected IGFBP-5 from proteolysis. In summary, treatment of RAC with IGF-I and IGF-II results in dose-dependent increases in both IGFBP-5 peptide in the CM and mRNA levels. These changes are mediated by interactions via the type 1 IGF receptor as well as IGFBPs, both transcriptionally and post-translationally.


Long-term prescribing of proton pump inhibitors in general practice.
Proton pump inhibitors (PPIs) constitute the largest sector of the National Health Service (NHS) community drugs bill (238 m Pounds; 5.6%). Little is known of the long-term prescribing component of this. To study the extent, the reasons for, and the cost implications of the long-term prescription of PPIs in general practice. Subjects on long-term therapy were identified by searches of computerized and paper records from three practices, comprising 21 GPs with 46,650 patients, representing a population cross section in north-east England. Two hundred and nine (0.45%) patients were on long-term PPIs (range between practices = 0.3% to 0.55%): 87% were on omeprazole, 13% lansoprazole; average age = 60 years (male = 56 years, female = 64 years; range = 14 to 91 years); male to female ratio = 47:53. The main indications were 'reflux' (39%), 'oesophagitis' (17%), non-specified 'dyspepsia' (24%), 'peptic ulcer' (8%). During the study year, 1952 prescriptions (28-day courses) were issued: a mean of nine per patient (range = 1 to 8). Sixteen per cent of patients requested fewer than six prescriptions, 27% requested between six and nine prescriptions, and only 21% requested sufficient prescriptions for the entire year. The average cost was 3707 Pounds per general practitioner per annum, or 320,000 Pounds for the district, representing 40% of the total PPI bill. Of the total population, 0.45% were prescribed long-term PPIs; most for symptom relief. The long-term component comprised 40% of all PPI costs estimated at 100 million Pounds per annum for the United Kingdom. Most patients took their treatment only intermittently. More research is needed into strategies for rationalization of long-term PPI therapy. For most patients, doctors can advise on-demand rather than regular once-daily therapy.


Received social support and exercising: An intervention study to test the enabling hypothesis.
Received social support is considered important for health-enhancing exercise participation. The enabling hypothesis of social support suggests an indirect association of social support and exercising via constructs of self-regulation, such as self-efficacy. This study aimed at examining an expanded enabling hypothesis by examining effects of different kinds of social support (i.e., emotional and instrumental) on exercising not only via self-efficacy but also via self-monitoring and action planning. An 8-week online study was conducted. Participants were randomly assigned to an intervention or a control group. The intervention comprised finding and then exercising regularly with a new exercise companion. Intervention and control group effects were compared by a manifest multigroup model. Received emotional social support predicted self-efficacy, self-monitoring, and action planning in the intervention group. Moreover, received emotional social support was indirectly connected with exercise via the examined mediators. The indirect effect from received emotional social support via self-efficacy mainly contributed to the total effect. No direct or indirect effect of received instrumental social support on exercise emerged. In the control group, neither emotional nor instrumental social support was associated with any of the self-regulation constructs nor with exercise. Actively looking for a new exercise companion and exercising together seems to be beneficial for the promotion of received emotional and instrumental social support. Emotional support in turn promotes exercise by enabling better self-regulation, in particular self-efficacy. Statement of contribution What is already known on this subject? With the 'enabling hypothesis', Benight and Bandura (2004, Behav. Res. Ther., 42, 1129) claimed that social support indirectly affects behaviour via self-efficacy. Research in the domain of physical exercise has provided evidence for this enabling hypothesis on a correlational basis only preventing causal inferences. What does this study add? We found evidence for the enabling hypothesis of received social support via self-efficacy on physical exercise in an intervention study. Moreover, this study demonstrated the distinct contribution of received emotional and instrumental social support in the context of the enabling hypothesis.


Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress.
Chronic exposure to high fluoride (F(-)) may lead to local tissue disturbances, known as fluorosis. F(-) is an oxidising agent and a well-known reversible enzymatic inhibitor that interferes with the enzyme activity of at least 80 proteins. The goals of the current study were to evaluate whether F(-) exposure affected the oral glucose tolerance test (OGTT) in C57BL6 mice; and to determine the mechanisms at work in glucose homeostasis at the cellular level, in mouse pancreatic beta-cells (betaTC-6) exposed to F(-). Mice received 45 mgl(-1) F(-), as NaF, via drinking water, and cells were exposed for 12h to NaF (equivalent to 0, 0.007, 0.045, 0.180, 1.35 or 2.26 mM F(-)) at a basal or stimulatory glucose concentration (2.8 or 16.6mM, respectively). Mice showed marginal hyperglycemia an impaired glucose tolerance after 4 weeks of F(-) exposure, while beta-cells exposed to 1.35 and 2.26 mM F(-) had significantly lower insulin mRNA expression and subsequent secretion in the presence of the stimulatory glucose concentration. Western blot analyses did not show any alteration in the levels of glucose transporter-2 protein beta-cells on exposure to F(-)in vitro. However, oxidative stress evaluated by the functional activity of superoxide dismutase (SOD) and generation of the superoxide anion (O(2)(-)), showed significantly decreased SOD activity, in a dose-dependent manner. This was accompanied by an increase in the generation of O(2)(-), and decreased mitochondrial membrane potential in F(-) exposed cells. Insulin secretion was lower in beta-cells exposed to F(-), even in the presence of glibenclamide, the ATP-sensitive K(+) (K(ATP)) channel blocker, suggesting down-regulation of the K(ATP) channel in the cell. Exposure to high levels of F(-) in drinking water may decrease insulin mRNA and its secretion from beta-cells, and might therefore affect the OGTT.


Pupil size reflects the focus of feature-based attention.
We measured pupil size in adult human subjects while they selectively attended to one of two surfaces, bright and dark, defined by coherently moving dots. The two surfaces were presented at the same location; therefore, subjects could select the cued surface only on the basis of its features. With no luminance change in the stimulus, we find that pupil size was smaller when the bright surface was attended and larger when the dark surface was attended: an effect of feature-based (or surface-based) attention. With the same surfaces at nonoverlapping locations, we find a similar effect of spatial attention. The pupil size modulation cannot be accounted for by differences in eye position and by other variables known to affect pupil size such as task difficulty, accommodation, or the mere anticipation (imagery) of bright/dark stimuli. We conclude that pupil size reflects not just luminance or cognitive state, but the interaction between the two: it reflects which luminance level in the visual scene is relevant for the task at hand.


