Large-scale production and purification of the human green cone pigment: characterization of late photo-intermediates.
We present the first characterization of the late photo-intermediates (Meta I, Meta II and Meta III) of a vertebrate cone pigment in a lipid environment. Marked differences from the same pathway in the rod pigment were observed. The histidine-tagged human green cone pigment was functionally expressed in large-scale suspension cultures in Sf9 insect cells using recombinant baculovirus. The recombinant pigment was extensively purified in a single step by immobilized metal affinity chromatography and displays the expected spectral characteristics. The purified pigment was able to activate the rod G-protein transducin at about half the rate of the rod pigment. Following reconstitution into bovine retina lipid proteoliposomes, identification and analysis of the photo-intermediates Meta I, Meta II and Meta III was accomplished. Similar to the rod pigment, our results indicate the existence of a Meta I-Meta II equilibrium, but we find no evidence for pH dependence. Replacement of native Cl- by NO3- in the anion-binding site of the cone pigment affected the spectral position of the pigment itself and of the Meta I intermediate, but not that of Meta II and Meta III. The decay rate of the 'active' intermediate Meta II did not differ for the Cl- and NO3- state. However, in qualitative agreement with results reported before for chicken cone pigments, the rate of Meta II decay was significantly higher in the human cone pigment than in the rod pigment.


How Do Patients with Chronic Neck Pain Experience the Effects of Qigong and Exercise Therapy? A Qualitative Interview Study.
Background. The high prevalence of chronic neck pain in high income countries impacts quality of life and the social and work-related activities of those afflicted. We aimed to understand how mind-body therapies and exercise therapy may influence the experience of pain among patients with chronic neck pain. Methods. This qualitative interview study investigated how patients with chronic neck pain experienced the effects of exercise or qigong therapy at two time points: during an intervention at three months and after the intervention at six months. Interviews were analysed thematically across interviews and within person-cases. Based on other qualitative studies, a sample size of 20 participants was deemed appropriate. Results. The sample (n = 20) consisted of 16 women and four men (age range: 29 to 59). Patients' experiences differed according to the therapies' philosophies. Exercise therapy group interviewees described a focus on correct posture and muscle tension release. Qigong group interviewees discussed calming and relaxing effects. Maintaining regular exercise was easier to achieve with exercise therapy. Conclusions. The findings of this study may help health care providers when counselling chronic pain patients on self-help interventions by informing them of different bodily and emotional experiences of mind-body interventions compared to exercise therapy.


Adaptive statistical iterative reconstruction versus filtered back projection in the same patient: 64 channel liver CT image quality and patient radiation dose.
To compare routine dose liver CT reconstructed with filtered back projection (FBP) versus low dose images reconstructed with FBP and adaptive statistical iterative reconstruction (ASIR). In this retrospective study, patients had a routine dose protocol reconstructed with FBP, and again within 17 months (median 6.1 months), had a low dose protocol reconstructed twice, with FBP and ASIR. These reconstructions were compared for noise, image quality, and radiation dose. Nineteen patients were included. (12 male, mean age 58). Noise was significantly lower in low dose images reconstructed with ASIR compared to routine dose images reconstructed with FBP (liver: p < .05, aorta: p < 0.001). Low dose FBP images were scored significantly lower for subjective image quality than low dose ASIR (2.1 ± 0.5, 3.2 ± 0.8, p < 0.001). There was no difference in subjective image quality scores between routine dose FBP images and low dose ASIR images (3.6 ± 0.5, 3.2 ± 0.8, NS).Radiation dose was 41% less for the low dose protocol (4.4 ± 2.4 mSv versus 7.5 ± 5.5 mSv, p < 0.05). Our initial results suggest low dose CT images reconstructed with ASIR may have lower measured noise, similar image quality, yet significantly less radiation dose compared with higher dose images reconstructed with FBP.


Exploring the complexity of quantum control optimization trajectories.
The control of quantum system dynamics is generally performed by seeking a suitable applied field. The physical objective as a functional of the field forms the quantum control landscape, whose topology, under certain conditions, has been shown to contain no critical point suboptimal traps, thereby enabling effective searches for fields that give the global maximum of the objective. This paper addresses the structure of the landscape as a complement to topological critical point features. Recent work showed that landscape structure is highly favorable for optimization of state-to-state transition probabilities, in that gradient-based control trajectories to the global maximum value are nearly straight paths. The landscape structure is codified in the metric R ≥ 1.0, defined as the ratio of the length of the control trajectory to the Euclidean distance between the initial and optimal controls. A value of R = 1 would indicate an exactly straight trajectory to the optimal observable value. This paper extends the state-to-state transition probability results to the quantum ensemble and unitary transformation control landscapes. Again, nearly straight trajectories predominate, and we demonstrate that R can take values approaching 1.0 with high precision. However, the interplay of optimization trajectories with critical saddle submanifolds is found to influence landscape structure. A fundamental relationship necessary for perfectly straight gradient-based control trajectories is derived, wherein the gradient on the quantum control landscape must be an eigenfunction of the Hessian. This relation is an indicator of landscape structure and may provide a means to identify physical conditions when control trajectories can achieve perfect linearity. The collective favorable landscape topology and structure provide a foundation to understand why optimal quantum control can be readily achieved.


Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis.
A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately. The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed. Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (ORPETO:3.26; 95%CI:1.12 to 9.50), nilotinib (ORPETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (ORPETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (ORPETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results. Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.


Basic research on uterus transplantation in nonhuman primates in Japan.
Uterus transplantation (UTx) is now a potential option for women with uterine factor infertility to have a child. However, UTx is still in an experimental stage and basic animal studies including in nonhuman primates are needed for accumulation of data that will provide important information for establishment of UTx in humans. Herein, we summarized our experiences using cynomolgus macaques, with the goal of promoting further development of UTx studies in nonhuman primates. Our basic studies using cynomolgus macaques were summarized, including the results of other teams in nonhuman primates. Our team in Japan launched UTx research in 2009 using cynomolgus macaques and has accumulated a large archive of results in the UTx research field, including examination of uterine blood flow, surgical procedures of autologous and allogeneic UTx, organ perfusion methods in deceased donor models, immunological response and rejection and ischemia/reperfusion injury. We achieved the first delivery after autologous UTx in primates and the first periodic recovery of menstruation after allogeneic UTx in nonhuman primate models. Results from animal studies, including those in nonhuman primates, provide the basis for clinical application of UTx. Therefore, our accumulated data since 2009 and our basic experience in cynomolgus macaque are meaningful for future UTx trials in Japan. In addition, more validation in nonhuman primate models is needed for resolution of medical issues and further development of UTx in humans, despite clinical application of UTx in several countries.


Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome and related autism spectrum disorders (Amir et al., 1999). MeCP2 is believed to be required for proper regulation of brain gene expression, but prior microarray studies in Mecp2 knock-out mice using brain tissue homogenates have revealed only subtle changes in gene expression (Tudor et al., 2002; Nuber et al., 2005; Jordan et al., 2007; Chahrour et al., 2008). Here, by profiling discrete subtypes of neurons we uncovered more dramatic effects of MeCP2 on gene expression, overcoming the "dilution problem" associated with assaying homogenates of complex tissues. The results reveal misregulation of genes involved in neuronal connectivity and communication. Importantly, genes upregulated following loss of MeCP2 are biased toward longer genes but this is not true for downregulated genes, suggesting MeCP2 may selectively repress long genes. Because genes involved in neuronal connectivity and communication, such as cell adhesion and cell-cell signaling genes, are enriched among longer genes, their misregulation following loss of MeCP2 suggests a possible etiology for altered circuit function in Rett syndrome.


Comprehensive study of liposome-assisted synthesis of membrane proteins using a reconstituted cell-free translation system.
Membrane proteins play pivotal roles in cellular processes and are key targets for drug discovery. However, the reliable synthesis and folding of membrane proteins are significant problems that need to be addressed owing to their extremely high hydrophobic properties, which promote irreversible aggregation in hydrophilic conditions. Previous reports have suggested that protein aggregation could be prevented by including exogenous liposomes in cell-free translation processes. Systematic studies that identify which membrane proteins can be rescued from irreversible aggregation during translation by liposomes would be valuable in terms of understanding the effects of liposomes and developing applications for membrane protein engineering in the context of pharmaceutical science and nanodevice development. Therefore, we performed a comprehensive study to evaluate the effects of liposomes on 85 aggregation-prone membrane proteins from Escherichia coli by using a reconstituted, chemically defined cell-free translation system. Statistical analyses revealed that the presence of liposomes increased the solubility of >90% of the studied membrane proteins, and ultimately improved the yields of the synthesized proteins. Bioinformatics analyses revealed significant correlations between the liposome effect and the physicochemical properties of the membrane proteins.