Mesentericin Y105 gene clusters in Leuconostoc mesenteroides Y105.
Because of their potential usefulness as natural food preservatives, increased interest has focused on bacteriocins from lactic acid bacteria. Mesentericin Y105 is a small non-lantibiotic bacteriocin (class II) encoded within a 35 kb plasmid from Leuconostoc mesenteroides Y105 and it is active against Listeria monocytogenes. Using reverse genetic methodologies, an 8 kb DraII fragment has been cloned that contains the mesentericin Y105 structural gene, mesY, which encodes a precursor of the bacteriocin with a 24 amino acid N-terminal extension ending with a Gly-Gly motif upstream of the cleavage site, which is typical of class II bacteriocins. Four other putative genes are associated with mesY within two divergent putative operons. In addition to mesY, the first putative operon is predicted to encode a protein, similar to that encoded by ORF2 in the leucocin A operon, whose function remains to be elucidated. The second putative operon contains three ORFs, two of which, mesD and mesE, encode proteins that resemble ATP-dependent transporters and accessory factors, respectively. For three other class II bacteriocin systems (lactococcin A, pediocin PA-1, colicin V), these proteins have been shown to be involved in bacteriocin secretion independently of the general sec-dependent secretion pathway. The last putative gene (mesC) does not resemble any previously characterized gene. Results concerning the heterologous expression of the cloned mesY in Lactobacillus johnsonii NCK64 suggest that the maturation and secretion functions dedicated to lactacin F (another class II bacteriocin) are efficient for mesentericin Y105 as well. This characteristic may be of great interest in the development of industrial fermentation starters producing multiple bactericidal activities.


Depth-selective fiber-optic probe for characterization of superficial tissue at a constant physical depth.
The in vivo assessment of superficial tissue has shown great promise in many biomedical applications. Significant efforts have been expended in designing compact fiber-optic probes with short tissue penetration depth targeting the superficial epithelium. In this paper, we present a compact and simple two-channel fiber-optic probe with superior depth selectivity for the superficial tissue. This probe employs a high-index ball-lens with an optimized illumination area and the maximal overlap between light illumination and collection spots, while maintaining sufficient light collection efficiency with minimized specular reflection. Importantly, we show that this probe allows the selection of a constant and shallow physical penetration depth, insensitive to a wide range of tissue-relevant scattering coefficients and anisotropy factors. We demonstrate the capability of this depth-selective fiber-optic probe to accurately quantify the absorber concentration in superficial tissue without the distortion of tissue scattering properties; and characterize the optical properties of superficial skin tissue.


Single-cell polymerase chain reaction-based pre-implantation genetic diagnosis using fragment analysis for β-thalassemia in an Indian couple with β-globin gene mutations.
Despite advances in diagnostic techniques, approximately 10,000 babies with β-thalassemia major are born annually in India. Pre-implantation genetic diagnosis (PGD), an alternative to prenatal diagnosis, helps in negative selection of affected embryos prior to implantation. Hereby, we report the first successful β-thalassemia PGD pregnancy in an Indian carrier couple. β-Thalassemia mutation analysis by Amplification-Refractory Mutation Sequence (ARMS)-polymerase chain reaction (PCR) in the parents, followed by PGD for β-thalassemia mutation in embryos in two consequent in vitro fertilization (IVF) cycles, with transfer for three β-thalassemia minor embryos, resulted in singleton successful pregnancy, the results of which were confirmed on prenatal diagnosis. With advances in assisted reproductive techniques and molecular diagnosis, PGD for monogenic diseases is feasible in high-risk couples. The methodology in the current study included two rounds of PCR using fluorescently labeled primers, fragment analysis using the ABI 3100 nucleotide sequencer and the GeneMapper software, purification, and concentration of PCR product, which enabled distinct clear peaks making the analysis and interpretation non-ambiguous.


Changes in airway resistance during sleep onset.
Ventilation is lower during sleep than wakefulness. An increase in airway resistance has been proposed as the critical factor. As the change in ventilation has been shown to occur abruptly at transitions between alpha and theta electroencephalogram activity, it was of interest to determine whether the increase in airway resistance between wakefulness and sleep also occurs at these transitions. Three young healthy male subjects were run for an average of 15 sleep onsets in each of three conditions. The three conditions were 1) an esophageal balloon was put in place to allow the measurement of airway resistance, 2) in addition to an esophageal balloon the nose was occluded, and 3) there was no esophageal balloon and the nose was not occluded. Ventilation and airway resistance were measured during sleep onset and analyzed as a function of arousal state. In those conditions of the experiment in which airway resistance was affected by state, the changes, like those in ventilation, occurred at transitions between alpha and theta electroencephalogram activity. However, in the three subjects studied, the magnitude of ventilatory changes at alpha-theta transitions and the extent to which changes in ventilation were associated with changes in airway resistance differed between subjects. It was concluded that although inspiratory airway resistance is a major component affecting the state-related changes in ventilation at sleep onset, the degree of its contribution may vary over individuals.


Clinical spectrum of STX1B-related epileptic disorders.
The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.