Non-speech oral motor treatment for children with developmental speech sound disorders.
Children with developmental speech sound disorders have difficulties in producing the speech sounds of their native language. These speech difficulties could be due to structural, sensory or neurophysiological causes (e.g. hearing impairment), but more often the cause of the problem is unknown. One treatment approach used by speech-language therapists/pathologists is non-speech oral motor treatment (NSOMT). NSOMTs are non-speech activities that aim to stimulate or improve speech production and treat specific speech errors. For example, using exercises such as smiling, pursing, blowing into horns, blowing bubbles, and lip massage to target lip mobility for the production of speech sounds involving the lips, such as /p/, /b/, and /m/. The efficacy of this treatment approach is controversial, and evidence regarding the efficacy of NSOMTs needs to be examined. To assess the efficacy of non-speech oral motor treatment (NSOMT) in treating children with developmental speech sound disorders who have speech errors. In April 2014 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (R) and Ovid MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Education Resources Information Center (ERIC), PsycINFO and 11 other databases. We also searched five trial and research registers, checked the reference lists of relevant titles identified by the search and contacted researchers to identify other possible published and unpublished studies. Randomised and quasi-randomised controlled trials that compared (1) NSOMT versus placebo or control; and (2) NSOMT as adjunctive treatment or speech intervention versus speech intervention alone, for children aged three to 16 years with developmental speech sound disorders, as judged by a speech and language therapist. Individuals with an intellectual disability (e.g. Down syndrome) or a physical disability were not excluded. The Trials Search Co-ordinator of the Cochrane Developmental, Psychosocial and Learning Problems Group and one review author ran the searches. Two review authors independently screened titles and abstracts to eliminate irrelevant studies, extracted data from the included studies and assessed risk of bias in each of these studies. In cases of ambiguity or information missing from the paper, we contacted trial authors. This review identified three studies (from four reports) involving a total of 22 children that investigated the efficacy of NSOMT as adjunctive treatment to conventional speech intervention versus conventional speech intervention for children with speech sound disorders. One study, a randomised controlled trial (RCT), included four boys aged seven years one month to nine years six months - all had speech sound disorders, and two had additional conditions (one was diagnosed as "communication impaired" and the other as "multiply disabled"). Of the two quasi-randomised controlled trials, one included 10 children (six boys and four girls), aged five years eight months to six years nine months, with speech sound disorders as a result of tongue thrust, and the other study included eight children (four boys and four girls), aged three to six years, with moderate to severe articulation disorder only. Two studies did not find NSOMT as adjunctive treatment to be more effective than conventional speech intervention alone, as both intervention and control groups made similar improvements in articulation after receiving treatments. One study reported a change in postintervention articulation test results but used an inappropriate statistical test and did not report the results clearly. None of the included studies examined the effects of NSOMTs on any other primary outcomes, such as speech intelligibility, speech physiology and adverse effects, or on any of the secondary outcomes such as listener acceptability.The RCT was judged at low risk for selection bias. The two quasi-randomised trials used randomisation but did not report the method for generating the random sequence and were judged as having unclear risk of selection bias. The three included studies were deemed to have high risk of performance bias as, given the nature of the intervention, blinding of participants was not possible. Only one study implemented blinding of outcome assessment and was at low risk for detection bias. One study showed high risk of other bias as the baseline characteristics of participants seemed to be unequal. The sample size of each of the included studies was very small, which means it is highly likely that participants in these studies were not representative of its target population. In the light of these serious limitations in methodology, the overall quality of the evidence provided by the included trials is judged to be low. Therefore, further research is very likely to have an important impact on our confidence in the estimate of treatment effect and is likely to change the estimate. The three included studies were small in scale and had a number of serious methodological limitations. In addition, they covered limited types of NSOMTs for treating children with speech sound disorders of unknown origin with the sounds /s/ and /z/. Hence, we judged the overall applicability of the evidence as limited and incomplete. Results of this review are consistent with those of previous reviews: Currently no strong evidence suggests that NSOMTs are an effective treatment or an effective adjunctive treatment for children with developmental speech sound disorders. Lack of strong evidence regarding the treatment efficacy of NSOMTs has implications for clinicians when they make decisions in relation to treatment plans. Well-designed research is needed to carefully investigate NSOMT as a type of treatment for children with speech sound disorders.


Self-shading correction for upwelling sea-surface radiance measurements made with buoyed instruments.
Upwelling radiance measurements made with instruments designed to float at the sea surface are shaded both by the instrument housing and by the buoy that holds the instrument. The amount of shading is wavelength dependent and is affected by the local marine and atmospheric conditions. Radiance measurements made with such instruments should be corrected for this self-shading error before being applied to remote sensing calibrations or remote sensing algorithm validation. Here we use Monte Carlo simulations to compute the self-shading error of a commercially available buoyed radiometer so that measurements made with this instrument can be improved. This approach can be easily adapted to the dimensions of other instruments.


Dbx1-Derived Pyramidal Neurons Are Generated Locally in the Developing Murine Neocortex.
The neocortex (NCx) generates at the dorsal region of the pallium in the forebrain. Several adjacent structures also contribute with neurons to NCx. Ventral pallium (VP) is considered to generate several populations of neurons that arrive through tangential migration to the NCx. Amongst them are the Cajal-Retzius cells and some transient pyramidal neurons. However, the specific site and timing of generation, trajectory of migration and actual contribution to the pyramidal population remains elusive. Here, we investigate the spatio-temporal origin of neuronal populations from VP in an in vivo model, using a transposase mediated in utero electroporation method in embryonic mouse. From E11 to E14 cells born at the lateral corner of the neocortical neuroepithelium including the VP migrated ventro-laterally to settle all areas of the ventral telencephalon. Specifically, neurons migrated into amygdala (Ag), olfactory cortices, and claustrum (Cl). However, we found no evidence for any neurons migrating tangentially toward the NCx, regardless the antero-posterior level and developmental time of the electroporation. Our results challenge the described ventral-pallial origin of the transient pyramidal neuron population. In order to find the exact origin of cortical neurons that were previously Dbx1-fate mapped we used the promoter region of the murine Dbx1 locus to selectively target Dbx1-expressing progenitors and label their lineage. We found these progenitors in low numbers in all pallial areas, and not only in the ventral pallial ventricular zone. Our findings on the local cortical origin of the Dbx1-derived pyramidal neurons reconcile the observation of Dbx1-derived neurons in the cortex without evidence of dorsal tangential migration from VP and provide a new framework for the origin of the transient Dbx1-derived pyramidal neuron population. We conclude that these neurons are born locally within the dorsal pallial neuroepithelium.


Session 3: Joint Nutrition Society and Irish Nutrition and Dietetic Institute Symposium on 'Nutrition and autoimmune disease' PUFA, inflammatory processes and rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease manifested by swollen and painful joints, bone erosion and functional impairment. The joint lesions are characterised by infiltration of T lymphocytes, macrophages and B lymphocytes into the synovium and by synovial inflammation involving eicosanoids, cytokines and matrix metalloproteinases. In relation to inflammatory processes, the main fatty acids of interest are the n-6 PUFA arachidonic acid, which is the precursor of inflammatory eicosanoids such as PGE2 and leukotriene B4, and the n-3 PUFA EPA and DHA, which are found in oily fish and fish oils. Eicosanoids derived from the n-6 PUFA arachidonic acid play a role in RA, and the efficacy of non-steroidal anti-inflammatory drugs in RA indicates the importance of pro-inflammatory cyclooxygenase pathway products of arachidonic acid in the pathophysiology of the disease. EPA and DHA inhibit arachidonic acid metabolism to inflammatory eicosanoids. EPA also gives rise to eicosanoid mediators that are less inflammatory than those produced from arachidonic acid and both EPA and DHA give rise to resolvins that are anti-inflammatory and inflammation resolving. In addition to modifying the lipid mediator profile, n-3 PUFA exert effects on other aspects of immunity relevant to RA such as antigen presentation, T-cell reactivity and inflammatory cytokine production. Fish oil has been shown to slow the development of arthritis in an animal model and to reduce disease severity. Randomised clinical trials have demonstrated a range of clinical benefits in patients with RA that include reducing pain, duration of morning stiffness and use of non-steroidal anti-inflammatory drugs.


Classification of Trigeminal Autonomic Cephalalgia: What has Changed in International Classification of Headache Disorders-3 Beta?
The term "Trigeminal Autonomic Cephalalgia (TAC)" was first coined by Goadsby and Lipton[1] to include a group of relatively rare primary headache disorders characterized by moderate to severe, short-lived head pain in the trigeminal distribution with unilateral cranial parasympathetic autonomic features, such as lacrimation, rhinorrhea, conjunctival injection, eyelid edema, and ptosis. In the current International Classification of Headache Disorders (ICHD-3 beta),[2] the TAC group includes cluster headache (CH), paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks (SUNHAs) and their 2 subforms - SUNHAs with conjunctival injection and tearing (SUNCT), SUNHAs with cranial autonomic symptoms (SUNA). Hemicrania Continua (HC) is also now included in the TAC group. Although the entities included under TACs seem broadly similar, they differ in attack duration, frequency and their response to different treatments. At one end of the spectrum lies CH, the prototypic TAC where the duration of attacks is the longest and at the other end is the SUNCT syndrome where the duration is shortest. There is some overlap across the entities; they are not difficult to recognize and subclassify. The umbrella term "TAC" for the short-lasting headaches with autonomic features was for the first time introduced in The ICHD, 2nd edition (ICHD-2) published in 2004.[3] The beta version of the 3rd edition of The ICHD[2] was published in 2013. Headache classification being an evolving process, there have been some changes within the TAC group between ICHD-2 and ICHD-3 beta.[45] Diagnostic criteria have been revised to reflect pathophysiological and clinical observations. Neuroimaging has provided insights into the pathophysiology of TACs. Functional neuroimaging has helped to elucidate key structures activated during attacks of TACs. Correct diagnosis remains the key to correct management of the TACs because treatment options vary. The aim of this article will be to highlight the changes in ICHD-3 beta to this group and to emphasize the clinical implications of these changes. Description of individual entities included under TACs are included elsewhere and will therefore not be detailed here.