Exposure to violence and cardiovascular and neuroendocrine measures in adolescents.
Exposure to violence has clear, detrimental psychological consequences, but the physiological effects are less well understood. This study examined the influence of exposure to violence on biological basal and reactivity measures in adolescents. There were 115 high school student participants. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), HR variability (HRV), and cortisol levels were recorded during baseline and a laboratory stressor. The Exposure to Violence interview was administered and assessed two dimensions: total observed violence and total personally experienced violence. These were then divided into component parts: lifetime frequency, proximity, and severity. Greater total experienced violence was associated with increased basal SBP (r = .19, p < .05) and decreased acute stress reactivity in terms of SBP (beta = -.13, p = .05), HR (beta = -.21, p = .00), and HRV (beta = .13, p = .05). Lifetime frequency of experienced violence was associated with higher basal DBP (r = .33, p < .05), HR (r = .33, p < .05), and cortisol (r = .53, p < .00), and decreased SBP (beta = -.27, p < .05) and DBP (beta = -.31, p < .05) reactivity. Exposure to violence is associated with increased biological basal levels in adolescents, supporting allostatic-load research and decreased cardiovascular reactivity, supporting the inoculation effect. The findings illustrate that being a victim of violence has more pervasive biological consequences than witnessing violence and that the accumulation of stressful experiences has the greatest effect on biological markers.


Pancoast Tumor: The Overlooked Etiology of Shoulder Pain in Smokers.
BACKGROUND Shoulder pain is a common complaint in general practice and typically has an orthopedic or rheumatological etiology. However, it may be the presenting symptom of a serious underlying condition, such as lung cancer. CASE REPORT A 60-year-old man with a 30 pack-year history of smoking presented with worsening right shoulder pain over the last 6 months. He had no respiratory symptoms or weight change. He was seen at several general practice clinics and treated for a rotator cuff injury. However, his pain became severe, to the point that it affected his activities of daily living. A shoulder X-ray revealed opacity in the right apical zone. After a thorough investigation, the patient was found to have lung cancer with local invasion and intracranial metastases. However, in light of the advanced stage of the disease, a palliative approach was taken. The patient remained on multiple oral analgesics for the control of his pain. CONCLUSIONS The present case shows that common symptoms such as shoulder pain can be indicative of serious underlying pathology. Physicians should remain alert and maintain a high index of suspicion for Pancoast tumor in patients who are heavy smokers. Furthermore, a chest X-ray needs to be performed in elderly patients and smokers with shoulder pain.


Big Effect of Small Nanoparticles: A Shift in Paradigm for Polymer Nanocomposites.
Polymer nanocomposites (PNCs) are important materials that are widely used in many current technologies and potentially have broader applications in the future due to their excellent property tunability, light weight, and low cost. However, expanding the limits in property enhancement remains a fundamental scientific challenge. Here, we demonstrate that well-dispersed, small (diameter ∼1.8 nm) nanoparticles with attractive interactions lead to unexpectedly large and qualitatively different changes in PNC structural dynamics in comparison to conventional nanocomposites based on particles of diameters ∼10-50 nm. At the same time, the zero-shear viscosity at high temperatures remains comparable to that of the neat polymer, thereby retaining good processability and resolving a major challenge in PNC applications. Our results suggest that the nanoparticle mobility and relatively short lifetimes of nanoparticle-polymer associations open qualitatively different horizons in the tunability of macroscopic properties in nanocomposites with a high potential for the development of advanced functional materials.


Regional fat depot masses are influenced by protein-coding gene variants.
Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92S70C, previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20K422R is a low-frequency variant with a large effect on arm fat only, and UQCC1R51Q is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.


Cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in lymphoma patients.
Febrile neutropenia is a serious toxicity of cancer chemotherapy that is usually treated in hospital. We assessed the cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in diffuse large B-cell lymphoma (DLBCL) patients undergoing chemotherapy. We used a Markov model that followed patients through induction chemotherapy to compare the three prophylaxis strategies: 1) no primary prophylaxis against febrile neutropenia; 2) primary prophylaxis with 10 days of filgrastim therapy; and 3) primary prophylaxis with a single dose of pegfilgrastim. The target population was a hypothetical cohort of 64-year-old men and women with DLBCL. Data sources included published literature and current clinical practice. The analysis was conducted from a publicly funded health-care system perspective. The main outcome measures included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). In the base-case analysis, costs associated with no primary prophylaxis, primary prophylaxis with 10 days of filgrastim, and primary prophylaxis with pegfilgrastim were CaD $7314, CaD $13947, and CaD $16290, respectively. The QALYs associated with the three strategies were 0.2004, 0.2015, and 0.2024, respectively. The ICER for the filgrastim vs no primary prophylaxis strategy was CaD $5796000 per QALY. The ICER for the pegfilgrastim vs filgrastim primary prophylaxis strategy was CaD $2611000 per QALY. All one-way sensitivity analyses yielded ICERs greater than CaD $400000 per QALY. Cost-effectiveness acceptability curves show that 20.0% of iterations are cost-effective at a willingness-to-pay threshold of CaD $1595000 for the filgrastim strategy and CaD $561000 for the pegfilgrastim strategy. Primary prophylaxis against febrile neutropenia with either filgrastim or pegfilgrastim is not cost-effective in DLBCL patients.


RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development.
Regulation of patterning and morphogenesis during embryonic development depends on tissue-specific signaling by retinoic acid (RA), the active form of Vitamin A (retinol). The first enzymatic step in RA synthesis, the oxidation of retinol to retinal, is thought to be carried out by the ubiquitous or overlapping activities of redundant alcohol dehydrogenases. The second oxidation step, the conversion of retinal to RA, is performed by retinaldehyde dehydrogenases. Thus, the specific spatiotemporal distribution of retinoid synthesis is believed to be controlled exclusively at the level of the second oxidation reaction. In an N-ethyl-N-nitrosourea (ENU)-induced forward genetic screen we discovered a new midgestation lethal mouse mutant, called trex, which displays craniofacial, limb, and organ abnormalities. The trex phenotype is caused by a mutation in the short-chain dehydrogenase/reductase, RDH10. Using protein modeling, enzymatic assays, and mutant embryos, we determined that RDH10(trex) mutant protein lacks the ability to oxidize retinol to retinal, resulting in insufficient RA signaling. Thus, we show that the first oxidative step of Vitamin A metabolism, which is catalyzed in large part by the retinol dehydrogenase RDH10, is critical for the spatiotemporal synthesis of RA. Furthermore, these results identify a new nodal point in RA metabolism during embryogenesis.