Pathways of lipid metabolism in marine algae, co-expression network, bottlenecks and candidate genes for enhanced production of EPA and DHA in species of Chromista.
The importance of n-3 long chain polyunsaturated fatty acids (LC-PUFAs) for human health has received more focus the last decades, and the global consumption of n-3 LC-PUFA has increased. Seafood, the natural n-3 LC-PUFA source, is harvested beyond a sustainable capacity, and it is therefore imperative to develop alternative n-3 LC-PUFA sources for both eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Genera of algae such as Nannochloropsis, Schizochytrium, Isochrysis and Phaedactylum within the kingdom Chromista have received attention due to their ability to produce n-3 LC-PUFAs. Knowledge of LC-PUFA synthesis and its regulation in algae at the molecular level is fragmentary and represents a bottleneck for attempts to enhance the n-3 LC-PUFA levels for industrial production. In the present review, Phaeodactylum tricornutum has been used to exemplify the synthesis and compartmentalization of n-3 LC-PUFAs. Based on recent transcriptome data a co-expression network of 106 genes involved in lipid metabolism has been created. Together with recent molecular biological and metabolic studies, a model pathway for n-3 LC-PUFA synthesis in P. tricornutum has been proposed, and is compared to industrialized species of Chromista. Limitations of the n-3 LC-PUFA synthesis by enzymes such as thioesterases, elongases, acyl-CoA synthetases and acyltransferases are discussed and metabolic bottlenecks are hypothesized such as the supply of the acetyl-CoA and NADPH. A future industrialization will depend on optimization of chemical compositions and increased biomass production, which can be achieved by exploitation of the physiological potential, by selective breeding and by genetic engineering.


Fine motor skills in adult Tourette patients are task-dependent.
Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics. Deficient motor inhibition underlying tics is one of the main hypotheses in its pathophysiology. Therefore the question arises whether this supposed deficient motor inhibition affects also voluntary movements. Despite severe motor tics, different personalities who suffer from Tourette perform successfully as neurosurgeon, pilot or professional basketball player. For the investigation of fine motor skills we conducted a motor performance test battery in an adult Tourette sample and an age matched group of healthy controls. The Tourette patients showed a significant lower performance in the categories steadiness of both hands and aiming of the right hand in comparison to the healthy controls. A comparison of patients' subgroup without comorbidities or medication and healthy controls revealed a significant difference in the category steadiness of the right hand. Our results show that steadiness and visuomotor integration of fine motor skills are altered in our adult sample but not precision and speed of movements. This alteration pattern might be the clinical vignette of complex adaptations in the excitability of the motor system on the basis of altered cortical and subcortical components. The structurally and functionally altered neuronal components could encompass orbitofrontal, ventrolateral prefrontal and parietal cortices, the anterior cingulate, amygdala, primary motor and sensorimotor areas including altered corticospinal projections, the corpus callosum and the basal ganglia.


Nitric oxide in prepubertal rat ovary contribution of the ganglionic nitric oxide synthase system via superior ovarian nerve.
Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. Considering the existence of the nitric oxide/ nitric oxide synthase system in the peripheral neural system and in the ovary, the aim of this work was to analyze if the liberation of NO in the ovarian compartment of prepubertal rats is of ovarian and/or ganglionic origin. The analysis is carried out from a physiological point of view using the experimental coeliac ganglion--Superior Ovarian Nerve--ovary model with and without ganglionic cholinergic stimulus Acetylcholine (Ach) 10(-6) M. Non selective and selective inhibitors of the synthase nitric oxide enzyme were added to the ovarian and ganglionic compartment, and the liberation of nitrites (soluble metabolite of the nitric oxide) in the ovarian incubation liquid was measured. We found that the non-selective inhibitor L-nitro-arginina methyl ester (L-NAME) in the ovarian compartment decreased the liberation of nitrites, and that Aminoguanidine (AG) in two concentrations in a non-dose dependent form provoked the same effect. The addition of Ach in ganglion magnified the effect of the inhibitors of the NOS enzyme. The most relevant results after the addition of inhibitors in ganglion were obtained with AG 400 and 800 microM. The inhibition was made evident with and without the joint action of Ach in ganglion. These data suggest that the greatest production of NO in the ovarian compartment comes from the ovary, mainly the iNOS isoform, though the coeliac ganglion also contributes through the superior ovarian nerve but with less quantity.


Molecular phylogeny and identification of the peach fruit fly, Bactrocera zonata, established in Egypt.
The genetic structure of the Egyptian peach fruit fly (Bactrocera zonata (Saunders) (Diptera: Tephritidae)) population was analyzed using total RNA from adult females. A portion of mitochondrial cytochrome oxidase I (COI), 369 bp was amplified using RT-PCR, and was sequenced and analyzed to clarify the phylogenetic relationship of B. zonata established in Egypt. The data suggested that the gene shared a similarity in sequence compared to Bactrocera COI gene found in GenBank. Molecular phylogenetic analyses were performed based on nucleotide sequences in order to examine the position of the Egyptian population among many other species of fruit flies. The results indicate that four accession numbers of B. zonata (three from New Zealand and one from India) are closely related, while the Egyptian B. zonata are close to the 71 accession numbers of Bactrocera include one B. zonata from New Zealand. These two B. zonata from Egypt and New Zealand showed a close relationship in neighbor-joining analysis using the seven accession numbers of B. zonata. In addition, a theoretical restriction map of the homology portion of the COI gene was constructed using 212 restriction enzymes obtained from the restriction enzyme database to identify the Egyptian and New Zealand B. zonata.


The hypolipidemic natural product Commiphora mukul and its component guggulsterone inhibit oxidative modification of LDL.
There is accumulating evidence that LDL oxidation is essential for atherogenesis, and that antioxidants that prevent this oxidation may either slow down or prevent atherogenesis. In the present study, we found that Commiphora mukul and its cholesterol-lowering component, guggulsterone, effectively inhibited LDL oxidation mediated by either catalytic copper ions, free radicals generated with the azo compound 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH), soybean lipoxygenase enzymatically, or mouse peritoneal macrophages. This inhibition was assessed by the decrease in the following parameters describing LDL oxidation: conjugated dienes, relative electrophoretic mobility (REM), thiobarbituric acid reactive substances, lipid hydroperoxides, oxidation-specific immune epitopes as detected with a monoclonal antibody against oxidized LDL, and the accumulation of LDL derived cholesterol esters in mouse peritoneal macrophages. We concluded that C. mukul and its lipid-lowering component, guggulsterone, significantly inhibit LDL oxidation. The combination of antioxidant and lipid-lowering properties of C. mukul and guggulsterone makes them especially beneficial against atherogenesis.


Are promyelocytic leukaemia protein nuclear bodies a scaffold for caspase-2 programmed cell death?
Promyelocytic leukaemia protein nuclear bodies (PML-NBs) are nuclear structures whose function is still poorly understood. They are implicated in various biological functions, such as viral infection, cellular transformation, innate immunity and growth control, and they might be dynamic hubs sensing stress and DNA damage. Data from PML(-/-) mice suggest that PML-NBs are involved in apoptosis via caspase-independent mechanisms, probably involving p53-dependent and independent pathways. However, the recently demonstrated co-localization of caspase-2 within the PML-NB nuclear structures presents a new paradigm for nuclear cell death. Here, we show that these nuclear structures have a protein known as SP100 that could contain a caspase recruitment domain (CARD). If verified experimentally, this discovery will suggest a mechanism by which caspase-2 could be recruited into the complex and ultimately lead to apoptosis.


Environmental risk factors for dementia: a systematic review.
Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementia have been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia. We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of review articles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed. We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields. Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations.


Phenotypic assortment mediates the effect of social selection in a wild beetle population.
Social interactions often have major fitness consequences, but little is known about how specific interacting phenotypes affect the strength of natural selection. Social influences on the evolutionary process can be assessed using a multilevel selection approach that partitions the effects of social partner phenotypes on fitness (referred to as social or group selection) from those of the traits of a focal individual (nonsocial or individual selection). To quantify the contribution of social selection to total selection affecting a trait, the patterns of phenotypic association among interactants must also be considered. We estimated selection gradients on male body size in a wild population of forked fungus beetles (Bolitotherus cornutus). We detected positive nonsocial selection and negative social selection on body size operating through differences in copulation success, indicating that large males with small social partners had highest fitness. In addition, we found that, in low-density demes, the phenotypes of focal individuals were negatively correlated with those of their social partners. This pattern reversed the negative effect of group selection on body size and led to stronger positive selection for body size. Our results demonstrate multilevel selection in nature and stress the importance of considering social selection whenever conspecific interactions occur nonrandomly.


Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines.
The cyanobacterial genus Microcystis is known to produce an elaborate array of structurally unique and biologically active natural products, including hazardous cyanotoxins. Cytotoxic aeruginoguanidines represent a yet unexplored family of peptides featuring a trisubstituted benzene unit and farnesylated arginine derivatives. In this study, we aimed at assigning these compounds to a biosynthetic gene cluster by utilizing biosynthetic attributes deduced from public genomes of Microcystis and the sporadic distribution of the metabolite in axenic strains of the Pasteur Culture Collection of Cyanobacteria. By integrating genome mining with untargeted metabolomics using liquid chromatography with mass spectrometry, we linked aeruginoguanidine (AGD) to a nonribosomal peptide synthetase gene cluster and coassigned a significantly smaller product to this pathway, microguanidine (MGD), previously only reported from two Microcystis blooms. Further, a new intermediate class of compounds named microguanidine amides was uncovered, thereby further enlarging this compound family. The comparison of structurally divergent AGDs and MGDs reveals an outstanding versatility of this biosynthetic pathway and provides insights into the assembly of the two compound subfamilies. Strikingly, aeruginoguanidines and microguanidines were found to be as widespread as the hepatotoxic microcystins, but the occurrence of both toxin families appeared to be mutually exclusive.