Magnesium in acute and chronic brain injury: an update.
While brain free magnesium levels have been shown to decline in a number of acute and chronic brain pathologies, the mechanisms of such decline and the potential for magnesium administration as a therapeutic intervention are still unclear. In acute brain injury, magnesium therapy has failed in recent clinical trials of trauma, presumably because of an intact blood brain barrier at the time of administration reducing central penetration. Under such conditions, magnesium's peripheral effects on cardiovascular parameters may dominate over the central, and potentially neuroprotective, effects of the compound. In contrast, magnesium has been demonstrated to be beneficial in lacunar strokes, albeit that recent animal studies indicate that this effect is without any significant reduction of lesion size. Postnatal magnesium has also been shown to improve neurological outcome in term neonates with perinatal asphyxia, although this may be limited to cases of mild to moderate brain injury; no effect is observed following severe brain injury. Prenatal magnesium has been reported to be beneficial for outcome in very preterm infants, although this may only be at low doses. Combination therapies are also showing promise in experimental studies, with combined magnesium and mild hypothermia as well as magnesium and polyethylene glycol proving effective in ischemic stroke and in spinal cord injury, respectively. With respect to chronic brain injury, recent results indicate that magnesium deficient mice are susceptible to developing Parkinson's disease, which is consistent with earlier findings that magnesium deficiency over a number of generations is associated with the development of Parkinson's disease. The latter was associated with the appearance of variants of the TRPM channels. Our recent studies have shown that Parkinson's disease is associated with reduced TRPM2 and TRPM7 channel mRNA expression. Taken together, a more complete picture is emerging of the role of magnesium in brain injury, its therapeutic potential as well the mechanisms associated with its decline.


Detection of potentially pathogenic bacteria in the drinking water distribution system of a hospital in Hungary.
The drinking water distribution system of a hospital was investigated using standard cultivation techniques, taxon-specific PCRs targeting pathogenic bacteria, denaturing gradient gel electrophoresis, cloning and sequencing. The results obtained verify the higher sensitivity of PCR compared to cultivation for detecting Legionella and Pseudomonas aeruginosa. Moreover, several other opportunistic pathogenic bacteria, such as Escherichia albertii, Acinetobacter lwoffi and Corynebacterium tuberculostrearicum, were detected, emphasizing that drinking water systems, especially those with stagnant water sections, could be the source of nosocomial infections.


Dynein-dependent movement of autophagosomes mediates efficient encounters with lysosomes.
Autophagy is a membrane trafficking pathway that carries cytosolic components to the lysosome for degradation. During this process, the autophagosome, a double-membraned organelle, is generated de novo, sequesters cytoplasmic proteins and organelles, and delivers them to lysosomes. However, the mechanism by which autophagosomes are targeted to lysosomes has not been determined. Here, we observed the real-time behavior of microtubule-associated protein light chain 3 (LC3), which localizes to autophagosomes, and showed that autophagosomes move in a microtubule- and dynein-dynactin motor complex-dependent manner. After formation, autophagosomes show a rapid vectorial movement in the direction of the centrosome, where lysosomes are usually concentrated. Microinjection of antibodies against LC3 inhibited this movement; furthermore, using FRAP, we showed that anti-LC3 antibody injection caused a defect in targeting of autophagosomes to lysosomes. Collectively, our data demonstrate the functional significance of autophagosome movement that enables effective delivery from the cytosol to lysosomes.


Case management effectiveness in reducing hospital use: a systematic review.
This systematic review synthesizes recent evidence of the effectiveness of case management in reducing hospital use by individuals with chronic illnesses. Hospital use by individuals with chronic illnesses accounts for 66% of healthcare costs in the United States. its has been cited as care coordination that can reduce healthcare costs; however, its effectiveness in improving hospital use outcomes is contradictory, and no review has yet synthesized recent studies of case management with respect to hospital use outcomes. This systematic review followed the Cochrane processes and was guided by use of PRISMA statements. Five electronic databases were searched to obtain randomized controlled trials published within the last 10 years that evaluated case management hospital use as a primary outcome by individuals with chronic illnesses. Ten studies published between 2007 and 2015 were retrieved and assessed for risk of methodological bias. All studies used case management as an intervention, focused on transitional care services and reported hospital use, including readmissions and emergency department and hospital visits, as a primary outcome. Analysis of the studies showed that case management greatly reduced hospital readmissions and emergency department visits. Only studies published in English were searched, and retrieved studies tended to report positive results. There was strong evidence of significant reductions in hospital use with case management as an intervention. However, other results about the efffectiveness of case management remain mixed; more rigorously designed studies with case management interventions are needed. The complexity and cost of chronic illnesses means that case management should be considered as a tool to improve quality of care and lower healthcare costs.


Cutaneous myxoid fibroblastoma. A histological, immunohistochemical, and ultrastructural study.
A fibroblastic skin tumor with a myxoid matrix is reported that cannot be easily classified as one of the well-known entities of fibrous/fibrohistiocytic and myxoid skin tumors. A 27-year-old white woman presented with a reddish, dome-shaped cutaneous nodule 8 mm in diameter on the left popliteal fossa that had developed spontaneously within the preceding 2 years. There was no sign of recurrence 30 months after excision. Light microscopic examination showed a well-circumscribed tumor confined to the upper dermis and consisting of stellate and spindle-shaped cells arranged loosely in a fascicular pattern resembling tissue cultures of fibroblasts. There were almost no collagen bundles between tumor cells, and Mowry's staining showed large amounts of glycosaminoglycans. Immunohistochemical studies of the tumor cells showed reactivity only to vimentin, whereas markers of histiocytes, dermal dendrocytes, and neurogenic and myogenic differentiation were negative. By electron microscopy, the majority of tumor cells contained elliptical nuclei, but some tumor cells had conspicuous multisegmented nuclei with several large and small nuclear segments connected by thin nuclear bridges (labyrinth nuclei). Single fibrils were found within the interstitium; collagen fibers were rare. Histological and ultrastructural examinations identified tumor cells as fibroblasts. High cellularity distinguishes this tumor from cutaneous myxoma. We conclude that this lesion represents a newly recognized tumor of fibroblastic origin. The name cutaneous myxoid fibroblastoma is proposed.