Reevaluation of brush border motility: calcium induces core filament solution and microvillar vesiculation.
The report that microvillar cores of isolated, demembranated brush borders retract into the terminal web in the presence of Ca(++) and ATP has been widely cited as an example of Ca(++)-regulated nonmuscle cell motility. Because of recent findings that microvillar core actin filaments are cross-linked by villin which, in the presence of micromolar Ca(++), fragments actin filaments, we used the techniques of video enhanced differential interference contrast, immunofluorescence, and phase contrast microscopy and thin-section electron microscopy (EM) to reexamine the question of contraction of isolated intestinal cell brush borders. Analysis of video enhanced light microscopic images of Triton- demembranated brush borders treated with a buffered Ca(++) solution shows the cores disintegrating with the terminal web remaining intact; membranated brush borders show the microvilli to vesiculate with Ca(++). Using Ca(++)/EGTA buffers, it is found that micromolar free Ca(++) causes core filament dissolution in membranated or demembranated brush borders, Ca(++) causes microvillar core solation followed by complete vesiculation of the microvillar membrane. The lengths of microvilli cores and rootlets were measured in thin sections of membranated and demembranated controls, in Ca(++)-, Ca(++) + ATP-, and in ATP-treated brush borders. Results of these measurements show that Ca(++) alone causes the complete solation of the microvillar cores, yet the rootlets in the terminal web region remain of normal length. These results show that microvilli do not retract into the terminal web in response to Ca(++) and ATP but rather that the microvillar cores disintegrate. NBD-phallicidin localization of actin and fluorescent antibodies to myosin reveal a circumferential band of actin and myosin in mildly permeabilized cells in the region of the junctional complex. The presence of these contractile proteins in this region, where other studies have shown a circumferential band of thin filaments, is consistent with the hypothesis that brush borders may be motile through the circumferential constriction of this "contractile ring," and is also consistent with the observations that ATP-treated brush borders become cup shaped as if there had been a circumferential constriction.


Organizational development with torture rehabilitation programs.
Torture rehabilitation has emerged as a field over the past several decades and much of the literature has focused on clinical interventions, related evaluation, and documentation of torture. Less discussed are organizational development initiatives that seek to strengthen organizational effectiveness in order to improve mental health outcomes for torture survivors. Based on applied experience in organizational development with torture rehabilitation programs in post-conflict contexts, the authors explore key organizational development needs in the field of torture rehabilitation, areas of future consideration for international agency donors, and additional future considerations for torture rehabilitation programs themselves. A case is made fo organizational development efforts that prioritize time for strategic thinking that includes participation from stakeholders across the organization's functions; staff care policies that prevent secondary trauma and promote wellbeing and retention; clarity surrounding organizational structure and roles; financial management systems that position the organization for growth and fund diversification strategies beyond the project-based international agency funding model. The work requires longterm commitment in terms of technical and subgrant assistance, including an ongoing process of assessing and adjusting approaches. The case examples included are representative of certain key challenges that may be addressed to some degree within the parameters of a similar project. While the work of torture rehabilitation is urgent by nature, the authors emphasize the need for practical approaches for the important (but not urgent) work of organizational development.


The interplay between mechanics and stability of viral cages.
The stability and strength of viral nanoparticles are crucial to fulfill the functions required through the viral cycle as well as using capsids for biomedical and nanotechnological applications. The mechanical properties of viral shells obtained through Atomic Force Microscopy (AFM) and continuum elasticity theory, such as stiffness or Young's modulus, have been interpreted very often in terms of stability. However, viruses are normally subjected to chemical rather than to mechanical aggression. Thus, a correct interpretation of mechanics in terms of stability requires an adequate linkage between the ability of viral cages to support chemical and mechanical stresses. Here we study the mechanical fragility and chemical stability of bacteriophage T7 in two different maturation states: the early proheads and the final mature capsids. Using chemical stress experiments we show that proheads are less stable than final mature capsids. Still, both particles present similar anisotropic stiffness, indicating that a continuum elasticity description in terms of Young's modulus is not an adequate measure of viral stability. In combination with a computational coarse-grained model we demonstrate that mechanical anisotropy of T7 emerges out of the discrete nature of the proheads and empty capsids. Even though they present the same stiffness, proheads break earlier and have fractures ten times larger than mature capsids, in agreement with chemical stability, thus demonstrating that fragility rather than stiffness is a better indicator of viral cages' stability.


HSV-1 not only in human vestibular ganglia but also in the vestibular labyrinth.
Reactivation of herpes simplex virus type 1 (HSV-1) in the vestibular ganglion (VG) is the suspected cause of vestibular neuritis (VN). Recent studies reported the presence of HSV-1 DNA not only in human VGs but also in vestibular nuclei, a finding that indicates the possibility of viral migration to the human vestibular labyrinth. Distribution of HSV-1 DNA was determined in geniculate ganglia, VGs, semicircular canals, and macula organs of 21 randomly obtained human temporal bones by nested PCR. Viral DNA was detected in 48% of the labyrinths, 62% of the VGs, and 57% of the geniculate ganglia. The potential significance of this finding is twofold: (1) Inflammation in VN could also involve the labyrinth and thereby cause acute unilateral vestibular deafferentation. (2) As benign paroxysmal positional vertigo often occurs in patients who have had VN, it could also be a sequel of viral labyrinthitis.


Risk factors for shunt malfunction in pediatric hydrocephalus: a multicenter prospective cohort study.
OBJECT The rate of CSF shunt failure remains unacceptably high. The Hydrocephalus Clinical Research Network (HCRN) conducted a comprehensive prospective observational study of hydrocephalus management, the aim of which was to isolate specific risk factors for shunt failure. METHODS The study followed all first-time shunt insertions in children younger than 19 years at 6 HCRN centers. The HCRN Investigator Committee selected, a priori, 21 variables to be examined, including clinical, radiographic, and shunt design variables. Shunt failure was defined as shunt revision, subsequent endoscopic third ventriculostomy, or shunt infection. Important a priori-defined risk factors as well as those significant in univariate analyses were then tested for independence using multivariate Cox proportional hazard modeling. RESULTS A total of 1036 children underwent initial CSF shunt placement between April 2008 and December 2011. Of these, 344 patients experienced shunt failure, including 265 malfunctions and 79 infections. The mean and median length of follow-up for the entire cohort was 400 days and 264 days, respectively. The Cox model found that age younger than 6 months at first shunt placement (HR 1.6 [95% CI 1.1-2.1]), a cardiac comorbidity (HR 1.4 [95% CI 1.0-2.1]), and endoscopic placement (HR 1.9 [95% CI 1.2-2.9]) were independently associated with reduced shunt survival. The following had no independent associations with shunt survival: etiology, payer, center, valve design, valve programmability, the use of ultrasound or stereotactic guidance, and surgeon experience and volume. CONCLUSIONS This is the largest prospective study reported on children with CSF shunts for hydrocephalus. It confirms that a young age and the use of the endoscope are risk factors for first shunt failure and that valve type has no impact. A new risk factor-an existing cardiac comorbidity-was also associated with shunt failure.


Empowerment and enterprise: the political economy of nursing.
Throughout the past decades, Australian nursing has made significant advances in the clinical, research, and political arenas. Capitalising on these advances is a critical step in empowering the professions and a sound investment in the health of the nation. There remains a need to energise and empower the professions, to see our work as an enterprise that has value and a sense of worth because of our professional activities as well as for the political and economic contributions we make to health and wellbeing, quality of life and social justice. The contributions made by nurses and midwives need to be articulated in the policy arena, focused in professional decision-making and elaborated in our research agendas. Our professional organisations provide opportunities for solidarity, and the leverage we need to effect change at the bedside, the community and the whole of society. Renewed commitment to primary health care at the global, national and community level provides a timely rallying call to the professions to refine the way we articulate our position in health care, re-commit to culturally appropriate, socially just actions and embolden our professional goals to inspire the next generations of nurses for a more equitable future.


Parvalbumin and calbindin D-28k immunoreactivity in transgenic mice with a G93A mutant SOD1 gene.
Immunohistochemical study was performed to examine if calcium-binding proteins are involved in the degeneration of motor neurons in the brain stems and the spinal cords of transgenic mice carrying a G93A mutant human SOD1 gene. Specimens from age-matched non-transgenic wild-type mice served as controls. In the spinal cord of the controls, the density of parvalbumin-immunoreactive neurons was highest in the large anterior horn neurons and lower in the posterior horn neurons in the spinal cord. On the other hand, calbindin D-28k immunoreactivity was much less apparent than that observed with parvalbumin antisera. Rexed's lamina II was densely immunostained for calbindin D-28k, whereas, in the anterior horn, calbindin-D-28k-positive small neurons were barely dispersed in a scattered pattern. In transgenic mice, parvalbumin-positive anterior horn neurons were severely reduced, even at the presymptomatic stage, whereas calbindin-positive neurons were largely preserved. At the symptomatic stage, both parvalbumin and calbindin D-28k immunoreactivity markedly diminished or disappeared in the anterior horn. Immunoblotting analysis revealed a significant reduction of immunoreactivity to parvalbumin antibody in transgenic mice compared with the controls. In the brain stem, parvalbumin-positive oculomotor and abducens neurons and the calbindin D-28k-positive sixth nucleus were well-preserved in transgenic mice as well as in the controls. Thus, the diffuse and severe loss of parvalbumin immunoreactivity of large motor neurons even at early stages in SOD1-transgenic mice and the absence of calbindin D-28k immunoreactivity of normal large motor neurons suggest that these calcium-binding proteins may contribute to selective vulnerability and an early loss of function of large motor neurons in this SOD1-transgenic mouse model.


Front-crawl instantaneous velocity estimation using a wearable inertial measurement unit.
Monitoring the performance is a crucial task for elite sports during both training and competition. Velocity is the key parameter of performance in swimming, but swimming performance evaluation remains immature due to the complexities of measurements in water. The purpose of this study is to use a single inertial measurement unit (IMU) to estimate front crawl velocity. Thirty swimmers, equipped with an IMU on the sacrum, each performed four different velocity trials of 25 m in ascending order. A tethered speedometer was used as the velocity measurement reference. Deployment of biomechanical constraints of front crawl locomotion and change detection framework on acceleration signal paved the way for a drift-free integration of forward acceleration using IMU to estimate the swimmers velocity. A difference of 0.6 ± 5.4 cm · s(-1) on mean cycle velocity and an RMS difference of 11.3 cm · s(-1) in instantaneous velocity estimation were observed between IMU and the reference. The most important contribution of the study is a new practical tool for objective evaluation of swimming performance. A single body-worn IMU provides timely feedback for coaches and sport scientists without any complicated setup or restraining the swimmer's natural technique.


Pulmonary arteriovenous malformations: diagnosis.
Pulmonary arteriovenous malformations (PAVMs) are rare, abnormal low resistance vascular structures that connect a pulmonary artery to a pulmonary vein, thereby bypassing the normal pulmonary capillary bed and resulting in an intrapulmonary right-to-left shunt. The spectrum of PAVMs extends from microscopic lesions causing profound hypoxemia and ground glass appearance on computed tomography (CT) but with normal catheter angiographic findings to classic pulmonary aneurysmal connections that abnormally connect pulmonary veins and arteries. These malformations most commonly are seen in hereditary hemorrhagic telangiectasia (HHT). They are rarely due to secondary conditions such as post congenital heart disease surgery or hepatopulmonary syndrome (HPS). The main complications of PAVM result from intrapulmonary shunt and include stroke, brain abscess, and hypoxemia. Local pulmonary complications include PAVM rupture leading to life-threatening hemoptysis or hemothorax. The preferred screening test for PAVM is transthoracic contrast echocardiography (TTCE). CT has become the gold standard imaging test to establish the presence of PAVM. Endovascular occlusion of the feeding artery is the treatment of choice. Collateralization and recanalization of PAVM following treatment may occur, and hence long term clinical and imaging follow-up is required to assess PAVM enlargement and PAVM reperfusion.


A molecular survey of phenylketonuria in Iceland: identification of a founding mutation and evidence of predominant Norse settlement.
Iceland was settled during the late 9th and early 10th centuries AD by Vikings who arrived from Norway and the British Isles. Although it is generally acknowledged that the Vikings brought with them Celtic slaves, the relative contribution of these peoples to the modern Icelandic gene pool has been a matter of considerable discussion. Most population genetic studies using classical markers have indicated a large Irish genetic contribution. We have investigated the molecular basis of phenylketonuria (PKU) in 17 Icelandic patients and found 9 different mutations in the phenylalanine hydroxylase gene. One novel mutation, Y377fsdelT, accounts for more than 40% of the mutant chromosomes. Haplotype data support a common ancestral origin of the mutation, and genealogical examination extending back more than 5 generations shows that this mutation has probably arisen in an isolated part of southern Iceland and was enriched by a founder effect. At least 7 PKU mutations have originated outside iceland. The almost exclusively Scandinavian background of these mutations and the complete absence of common Irish PKU mutations strongly support historical and linguistic evidence of a predominant Scandinavian heritage of the Icelandic people.


Wnt signalling controls the response to mechanical loading during zebrafish joint development.
Joint morphogenesis requires mechanical activity during development. Loss of mechanical strain causes abnormal joint development, which can impact long-term joint health. Although cell orientation and proliferation are known to shape the joint, dynamic imaging of developing joints in vivo has not been possible in other species. Using genetic labelling techniques in zebrafish we were able, for the first time, to dynamically track cell behaviours in intact moving joints. We identify that proliferation and migration, which contribute to joint morphogenesis, are mechanically controlled and are significantly reduced in immobilised larvae. By comparison with strain maps of the developing skeleton, we identify canonical Wnt signalling as a candidate for transducing mechanical forces into joint cell behaviours. We show that, in the jaw, Wnt signalling is reduced specifically in regions of high strain in response to loss of muscle activity. By pharmacological manipulation of canonical Wnt signalling, we demonstrate that Wnt acts downstream of mechanical activity and is required for joint patterning and chondrocyte maturation. Wnt16, which is also downstream of muscle activity, controls proliferation and migration, but plays no role in chondrocyte intercalation.


Hospital quality for acute myocardial infarction: correlation among process measures and relationship with short-term mortality.
The Centers for Medicare & Medicaid Services (CMS) and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) measure and report quality process measures for acute myocardial infarction (AMI), but little is known about how these measures are correlated with each other and the degree to which inferences about a hospital's outcomes can be made from its performance on publicly reported processes. To determine correlations among AMI core process measures and the degree to which they explain the variation in hospital-specific, risk-standardized, 30-day mortality rates. We assessed hospital performance in the CMS/JCAHO AMI core process measures using 2002-2003 data from 962 hospitals participating in the National Registry of Myocardial Infarction (NRMI) and correlated these measures with each other and with hospital-level, risk-standardized, 30-day mortality rates derived from Medicare claims data. Hospital performance on AMI core measures; hospital-specific, risk-standardized, 30-day mortality rates for AMI patients aged 66 years or older. We found moderately strong correlations (correlation coefficients > or =0.40; P values <.001) for all pairwise comparisons between beta-blocker use at admission and discharge, aspirin use at admission and discharge, and angiotensin-converting enzyme inhibitor use, and weaker, but statistically significant, correlations between these medication measures and smoking cessation counseling and time to reperfusion therapy measures (correlation coefficients <0.40; P values <.001). Some process measures were significantly correlated with risk-standardized, 30-day mortality rates (P values <.001) but together explained only 6.0% of hospital-level variation in risk-standardized, 30-day mortality rates for patients with AMI. The publicly reported AMI process measures capture a small proportion of the variation in hospitals' risk-standardized short-term mortality rates. Multiple measures that reflect a variety of processes and also outcomes, such as risk-standardized mortality rates, are needed to more fully characterize hospital performance.


VMAF Oriented Perceptual Coding Based on Piecewise Metric Coupling.
It has been recognized that videos have to be encoded in a rate-distortion optimized manner for high coding performance. Therefore, operational coding methods have been developed for conventional distortion metrics such as Sum of Squared Error (SSE). Nowadays, with the rapid development of machine learning, the state-of-the-art learning based metric Video Multimethod Assessment Fusion (VMAF) has been proven to outperform conventional ones in terms of the correlation with human perception, and thus deserves integration into the coding framework. However, unlike conventional metrics, VMAF has no specific computational formulas and may be frequently updated by new training data, which invalidates the existing coding methods and makes it highly desired to develop a rate-distortion optimized method for VMAF. Moreover, VMAF is designed to operate at the frame level, which leads to further difficulties in its application to today's block based coding. In this paper, we propose a VMAF oriented perceptual coding method based on piecewise metric coupling. Firstly, we explore the correlation between VMAF and SSE in the neighborhood of a benchmark distortion. Then a rate-distortion optimization model is formulated based on the correlation, and an optimized block based coding method is presented for VMAF. Experimental results show that 3.61% and 2.67% bit saving on average can be achieved for VMAF under the low_delay_p and the random_access_main configurations of HEVC coding respectively.


Use of the nicotine skin patch by smokers in 20 communities in the United States, 1992-1993.
To measure the characteristics of smokers associated with the use of the nicotine skin patch in the general population and to evaluate whether use of the patch is associated with successful smoking cessation. Data from two surveys conducted in 20 communities in the United States as part of the National Cancer Institute's Community Intervention Trial for Smoking Cessation (COMMIT) study. Nicotine patch prevalence was estimated using data from a 1993 cross-sectional survey of 13691 current and former smokers. The effectiveness of the nicotine skin patch as a smoking cessation aid was evaluated adjusting for other covariants using data from a cohort tracking study of 9809 smokers who were followed between 1988 and 1993. As the nicotine patch was not available to consumers until January 1992, analyses were restricted to respondents who reported themselves to be current smokers in 1993 or former smokers who reported quitting after January 1992. Current and former smokers who reported having made a serious effort to stop smoking in the past five years were asked to indicate whether they had used the nicotine skin patch to help them stop smoking. Those answering "Yes", were classified as nicotine patch users. Smoking cessation was based on self-report. A "quitter" was defined as someone who had been a smoker as of January 1992 who reported in 1993 not smoking any cigarettes for the preceding six months or longer. The prevalence of nicotine patch use by smokers averaged across the 20 study communities was 12.8%, making the patch one of the most popular cessation methods used by smokers. Compared with non-users, patch users were more likely to be female, white, have higher annual household incomes, be more motivated to stop smoking, and to smoke more heavily. Among low-income smokers (annual household income below US$10000), nicotine patch use was significantly higher among those who lived in a state where the public insurance programme (Medicaid or Medi-Cal) included the patch as a benefit (12.1% vs 7.7%). Among those who made an attempt to quit smoking, the likelihood of successful quitting was more than twice as high among patch users compared with non-users. Among patch users, the highest quit rates were observed among those who used the patch for between one and three months. The nicotine skin patch is a popular and effective means of smoking cessation. Use of the nicotine patch, especially by low-income smokers, could be increased by reducing the out-of-pocket expenditure required for smokers to get the product.