Olfactory cues from romantic partners and strangers influence women's responses to stress.
The scent of another person can activate memories, trigger emotions, and spark romantic attraction; however, almost nothing is known about whether and how human scents influence responses to stress. In the current study, 96 women were randomly assigned to smell one of three scents (their romantic partner's, a stranger's, or a neutral scent) and exposed to an acute stressor (Trier Social Stress Test). Perceived stress and cortisol were measured continuously throughout the study (5 and 7 times, respectively). Perceived stress was reduced in women who were exposed to their partner's scent. This reduction was observed during stress anticipation and stress recovery. Cortisol levels were elevated in women who were exposed to a stranger's scent. This elevation was observed throughout stress anticipation, peak stress, and stress recovery. The current work speaks to the critical role of human olfactory cues in social communication and reveals that social scents can impact both psychological and physiological reactions to stress. (PsycINFO Database Record


Enclosing the commons: reasons for the adoption and adaptation of enclosures in the arid and semi-arid rangelands of Chepareria, Kenya.
The adoption and adaptation of enclosures in the arid and semi-arid rangelands of sub-Saharan Africa is driven and sustained by a combination of factors. However, reviews indicate that these factors cannot be generalized, as they tend to be case specific. A study was therefore conducted to explore the history and reasons for enclosure establishment in Chepareria, a formerly degraded communal rangeland in north-western Kenya. While Vi-Agroforestry Organization accounting for 52.5 % was the main source of knowledge on enclosure establishment; it has now emerged that rangeland enclosures among the Pokot pastoral community existed prior to land management interventions by Vi- Agroforestry. Results indicated that there are three categories of enclosures which were established for boundary demarcation, provide grazing reserves, enable proper land management, facilitate crop cultivation in a pastoral setup and to curb land degradation. The role of self-trigger [accounting for most of the spontaneous enclosures (73.5 %)] indicates the continued establishment and expansion of areas under enclosure management as private land ownership accounting for 51.7 % of enclosure tenure continues to gain momentum in Chepareria. While rangeland enclosures in Chepareria were mainly established for boundary demarcation, to alleviate pasture scarcity and enable proper management of formerly degraded areas; they have facilitated land restoration and rehabilitation by increasing flexibility in land, fodder and livestock management amongst agro-pastoralists in Chepareria over the last three decades. To ensure that rehabilitated areas do not revert to their previously degraded state; technical interventions are needed to allow for a more intensive use of rangeland resources within enclosed areas.


Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy.
Evaluations of the African childhood malaria burden do not fully quantify the contributions of cerebral malaria (CM), CM-associated neurological sequelae, malarial anemia, respiratory distress, hypoglycemia, and pregnancy-related complications. We estimated the impact of these malaria manifestations on members of the African population < 5 years old. Calculations were based on an extensive literature review that used National Library of Medicine search engines, other bibliographic sources, and demographic data. In sub-Saharan Africa, CM annually affects 575,000 children < 5 years of age and 110,000 (approximately 19% case fatality rate [CFR]) die. Childhood survivor, of CM experience developmental and behavioral impairments: each year, 9,000-19,000 children (> 2% of survivors of CM) < 5 years of age in Africa experience neurological complications lasting > 6 months. Severe malarial anemia heavily burdens hospitals with rising admission and CFRs and with treatments that are complicated by limited and sometimes contaminated blood supplies. Severe malarial anemia occurs 1.42-5.66 million times annually and kills 190,000-974,000 (> 13% CFR) children < 5 years of age annually. Respiratory distress, hypoglycemia, and overlapping clinical manifestations cause 1.12-1.99 million cases and > 225,000 (> 18% CFR) additional deaths among African children with malaria. Maternal, placental, or fetal malaria infection during pregnancy adversely affects development and survival of fetuses and newborns through low birth weight (LBW), maternal anemia, and possibly abortion and stillbirth. Between 167,000 and 967,000 cases of malaria-associated LBW occur yearly; malaria-induced LBW kills 62,000-363,000 (> 38% CFR) newborns each year. All the gaps in the burden comprise 0.4-1.7 million deaths annually, > 50% of which are due to severe malarial anemia. These malaria-induced medical problems constitute major clinical, public health, and research challenges in that they may contribute to more than double the mortality than is generally acknowledged.


School bullying: its nature and ecology.
Recent youth suicides only highlight a persistent problem in schools - bullying and sustained peer victimization. Being a target or victim of bullying has long been recognized has having short- and long-term psychological effects on children and adolescents across the world today. School bullying is one of the most significant public health concerns facing children and adolescents. Involvement in the social phenomena of school bullying is often explained as emerging from a wide range of risk and protective factors within the social-ecology of youth. The social-ecological model posits that bullying behaviors are shaped by various interrelated contexts including individual characteristics, family, peers and the school environment. Research is reviewed to highlight the correlates of bullying involvement across these context using social-ecological and social-learning frameworks. Meta-analytic studies are reviewed on the short- and long-term impact of bullying involvement and efficacy of bullying prevention programs. Specific recommendations for prevention planning and future research efforts are provided. Bullying is a multi-faceted issue, which is best understood in the larger social context in which it occurs. Individual characteristics of students contribute to bullying involvement when students have families that promote violence, teachers that ignore or dismiss bullying, schools that have negative climates and students who socialize with friends who bully. These social contexts need to be targeted in bully prevention programs to reduce bullying and peer victimization in schools.