Carbohydrate Mouth Rinse Improves Relative Mean Power During Multiple Sprint Performance.
Multiple investigations have confirmed carbohydrate mouth rinse (CMR) enhances high intensity endurance performance lasting under 1 hour, but the effects of CMR on high intensity intermittent exercise has received less attention. This study examined the effect of CMR on high intensity multiple sprint performances in a protocol designed to emulate a cyclocross or mountain biking event. Seven trained men (28.2 ± 6.8 years, 185 ± 9 cm, 85.3 ± 14.8 kg, VO2peak 51.4 ± 7.3 ml/kg*min-1) completed two, 48 min high intensity intermittent cycling protocols that consisted of 6 bouts of 5 min cycling at 50% VO2 peak followed by sets of three, 10-s Wingate sprints with 50 s of recovery between sprints. Prior to each set of Wingate sprints, either a 6.4% carbohydrate solution (CMR) or placebo (PLA) were rinsed for 10 s using a counterbalanced crossover design. There was a significant main effect (CMR 10.51 ± 0.82, PLA 10.33 ± 0.87 W/kg; p < 0.05 ES=0.21) for mean power, but post hoc tests only revealed statistically significant performance improvement with CMR during the 6th bout (CMR 10.5 ± 0.75, PLA 10.22 ± 0.92 W/kg; p = 0.01 ES=0.33). No treatment effect was exhibited for peak power, fatigue index, ratings of perceived exertion, or blood glucose. Most team sport situations provide multiple opportunities for access to beverages, but gastrointestinal distress associated with fluid intake may reduce desire for significant beverage consumption. Under such circumstances, a small but practical ergogenic advantage may be exhibited if the fluid rinsed in the mouth contains carbohydrates.


Bladder cancer in the textile industry.
This study examined the occupations and industries at high risk for bladder cancer in an area where the textile industry is plentiful and the incidence of the disease is very high. A case-referent study concerning 218 incident bladder cancer cases diagnosed during 1993-1995 in the county of Vallès Occidental, Barcelona, was carried out. A reference group (N=344) was selected from municipal lists matched to the cases by age, gender, and area of residence. All the subjects were personally interviewed, and a complete occupational history was abstracted together with other sociodemographic and life-style factors. All odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, and smoking. No overall excess risk was found forever having worked in the textile industry (OR 1.13, 95% CI 0.79-1.63) nor for specific sectors of this industry (ie cotton, wool, silk). An excess risk was observed for spinners and winders employed for more than 20 years (OR 3.28, 95% CI 1.08-9.97) and for machine setters employed between 1960 and 1974 (OR 4.26, 95% CI 1.09-16.7). The results of this study do not support the findings of some earlier studies for an increased bladder cancer risk in the textile industry. However, some elevated risks were observed among the workers with the highest exposures.


Family cluster of Rocky Mountain spotted fever.
Soon after a patient from Tennessee died of Rocky Mountain spotted fever (RMSF), several family members developed symptoms suggestive of the disease and were treated presumptively for RMSF. Fifty-four persons visiting the index patient's home were interviewed; serum samples were collected from 35. Three additional cases of RMSF were confirmed, all of which occurred in first-degree relatives. Time spent at the family home and going into the surrounding woods were significantly associated with developing antibodies to Rickettsia rickettsii. Ticks were collected and examined for rickettsiae by polymerase chain reaction analysis. Because hyperendemic foci and family clusters of RMSF can occur, when a case is suspected clinicians should be vigilant for signs and symptoms consistent with R. rickettsii infection in other persons who may have been similarly exposed.


B Cell-Specific MHC Class II Deletion Reveals Multiple Nonredundant Roles for B Cell Antigen Presentation in Murine Lupus.
B cells have both Ab-dependent and Ab-independent functions in systemic autoimmune diseases, including systemic lupus erythematosus (SLE). Ab-independent functions are known to be important, because mice with B cells but no secreted Ig have severe disease. These functions could include roles in lymphoid development, cytokine secretion, and Ag presentation; however, these possibilities have not been directly tested in SLE models. In this study, we show by lineage-specific ablation of MHC class II (MHCII) that B cell Ag presentation plays a nonredundant role in CD4(+) T cell activation and effector differentiation in the MRL.Fas(lpr) mouse model of SLE. MHCII-mediated interactions between B and T cells further promote B cell proliferation and differentiation, and, in fact, inefficient MHCII deletion on B cells led to strong selection of escaped cells in activated and plasmablast compartments, further underscoring the central role of B cell Ag presentation. Despite the leakiness in the system, B cell-specific MHCII deletion resulted in substantially ameliorated clinical disease. Hence, B cell Ag presentation is critical for T and B cell activation and differentiation, as well as target organ damage.


Comparative analysis of EMF monitoring campaigns in the campus area of the University of Novi Sad.
Following an increasing number of artificial electromagnetic field (EMF) sources in human surrounding, a number of research studies have been devoted to the issue of environmental EMF pollution. A particular attention has been attributed to the highly sensitive EMF zones, where people can stay for a longer period of time, which, among others, includes university campuses. Thus, the modern approach of long-term EMF monitoring has been established, carrying out cumulative field strength measurements at locations that are most visited by student population and university staff. The goal was to establish periodic and systematic EMF investigation over such highly sensitive areas, through a standardized procedure for EMF monitoring. In this paper, details about two EMF monitoring campaigns over the University of Novi Sad campus were presented, performing comparative analysis of their results. The obtained results revealed the increase (up to four times) of the cumulative field strength values, as well as the general population exposure, at specific locations. Between these two campaigns, the emergence of the new base station, as well as numerous Wi-Fi networks, was noticed in the campus. Consequently, the highest field strength values were acquired at two locations, most directly exposed to the main beams of base station's antennas, although all obtained values were at least five times lower than the minimal reference levels prescribed by the Serbian legislation. Even though such results are acceptable, the future monitoring campaigns should be planned, particularly since the installation of new EMF sources are expected in the campus of the University of Novi Sad.


Alterations in the contents of consciousness in partial epileptic seizures.
Epilepsy research suffers from a deficiency of systematic studies concerning the phenomenology of the contents of consciousness during seizures, partially because of the lack of suitable research methods. The Phenomenology of Consciousness Inventory (PCI), a standardized, valid, and reliable questionnaire, was used here to study which dimensions of the contents of consciousness are distorted during partial epileptic seizures compared with baseline. Further, the similarity of the altered pattern of subjective experiences across recurring seizures was also explored. Our results indicate that patients with epilepsy report alterations on most dimensions of the contents of consciousness in conjunction with seizures, but individual seizure experiences remain similar from one seizure to another. The PCI was found suitable for the assessment of subjective experiences during epileptic seizures and could be a valuable tool in providing new information about phenomenal consciousness in epilepsy in both the research and clinical settings.


Antibiotics for bronchiolitis in children.
Bronchiolitis is a serious, potentially life-threatening respiratory illness commonly affecting babies. It is often caused by respiratory syncytial virus (RSV). Antibiotics are not recommended for bronchiolitis unless there is concern about complications such as secondary bacterial pneumonia or respiratory failure. Nevertheless, they are used at rates of 34% to 99% in uncomplicated cases. To evaluate the effectiveness of antibiotics for bronchiolitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2010, issue 4), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register, and the Database of Abstracts of Reviews of Effects, MEDLINE (January 1966 to November 2010), EMBASE (1990 to December 2010) and Current Contents (2001 to December 2010). Randomised controlled trials (RCTs) comparing antibiotics to placebo in children under two years diagnosed with bronchiolitis, using clinical criteria (including respiratory distress preceded by coryzal symptoms with or without fever). Primary clinical outcomes included time to resolution of signs or symptoms (pulmonary markers included respiratory distress, wheeze, crepitations, oxygen saturation and fever). Secondary outcomes included hospital admissions, length of hospital stay, re-admissions, complications or adverse events and radiological findings. Two review authors independently analysed the search results. Five studies (543 participants) met our inclusion criteria. One study randomised 52 children to either ampicillin or placebo and found no significant difference between the two groups for length of illness. A small study (21 children) with higher risk of potential bias randomised children with proven RSV infection to clarithromycin or placebo and found clarithromycin may reduce hospital re-admission (8% antibiotics versus 44% placebo; Fishers exact; P = 0.081). The two studies (267 children) providing adequate data for length of hospital stay showed no difference between antibiotics and control (pooled mean difference 0.34; 95% CI -0.71 to 1.38). Two studies randomised children to intravenous ampicillin, oral erythromycin and control and found no difference for most symptom measures. None of the trials reported deaths. This review found minimal evidence to support the use of antibiotics for bronchiolitis. Research to identify a possible small subgroup of patients who have complications from bronchiolitis such as respiratory failure and who may benefit from antibiotics is justified.


Dispersive liquid-liquid microextraction of propranolol enantiomers from human plasma based on the solidification of a floating organic droplet.
A dispersive liquid-liquid microextraction based on the solidification of a floating organic droplet was developed and validated for the extraction of propranolol enantiomers from human plasma. The studied enantiomers were extracted from diluted and alkalized plasma samples using 1-undecanol as the extracting solvent. HPLC-fluorescence detection analyses were carried out on a chiral column, using n-hexane-ethanol (80:20, v/v) plus 0.2% triethylamine as the mobile phase, at a flow rate of 0.8 ml/min. The significant factors in the microextraction procedure, including extracting and disperser solvents volume, solution pH and salt contents were optimized by using a central composite design and the response surface methodology. Under optimized conditions, the mean recoveries were approximately 14% with linear responses over the 0.5-100 ng/ml concentration range for both enantiomers. The LOQ was 0.5 ng/ml (S/N = 10). Intra-day (n = 5) and inter-day (n = 3) assay precision (1 and 50 ng/ml) showed RSD lower than 8 and 9.5% for studied enantiomers, respectively. Finally, the method was successfully used for the determination of propranolol enantiomers in plasma samples obtained after single drug administration of racemic propranolol tablet to three healthy volunteers. The plasmatic concentrations of (-)-(S)-PROP were higher than those of (+)-(R)-PROP in all times after oral administration of the racemic drug. The obtained results proved that the proposed method is a powerful technique for sample preparation, providing suitable recoveries, efficient cleanup, high selectivity and sensitivity and low consumption of organic solvent for determination of the studied enantiomers in plasma samples after oral administration of the racemic drug to volunteers.