Serum apolipoprotein C-III is independently associated with chronic hepatitis C infection and advanced fibrosis.
The hepatitis C virus (HCV) is known to disrupt lipid metabolism, making serum lipoprotein levels good candidates to explore as markers of HCV disease progression. Assessment of the major apolipoproteins (Apo) and their relationship to hepatic fibrosis remain largely unexplored. We compared the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and Apo A-I, -B, -C-III, and -E between patients with cleared versus active infection (n = 83), and between those chronically infected patients (n = 216) with advanced versus mild-moderate hepatic fibrosis (METAVIR stage F3-4 vs. F0-2) using multiple logistic regression. Apo C-III levels were 25% higher in subjects with cleared infection versus those with active infection (p = 0.009). Low levels of Apo C-III (p = 1.3 × 10(-5)), Apo A-I (p = 2.9 × 10(-5)), total cholesterol (p = 5.0 × 10(-4)), LDL-C (p = 0.005), and HDL-C (p = 2.0 × 10(-4)) were associated with advanced fibrosis in univariate analyses. Multivariable analysis revealed Apo C-III as the most significant factor associated with advanced fibrosis (p = 0.0004), followed by age (p = 0.013) and Apo A-I (p = 0.022). Inclusion of both Apo C-III and Apo A-I in a model to predict advanced fibrosis improved the area under the receiver operator curve only modestly. Relative to other lipoproteins, low serum Apo C-III levels are the most strongly associated with chronic versus cleared infection and decline with increasing severity of hepatic fibrosis. Apo C-III deserves further attention as a possible marker of HCV disease progression.


The associations between personality, diet and body mass index in older people.
Personality traits are related to numerous health outcomes and health-related behaviors. To date, however, little is known about how personality traits are associated with dietary behavior, an important aspect of lifestyle in the current "toxic food environment." The present study investigated the associations of between Five-Factor Model personality traits, dietary patterns, and body mass index (BMI). The sample consisted of 1,091 members of Lothian Birth Cohort 1936 tested at age 70 years. Dietary patterns were measured using a detailed and validated food frequency questionnaire (FFQ). Principal components analysis of the FFQ items identified four dietary dimensions, which were named 'Mediterranean style diet,' 'health aware diet,' 'convenience diet,' and 'sweet foods'. Personality traits were measured with NEO Five-Factor Inventory. The effects of childhood intelligence, education, and sex were controlled. Endorsing the Mediterranean style diet dimension was associated with high Openness and Extraversion, and low Neuroticism. High scores on the health aware diet dimension were associated with high Agreeableness and Conscientiousness. Endorsing the convenience diet dimension was associated with low Openness and high Neuroticism. Preference for sweet foods was associated with low Openness. High BMI was associated with high scores on the convenience diet dimension and low Conscientiousness. Personality traits, especially Openness, are associated with dietary patterns in older age. The pattern of findings may indicate that, in older people, dietary habits may be less related to how controlled they are and more related to their levels of openness and emotional and social adjustment. Policy implications are discussed.


Giant deuteron migration during the isosymmetric phase transition in deuterated 3,5-pyridinedicarboxylic acid.
Deuterated 3,5-pyridinedicarboxylic acid exhibits reversible temperature-induced deuteron migration of a magnitude unprecedented in this class of compounds. We used a combination of variable-temperature powder and single-crystal neutron diffraction and density functional theory (DFT)-based computational methods to elucidate the origin of this remarkable behaviour. Single-crystal neutron diffraction shows that between 15 and 300 K, the deuteron moves by 0.32(1) Å and the structure changes from a low-temperature N-D···O form to a high-temperature N···D-O form. Variable-temperature powder neutron-diffraction data, which was fitted by using parametric Rietveld refinement, show that this deuteron migration is due to an isosymmetric, first-order phase transition that occurs by growth of the daughter phase in the parent-phase matrix. Similar phase transitions are observed in two selectively deuterated forms of the material. DFT calculations demonstrate the role of phonons and show that vibrational free-energy stabilisation, which plays a key role in the observed structural phase transitions, is more pronounced in the fully deuterated material and proportional to the mass of the molecule, that is, the level of deuteration. This is consistent with our experimental work, for which distinct crystallographic phase transitions were clearly observed for the three deuterated systems, but not for the fully protonated material.


Missouri's 2005 Medicaid cuts: how did they affect enrollees and providers?
In 2005, Missouri adopted sweeping Medicaid cutbacks. More than 100,000 people lost coverage, and many more faced reduced benefits and higher cost sharing. Using a range of data sources, we show that the cutbacks were followed by a major increase in the numbers of uninsured people, greater uncompensated care burden on hospitals, and revenue shortfalls that forced community health centers to obtain larger state grants and charge patients more. Competing demands on state budgets and the need to balance budgets even during recessions could result in policies that disadvantage those with great needs as well as the providers who serve them.


Improvement of lacrimal function by topical application of CyA in murine models of Sjögren's syndrome.
The object of this study was to evaluate improvement of lacrimal gland (LG) function after topical cyclosporin A (CyA). Topical CyA (0.01% and 0.1%) was applied to two mouse models of Sjögren's syndrome, the NFS/sld after thymectomy and the nonobese diabetic (NOD) mouse, and the functional integrity of the lacrimal gland was evaluated by measuring basal and stimulated tear secretion and its histologic integrity by examining it for apoptosis and lymphocyte invasion. After treatment with CyA at 0.1% in the NFS/sld mice, tear function increased, and there was a decrease in lymphocyte infiltration of the LG and a decrease in apoptotic figures among the acinar cells. In the NOD mice, tear function also improved, but there was no associated decrease in lymphocyte infiltration. However, the expression of Fas ligand (FasL) in NOD mice by infiltrating lymphocytes was suppressed with 0. 1% CyA eye drops. CyA appears to improve tear secretion in mouse models of Sjögren's syndrome by preventing lymphocyte-induced apoptosis of acinar cells. In one model this was achieved by preventing lymphocyte infiltration and in the other by reducing expression of FasL expression on infiltrating lymphocytes.


Daily sedentary time and physical activity as assessed by accelerometry and their correlates in older adults.
Higher physical activity is associated with lower chronic disease risk among older adults. However, less is known about the optimal balance between daily physical activity and sedentary time and their correlates among older adults. We described objectively measured physical activity patterns using 7 day hip-accelerometry and assessed its correlates in a large cross-sectional sample of the Longitudinal Aging Study Amsterdam, a population-based cohort of older Dutch adults. In addition, we examined different combined profiles of sedentary time and physical activity across strata of sex, age, education and BMI groups. Mean age was 71 (SD 8) years and 51% (n = 615) were women. The majority of wear time was spent sedentary (65%) followed by light (33%), and MVPA (2%). Higher age and higher BMI were related to more time spent sedentary, while female sex and lower education were related lower sedentary time. The combination of high sedentary time (≥65.4% of waking time) and low physical activity (< 9.1% of waking time) was significantly associated with higher age, higher BMI, and slower walking speed compared to the combination of low sedentary time and high physical activity P < 0.001. Dutch older adults spend on average 65% of their waking time sedentary. Older adults' sedentary time differs by age, sex, education and BMI groups. The combination of high sedentary time and low physical was associated with higher age, higher BMI, and slower walking speed compared to the combination of low sedentary time and high MVPA. This suggests that increasing light activity might be an effective and feasible strategy in older persons to reduce sedentary time. Future studies should assess whether low- sedentary and high-light physical activity are associated with improved long-term health outcomes (also independent of MVPA).


Diversity, distribution and hydrocarbon biodegradation capabilities of microbial communities in oil-contaminated cyanobacterial mats from a constructed wetland.
Various types of cyanobacterial mats were predominant in a wetland, constructed for the remediation of oil-polluted residual waters from an oil field in the desert of the south-eastern Arabian Peninsula, although such mats were rarely found in other wetland systems. There is scarce information on the bacterial diversity, spatial distribution and oil-biodegradation capabilities of freshwater wetland oil-polluted mats. Microbial community analysis by Automated Ribosomal Spacer Analysis (ARISA) showed that the different mats hosted distinct microbial communities. Average numbers of operational taxonomic units (OTUsARISA) were relatively lower in the mats with higher oil levels and the number of shared OTUsARISA between the mats was <60% in most cases. Multivariate analyses of fingerprinting profiles indicated that the bacterial communities in the wetland mats were influenced by oil and ammonia levels, but to a lesser extent by plant density. In addition to oil and ammonia, redundancy analysis (RDA) showed also a significant contribution of temperature, dissolved oxygen and sulfate concentration to the variations of the mats' microbial communities. Pyrosequencing yielded 282,706 reads with >90% of the sequences affiliated to Proteobacteria (41% of total sequences), Cyanobacteria (31%), Bacteriodetes (11.5%), Planctomycetes (7%) and Chloroflexi (3%). Known autotrophic (e.g. Rivularia) and heterotrophic (e.g. Azospira) nitrogen-fixing bacteria as well as purple sulfur and non-sulfur bacteria were frequently encountered in all mats. On the other hand, sequences of known sulfate-reducing bacteria (SRBs) were rarely found, indicating that SRBs in the wetland mats probably belong to yet-undescribed novel species. The wetland mats were able to degrade 53-100% of C12-C30 alkanes after 6 weeks of incubation under aerobic conditions. We conclude that oil and ammonia concentrations are the major key players in determining the spatial distribution of the wetland mats' microbial communities and that these mats contribute directly to the removal of hydrocarbons from oil field wastewaters.


Using Zebrafish for Investigating the Molecular Mechanisms of Drug-Induced Cardiotoxicity.
Over the last decade, the zebrafish (Danio rerio) has emerged as a model organism for cardiovascular research. Zebrafish have several advantages over mammalian models. For instance, the experimental cost of using zebrafish is comparatively low; the embryos are transparent, develop externally, and have high fecundity making them suitable for large-scale genetic screening. More recently, zebrafish embryos have been used for the screening of a variety of toxic agents, particularly for cardiotoxicity testing. Zebrafish has been shown to exhibit physiological responses that are similar to mammals after exposure to medicinal drugs including xenobiotics, hormones, cancer drugs, and also environmental pollutants, including pesticides and heavy metals. In this review, we provided a summary for recent studies that have used zebrafish to investigate the molecular mechanisms of drug-induced cardiotoxicity. More specifically, we focused on the techniques that were exploited by us and others for cardiovascular toxicity assessment and described several microscopic imaging and analysis protocols that are being used for the estimation of a variety of cardiac hemodynamic parameters.


DGT-induced copper flux predicts bioaccumulation and toxicity to bivalves in sediments with varying properties.
Many regulatory frameworks for sediment quality assessment include consideration of contaminant bioavailability. However, the "snap-shots" of metal bioavailability provided by analyses of porewaters or acid-volatile sulfide-simultaneously extractable metal (AVS-SEM) relationships do not always contribute sufficient information. The use of inappropriate or inadequate information for assessing metal bioavailability in sediments may result in incorrect assessment decisions. The technique of diffusive gradients in thin films (DGT) enables the in situ measurement of metal concentrations in waters and fluxes from sediment porewaters. We utilized the DGT technique to interpret the bioavailability of copper to the benthic bivalve Tellina deltoidalis in sediments of varying properties contaminated with copper-based antifouling paint particles. For a concentration series of copper-paint contaminated sandy, silty-sand, and silty sediment types, DGT-probes were used to measure copper fluxes to the overlying water, at the sediment-water interface, and in deeper sediments. The overlying water copper concentrations and DGT-Cu fluxes were shown to provide excellent exposure concentration-response relationships in relation to lethal effects occurring to the copper-sensitive benthic bivalve, T. deltoidalis. The study demonstrates the strength of the DGT technique, which we expect will become frequently used for assessing metal bioavailability in sediments.