Leuko-araiosis.
Problems in the literature in the appraisal of brain deep white-matter changes are considered. The identification of the changes with Binswanger's disease alone is rejected, and evidence is reviewed that demonstrates that they are associated with cognitive impairment and, to some extent, with vascular disease. Possible causes of white-matter changes and their relationships to Alzheimer's disease are examined, and it is argued that a neutral term, exact enough to define white-matter changes, sufficient as a description or label, and demanding enough to require precise clinical and imaging descriptions is needed. We suggest herein the term "leuko-araiosis" on the basis of Greek etymology and Hippocratic usage.


Variables in health care policy-making: resolving a quandary?
Contemporary debate on health care resource management is tied to a central moral issue: how to achieve an optimum level of reasonable or appropriate treatment based on the medical condition of each patient. Failure to tackle and resolve this issue in a confident and forthright manner ensures that the present approach to health care decision-making will continue in a state of indecisiveness if not, indeed, lethargy. Undergirding this moral issue is the foundational economic dilemma of controlling costs while limiting access to health care resources. Crafting a just solution to an equitable distribution of finite health care resources is, indeed, a quandary, if not almost an impossibility. What this article seeks to do, nonetheless, is to undertake an examination of the principles, socio-economic values and public policies needed to formulate health care compromises necessary to achieve greater stability in the normative decision-making process. In turn, this will ensure, ideally, a level of distributive justice in the total allocative process.


Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase.
Steroid sulfatase (STS) is an important new therapeutic target in oncology. Attempts to design nonsteroidal STS inhibitors, because of the oestrogenicity of the original lead oestrone 3-O-sulfamate in rodents, have led to the discovery of benzophenone-4,4'-O,O-bis-sulfamate (BENZOMATE, 3). The nonfused bicyclic BENZOMATE is a highly potent STS inhibitor in vitro, inhibiting STS activity in intact MCF-7 breast cancer cells by > 70% at 0.1 microM and in placental microsomes by > 98% at 10 microM. When MCF-7 cells were pre-treated with 3 at 1 microM and then washed to remove unbound inhibitor, the initial 94% inhibition was reduced to 89% suggesting that 3, like other sulfamate-based STS inhibitors, inhibits the enzyme irreversibly. This agent also inhibits rat liver STS activity by 84% and 93% respectively 24 h after a single dose of 1 or 10 mg/kg, demonstrating that BENZOMATE possesses similar in vivo potency to the established potent nonsteroidal inhibitor 667COUMATE. Several modifications were made to BENZOMATE structurally and effects on in vitro activity were examined. These structure-activity relationship studies show that its carbonyl and bis-sulfamate groups are pivotal for activity, although conformational flexibility is not required. Two rigid anthraquinone-based sulfamate derivatives however showed inhibitory activity significantly better than BENZOMATE in the MCF-7 cell assay. BENZOMATE and related analogues therefore represent an important class of non-steroidal STS inhibitor and lead compounds for future drug design.


Did you have an impact? A theory-based method for planning and evaluating knowledge-transfer and exchange activities in occupational health and safety.
Few evaluation tools are available to assess knowledge-transfer and exchange interventions. The objective of this paper is to develop and demonstrate a theory-based knowledge-transfer and exchange method of evaluation (KEME) that synthesizes 3 theoretical frameworks: the promoting action on research implementation of health services (PARiHS) model, the transtheoretical model of change, and a model of knowledge use. It proposes a new term, keme, to mean a unit of evidence-based transferable knowledge. The usefulness of the evaluation method is demonstrated with 4 occupational health and safety knowledge transfer and exchange (KTE) implementation case studies that are based upon the analysis of over 50 pre-existing interviews. The usefulness of the evaluation model has enabled us to better understand stakeholder feedback, frame our interpretation, and perform a more comprehensive evaluation of the knowledge use outcomes of our KTE efforts.


Updated guide for the management of malignant hyperthermia.
This continuing professional development module aims to prepare anesthesiologists for the timely recognition and management of a malignant hyperthermia (MH) reaction, which is crucial for averting its life-threatening complications and ultimately for the patient's survival. Malignant hyperthermia is a genetic disorder of skeletal muscle cells affecting myoplasmic calcium homeostasis. It can present with nonspecific signs of a hypermetabolic reaction, which can be fatal if treatment, including administration of dantrolene sodium, is not implemented promptly. Rapid evaluation and rejection of alternative diagnoses can lead to a prompt diagnosis and treatment and therefore will significantly reduce the complications, including renal failure, cardiac dysfunction, disseminated intravascular coagulation, and death. After the reaction, patients should be observed for a minimum of 24 hr because of the possibility of recrudescence. As it is a genetic condition, survivors and their family members should be referred to a specialized MH centre for further testing and counselling. The risk of dying from MH has increased over the past few years. A knowledgeable anesthesiologist who is diligent and attentive can recognize signs of an impending MH reaction and treat promptly to avoid complications of this deadly condition.


Entangled images from four-wave mixing.
Two beams of light can be quantum mechanically entangled through correlations of their phase and intensity fluctuations. For a pair of spatially extended image-carrying light fields, the concept of entanglement can be applied not only to the entire images but also to their smaller details. We used a spatially multimode amplifier based on four-wave mixing in a hot vapor to produce twin images that exhibit localized entanglement. The images can be bright fields that display position-dependent quantum noise reduction in their intensity difference or vacuum twin beams that are strongly entangled when projected onto a large range of different spatial modes. The high degree of spatial entanglement demonstrates that the system is an ideal source for parallel continuous-variable quantum information protocols.


The change in cerebrovascular reactivity between 3 T and 7 T measured using graded hypercapnia.
Mapping cerebrovascular reactivity (CVR) to hypercapnia is important both clinically and for improved understanding of the haemodynamic properties of the BOLD effect. In this work, BOLD/R2 CVR was investigated by using a device which provided small, repeatable and stable steps in PETCO2, whilst maintaining a steady PETO2 level. Significant CVR was observed in both grey and white matter at both 3 and 7 T, whilst an approximately linear relationship found between R2 CVR and field strength has implications for BOLD models and calibration. Grey matter R2 CVR was 0.066+/-0.004 s(-1) mm Hg(-1) at 3 T and 0.141+/-0.008 s(-1) mm Hg(-1) at 7 T. White matter R2 CVR was 0.021+/-0.003 s(-1) mm Hg(-1) at 3 T and 0.040+/-0.007 s(-1) mm Hg(-1) at 7 T.


FIRE (Facilitating Implementation of Research Evidence): a study protocol.
Research evidence underpins best practice, but is not always used in healthcare. The Promoting Action on Research Implementation in Health Services (PARIHS) framework suggests that the nature of evidence, the context in which it is used, and whether those trying to use evidence are helped (or facilitated) affect the use of evidence. Urinary incontinence has a major effect on quality of life of older people, has a high prevalence, and is a key priority within European health and social care policy. Improving continence care has the potential to improve the quality of life for older people and reduce the costs associated with providing incontinence aids. This study aims to advance understanding about the contribution facilitation can make to implementing research findings into practice via: extending current knowledge of facilitation as a process for translating research evidence into practice; evaluating the feasibility, effectiveness, and cost-effectiveness of two different models of facilitation in promoting the uptake of research evidence on continence management; assessing the impact of contextual factors on the processes and outcomes of implementation; and implementing a pro-active knowledge transfer and dissemination strategy to diffuse study findings to a wide policy and practice community. Four European countries, each with six long-term nursing care sites (total 24 sites) for people aged 60 years and over with documented urinary incontinence Pragmatic randomised controlled trial with three arms (standard dissemination and two different programmes of facilitation), with embedded process and economic evaluation. The primary outcome is compliance with the continence recommendations. Secondary outcomes include proportion of residents with incontinence, incidence of incontinence-related dermatitis, urinary tract infections, and quality of life. Outcomes are assessed at baseline, then at 6, 12, 18, and 24 months after the start of the facilitation interventions. Detailed contextual and process data are collected throughout, using interviews with staff, residents and next of kin, observations, assessment of context using the Alberta Context Tool, and documentary evidence. A realistic evaluation framework is used to develop explanatory theory about what works for whom in what circumstances. Current Controlled Trials ISRCTN11598502.


Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review.
Amyotrophic Lateral Sclerosis (ALS) is a mid-life onset neurodegenerative disease that manifests its symptomatology with motor impairments and cognitive deficits overlapping with Frontotemporal Lobar Degeneration (FTLD). The etiology of ALS remains elusive, with various mechanisms and cellular targets implicated, and no treatment can reverse or stop the progression of the pathology. Therapeutic interventions based on passive immunization are gaining attention for neurodegenerative diseases, and FDA recently approved the first antibody-based approach for Alzheimer's disease. The present systematic review of the literature aims to highlight the efforts made over the past years at developing antibody-based strategies to cure ALS. Thirty-one original research papers have been selected where the therapeutic efficacy of antibodies were investigated and described in patients and animal models of ALS. Antibody-based interventions analyzed, target both extracellular molecules implicated in the pathology and intracellular pathogenic proteins known to drive the disease, such as SOD1, TDP-43 or C9ORF72 repeats expansions. The potentials and limitations of these therapeutic interventions have been described and discussed in the present review.