Toxoplasma DJ-1 Regulates Organelle Secretion by a Direct Interaction with Calcium-Dependent Protein Kinase 1.
Human DJ-1 is a highly conserved and yet functionally enigmatic protein associated with a heritable form of Parkinson's disease. It has been suggested to be a redox-dependent regulatory scaffold, binding to proteins to modulate their function. Here we present the X-ray crystal structure of the Toxoplasma orthologue Toxoplasma gondii DJ-1 (TgDJ-1) at 2.1-Å resolution and show that it directly associates with calcium-dependent protein kinase 1 (CDPK1). The TgDJ-1 structure identifies an orthologously conserved arginine dyad that acts as a phospho-gatekeeper motif to control complex formation. We determined that the binding of TgDJ-1 to CDPK1 is sensitive to oxidation and calcium, and that this interaction potentiates CDPK1 kinase activity. Finally, we show that genetic deletion of TgDJ-1 results in upregulation of CDPK1 expression and that disruption of the CDPK1/TgDJ-1 complex in vivo prevents normal exocytosis of parasite virulence-associated organelles called micronemes. Overall, our data suggest that TgDJ-1 functions as a noncanonical kinase-regulatory scaffold that integrates multiple intracellular signals to tune microneme exocytosis in T. gondiiIMPORTANCE Apicomplexan parasites such as Toxoplasma and Plasmodium are obligate intracellular parasites that require the protective environment of a host cell in order to replicate and survive within a host organism. These parasites secrete effector proteins from specialized apical organelles to select and invade a chosen host cell. The secretion of these organelles is a tightly regulated process coordinated by endogenous small molecules and calcium-dependent protein kinases. We previously identified the Toxoplasma orthologue of the highly conserved protein DJ-1 as a regulator of microneme secretion, but the molecular basis for this was not known. We have now identified the molecular mechanism for how TgDJ-1 regulates microneme secretion. TgDJ-1 interacts with the kinase responsible for the secretion of these organelles (calcium-dependent kinase 1) and synergizes with calcium to potentiate kinase activity. This interaction is direct, phosphodependent, and necessary for the normal secretion of these important organelles.


Analyses of the oligopeptide transporter gene family in poplar and grape.
Oligopeptide transporters (OPTs) are a group of membrane-localized proteins that have a broad range of substrate transport capabilities and that are thought to contribute to many biological processes. The OPT proteins belong to a small gene family in plants, which includes about 25 members in Arabidopsis and rice. However, no comprehensive study incorporating phylogeny, chromosomal location, gene structure, expression profiling, functional divergence and selective pressure analysis has been reported thus far for Populus and Vitis. In the present study, a comprehensive analysis of the OPT gene family in Populus (P. trichocarpa) and Vitis (V. vinifera) was performed. A total of 20 and 18 full-length OPT genes have been identified in Populus and Vitis, respectively. Phylogenetic analyses indicate that these OPT genes consist of two classes that can be further subdivided into 11 groups. Gene structures are considerably conserved among the groups. The distribution of OPT genes was found to be non-random across chromosomes. A high proportion of the genes are preferentially clustered, indicating that tandem duplications may have contributed significantly to the expansion of the OPT gene family. Expression patterns based on our analyses of microarray data suggest that many OPT genes may be important in stress response and functional development of plants. Further analyses of functional divergence and adaptive evolution show that, while purifying selection may have been the main force driving the evolution of the OPTs, some of critical sites responsible for the functional divergence may have been under positive selection. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the Populus and Vitis OPT gene family and of the function and evolution of the OPT gene family in higher plants.


Reliability of the Gross Motor Performance Measure.
The reporting of reliability coefficients and the method of their determination is expected of test developers. The purpose of this study was to estimate the interrater, intrarater, and test-retest reliability of the Gross Motor Performance Measure, a measure of quality of movement designed to accompany the Gross Motor Function Measure. Subjects were 28 children (25 with cerebral palsy, 2 nondisabled, 1 with head injury) between the ages of 1 and 10 years. Reliability data were obtained from assessments of 19 therapists. Intraclass correlation coefficients for reliability varied from .92 to .96 for the total scores and from .84 to .94 for the five attribute scores. When the Gross Motor Performance Measure was administered by therapists who are familiar with the Gross Motor Function Measure and had a 1-day training workshop, reliability of the total scores was above recommended minimums. Scores of single attributes were less reproducible.


Stability and change in level of probable depression and depressive symptoms in a sample of middle and older-aged adults.
Findings from studies investigating depression in adults in late life are mixed due to a lack of large longitudinal studies with the power necessary to yield reliable estimates of stability or change. We examined the long-term stability of probable depression and depressive symptomology over a 13-year period in the Dynamic Analyses to Optimize Ageing (DYNOPTA) project. Community-living participants (N = 35,200) were aged 45-103 at baseline, predominantly female (79%), partnered (73%), and educated to secondary school only (61%) and followed for up to 13 years. At baseline, increased age was associated with lower prevalence of probable depression and depressive symptomology. Over time, prevalence of probable depression was stable while levels of depressive symptomology reported a small decline. However, this finding was not consistent for all age groups; there was evidence for increasing levels of depressive symptomology, but not probable depression, as individuals aged. This effect was particularly notable among males aged 70 plus years. These results answer important questions relating to the longitudinal prevalence of probable depression and depressive symptomology in a sample of older Australians. These findings have policy implications for mental health service provision for older adults.


Tropomodulin caps the pointed ends of actin filaments.
Many proteins have been shown to cap the fast growing (barbed) ends of actin filaments, but none have been shown to block elongation and depolymerization at the slow growing (pointed) filament ends. Tropomodulin is a tropomyosin-binding protein originally isolated from red blood cells that has been localized by immunofluorescence staining to a site at or near the pointed ends of skeletal muscle thin filaments (Fowler, V. M., M. A., Sussman, P. G. Miller, B. E. Flucher, and M. P. Daniels. 1993. J. Cell Biol. 120: 411-420). Our experiments demonstrate that tropomodulin in conjunction with tropomyosin is a pointed end capping protein: it completely blocks both elongation and depolymerization at the pointed ends of tropomyosin-containing actin filaments in concentrations stoichiometric to the concentration of filament ends (Kd < or = 1 nM). In the absence of tropomyosin, tropomodulin acts as a "leaky" cap, partially inhibiting elongation and depolymerization at the pointed filament ends (Kd for inhibition of elongation = 0.1-0.4 microM). Thus, tropomodulin can bind directly to actin at the pointed filament end. Tropomodulin also doubles the critical concentration at the pointed ends of pure actin filaments without affecting either the rate of extent of polymerization at the barbed filament ends, indicating that tropomodulin does not sequester actin monomers. Our experiments provide direct biochemical evidence that tropomodulin binds to both the terminal tropomyosin and actin molecules at the pointed filament end, and is the long sought-after pointed end capping protein. We propose that tropomodulin plays a role in maintaining the narrow length distributions of the stable, tropomyosin-containing actin filaments in striated muscle and in red blood cells.