[Safe improvement of drug absorption by combinatorial use of sodium laurate with amino acids: cytoprotection by amino acids and its mechanisms].
The development of combinatorial chemistry and high-throughput screening techniques has made it possible to generate many new drug candidates very rapidly, but it has also resulted in a number of poorly soluble and/or poorly absorbable candidates. A new trend in drug development based on pharmacogenomics or the development of molecular-targeted drugs is also spurring the tendency, and it does not necessarily lead to good output in terms of the development of new drugs. It is attractive to improve membrane permeability as well as solubility by using adjuvants, because this method could be applicable for various drugs. However, the practical use of absorption-enhancing adjuvants has been limited because of the potential local toxicity. Therefore suppressing the potential local toxicity would lead to the successful development of safe preparations with improved absorption using adjuvants. Our biochemical and histopathologic studies showed that several amino acids such as taurine and L-glutamine had cytoprotective activity, and it has been found that the combinatorial use of sodium laurate (C12) with these amino acids could maintain the absorption-enhancing ability of C12. A suppository preparation containing C12 and taurine remarkably improved the rectal absorption of rebamipide, classified as BCS class IV, and the preparation was safe to the rectal mucosa. For the mechanisms of cytoprotective action by these amino acids, it has been found that they suppress the intracellular calcium level, induce the expression of heat-shock protein 70, and inhibit the release of histamine and apoptosis.


Albendazole residues in goat's milk: Interferences in microbial inhibitor tests used to detect antibiotics in milk.
Albendazole (ABZ) residues in goat's milk and their effect on the response of microbial inhibitor tests used for screening antibiotics were evaluated. A total of 18 Murciano-Granadina goats were treated with ABZ and individually milked once a day over a 7-day period. ABZ quantification was performed by high performance liquid chromatography. The ABZ parent drug was not detected. The maximum concentration of its metabolites (ABZ sulfoxide, ABZ sulfone, and ABZ 2-aminosulfone) was reached on the 1st day post treatment (260.0 ± 70.1 μg/kg, 112.8 ± 28.7 μg/kg, 152.0 ± 23.6 μg/kg, respectively), decreasing to lower than the maximum residue limit (MRL, 100 μg/kg) on the 3rd day post treatment. Milk samples were also analyzed by microbial tests [Brilliant Black Reduction Test (BRT) MRL, Delvotest SP-NT MCS and Eclipse 100], and only one positive result was found for Delvotest SP-NT MCS and Eclipse 100. However, a high occurrence of positive outcomes was obtained for BRT MRL during 6 days post treatment, whereas ABZ residues were not detected from the 4th day post administration, suggesting that factors other than the antiparasitic agent might affect the microbial test response.


Linking Work Values Profiles to Basic Psychological Need Satisfaction and Frustration.
The association between work values and key motivational variables has been repeatedly supported in previous studies. However, little attention has been devoted to understanding intraindividual patterns of work values and how combinations of work values relate to other motivational variables. This study aimed to identify profiles of work values based on a four-factor model (i.e., intrinsic, extrinsic, social, and status). It also investigated how profile membership relates to basic psychological need satisfaction and frustration at work using a self-determination perspective. A sample of French Canadian adults (N = 476) participated in this study by filling out an online questionnaire. Latent profile analyses revealed five distinct work values profiles. Results showed that participants in more positive profiles (i.e., high level of intrinsic, social, and status work values) generally reported higher level of need satisfaction and lower level of need frustration at work than participants belonging to more negative profiles (i.e., low level of intrinsic, social, and status work values). These results support the importance of considering work values in organizational and career development interventions, and to do so using a person-centered approach, to better understand need satisfaction and frustration at work.


Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT.
We evaluated the incidence and risk factors for hypogammaglobulinemia after allogeneic hematopoietic SCT (HSCT) in pediatric patients. Ig levels were measured pre-transplant, every 2 weeks until day 100 and then monthly post SCT in 185 patients undergoing myeloablative HSCT. Median age was 9 years; 142 (77%) had malignant disease and 114 (62%) received stem cells from an unrelated source. Hypogammaglobulinemia (IgG <500 mg/dL) developed in 143 (77%) of the patients at a median of 56 days (range 15-339) post SCT. The cumulative incidence of hypogammaglobulinemia at 1 year was higher among patients who developed acute GVHD (97% vs 54%, P<0.001), and for those receiving stem cells from an unrelated source (94% vs 51%, P<0.001). The cumulative incidence of TRM was significantly higher for patients with hypogammaglobulinemia (P=0.026). In multivariable analysis, lower pre-transplant IgG level (P<0.001), younger age (P=0.012), diagnosis of malignant disease (P<0.001), receiving unrelated SCT (P<0.001) and development of acute GVHD (P<0.001) were all significantly associated with higher risk of hypogammaglobulinemia post HSCT. We conclude that hypogammaglobulinemia is common, following allogeneic HSCT in pediatric patients, especially in those with malignant diseases, those who receive an unrelated transplant or patients who develop GVHD.


Ultrafast Exciton Dissociation and Long-Lived Charge Separation in a Photovoltaic Pentacene-MoS2 van der Waals Heterojunction.
van der Waals heterojunctions between two-dimensional (2D) layered materials and nanomaterials of different dimensions present unique opportunities for gate-tunable optoelectronic devices. Mixed-dimensional p-n heterojunction diodes, such as p-type pentacene (0D) and n-type monolayer MoS2 (2D), are especially interesting for photovoltaic applications where the absorption cross-section and charge transfer processes can be tailored by rational selection from the vast library of organic molecules and 2D materials. Here, we study the kinetics of excited carriers in pentacene-MoS2 p-n type-II heterojunctions by transient absorption spectroscopy. These measurements show that the dissociation of MoS2 excitons occurs by hole transfer to pentacene on the time scale of 6.7 ps. In addition, the charge-separated state lives for 5.1 ns, up to an order of magnitude longer than the recombination lifetimes from previously reported 2D material heterojunctions. By studying the fractional amplitudes of the MoS2 decay processes, the hole transfer yield from MoS2 to pentacene is found to be ∼50%, with the remaining holes undergoing trapping due to surface defects. Overall, the ultrafast charge transfer and long-lived charge-separated state in pentacene-MoS2 p-n heterojunctions suggest significant promise for mixed-dimensional van der Waals heterostructures in photovoltaics, photodetectors, and related optoelectronic technologies.


Substrate-strain-induced tunability of dense wavelength-division multiplexing thin-film filters.
Classic dense wavelength-division multiplexing thin-film filters can be spectrally tuned through the substrate's strain. We analyze the theoretical shift of the design wavelength of a narrow-bandpass filter when uniform, uniaxial compressive stress is applied to the substrate, and we compare calculated sensitivity with experimental data. We measure the transmittance shape of a 200-GHz standard filter for several loading cases to quantify the increase of insertion losses.


Non-Skeletal Activities of Vitamin D: From Physiology to Brain Pathology.
Vitamin D is a secosteroid hormone regulating the expression of almost 900 genes, and it is involved in the regulation of calcium and phosphate metabolism, immune response, and brain development. Low blood vitamin D levels have been reported in patients affected by various diseases. Despite a large amount of literature data, there is uncertainty surrounding the role of vitamin D as a serum biomarker in Alzheimer's disease (AD) and Parkinson's disease (PD). Indeed, the lack of internationally recognized 25(OH)D3 reference measurement procedures and standard materials in the past led to unstandardized serum total 25(OH)D3 results among research and clinical care laboratories. Thus, most of the literature studies reported unstandardized data, which are of little use and make it difficult to draw conclusions of the role of vitamin D in AD and PD. This review summarizes the extra-skeletal actions of vitamin D, focusing its role in immunomodulation and brain function, and reports the issue of lacking standardized literature data concerning the usefulness of vitamin D as a biomarker in AD and PD.


Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C.
NKG2 is a small family of type II transmembrane proteins possessing extracellular C-type lectin domains expressed primarily on NK cells. The function of these proteins is unknown. We have developed mAbs that recognize NKG2 family members on Western blots. Examination of cell extracts from NK cell clones demonstrates that individual NKG2 family members are expressed on subsets of NK cells. Because the anti-NKG2 mAb do not react with the cell surface Ag, signaling function was studied by generating cell lines that express a chimeric receptor consisting of a cytoplasmic and transmembrane domain from NKG2-A or NKG2-C fused to the extracellular segment of mouse NKR-P1C (NK1.1 Ag). Transfectants of the rat NK cell line, RNK-16, were tested for the effect of anti-NK1.1 mAb on cytolytic activity against the FcR+ target cell lines, P388D1 and P815. The anti-NK1.1 mAb stimulated lytic activity and calcium mobilization in the NK cell line expressing the NKG2-C/NKR-P1C chimeric receptor. By contrast, anti-NK1.1 inhibited the lytic activity and failed to stimulate a calcium response in cells expressing the NKG2-A/NKR-P1C chimeric receptor. Immunoprecipitation experiments demonstrated that the inhibitory cytoplasmic tyrosine phosphatase SHP-1 selectively associates with the NKG2-A/NKR-P1C chimeric receptor, but not with the stimulatory NKG2-C/NKR-P1C receptor. These data indicate that NKG2-A and NKG2-C deliver, respectively, inhibitory and activating transmembrane signals in NK cells.