Information issues for providers of services to people with dementia living in the community in Australia: breaking the cycle of frustration.
The rising prevalence of dementia and concomitant demands upon dementia services are global issues. In Australia, dementia has attained national health priority status and governments at all levels have implemented service strategies to help manage the complex lives of people with dementia. Despite recognition that information is pivotal to effective dementia service delivery, little is known about the information needs of individual providers and the processes used to transfer information between providers. This qualitative study scoped information issues for key service providers for people with dementia living in the community in southern Tasmania, Australia, including information needs, availability, and transfer. Eleven focus groups were held with general practitioners, residential aged care facility staff, home carers, community health nurses, and aged care-assessment team members. Findings revealed that provider groups shared common, albeit unbeknown to them, information needs (e.g. diagnosis, behaviours, and services) and information concerns (e.g. untrustworthy information and poor information transfer) leading to poor service coordination. General practitioners emerged as a stand-out group with markedly fewer needs and concerns than other providers, a finding of special interest given their pivotal role in dementia diagnosis and referral. Participants were adamant in their view that electronic data bases and single points of entry to dementia services would improve service provision and should be developed. The research highlights complexities and associated frustrations of information transferability, accessibility, and trustworthiness for dementia service providers in the community. Increased understanding of providers' diverse yet interdependent roles could, we believe, play an important part in breaking the cycle of frustration experienced by all participants and thus contribute to system reform.


Nutritional Supplement Based on Zinc, Prebiotics, Probiotics and Vitamins to Prevent Radiation-related Gastrointestinal Disorders.
The present phase II study aimed to evaluate the tolerance and safety of Dixentil, a nutritional supplement based on zinc with the addition of prebiotics (galacto-oligosaccharides), tyndalized probiotics (Lactobacillus acidophilus and L. casei) and vitamins B1, B2 and B6, and nicotinamide), given as prophylaxis to patients undergoing pelvic radiotherapy and its efficacy in the prevention and reduction of radiation-related gastrointestinal disorders. Forty consecutive patients who were candidates for pelvic radiotherapy received Dixentil before starting and during radiotherapy. The primary end-point was to evaluate the safety and tolerance of Dixentil. Secondary end-points were incidence and severity of radiation-induced diarrhea and number of patients who discontinued radiotherapy because of diarrhea. Radiation-induced enteritis occurred in 17 patients, grade I and grade II diarrhea was documented in 14 and 3 patients respectively; no grade III or IV diarrhea was observed. Radiotherapy was discontinued due to treatment-induced enteritis only in two patients for 6 days. Use of Dixentil is an easy, safe, and feasible approach to protect patients against the risk of radiation-induced diarrhea.


The cortisol awakening response and autonomic nervous system activity during nocturnal and early morning periods.
The current study focuses on autonomic nervous system activity during sleep as a physiological aspect of sleep quality, and investigated the associations between the cortisol awakening response (CAR) and autonomic activity during sleep and after awakening. Ambulatory electrocardiograms were obtained from 20 participants, who also provided saliva samples (at the time of awakening, and 30, 45, and 60 min after awakening) and rated the subjective quality of their sleep at home. Autonomic activity was assessed with the Lorenz plot indices, cardiac sympathetic index (CSI) and cardiac vagal index. Total salivary cortisol secretion after awakening was calculated as area under the curve with respect to ground (AUC(G)) and increase (AUC(I)). After controlling for confounding factors, including sleep duration and awakening time, cortisol AUC(G) and AUC(I) were both found to be negatively correlated with CSI during the 30 min before and after awakening: before (r = -0.526 and -0.601 respectively) and after (r = -0.540 and -0.493 respectively). Self-reported sleep quality was not associated with the CAR. These results suggest that the CAR is negatively affected by basal sympathetic activity immediately before and after awakening, but not affected by subjective sleep quality. Physiological arousals around the time of awakening might inhibit the CAR.


Divergence of transcription factor binding sites across related yeast species.
Characterization of interspecies differences in gene regulation is crucial for understanding the molecular basis of both phenotypic diversity and evolution. By means of chromatin immunoprecipitation and DNA microarray analysis, the divergence in the binding sites of the pseudohyphal regulators Ste12 and Tec1 was determined in the yeasts Saccharomyces cerevisiae, S. mikatae, and S. bayanus under pseudohyphal conditions. We have shown that most of these sites have diverged across these species, far exceeding the interspecies variation in orthologous genes. A group of Ste12 targets was shown to be bound only in S. mikatae and S. bayanus under pseudohyphal conditions. Many of these genes are targets of Ste12 during mating in S. cerevisiae, indicating that specialization between the two pathways has occurred in this species. Transcription factor binding sites have therefore diverged substantially faster than ortholog content. Thus, gene regulation resulting from transcription factor binding is likely to be a major cause of divergence between related species.


Metabolic power in hurling with respect to position and halves of match-play.
The current investigation compared the metabolic power and energetic characteristics in team sports with respect to positional lines and halves of match-play. Global positioning system (GPS) technology data were collected from 22 elite competitive hurling matches over a 3-season period. A total of 250 complete match-files were recorded with players split into positional groups of full-back; half-back; midfield; half-forward; full-forward. Raw GPS data were exported into a customized spreadsheet that provided estimations of metabolic power and speed variables across match-play events (average metabolic power [Pmet], high metabolic load distance [HMLD], total distance, relative distance, high-speed distance, maximal speed, accelerations, and deceleration). Pmet, HMLD, total, relative and high-speed distance were 8.9 ± 1.6 W·kg-1, 1457 ± 349 m, 7506 ± 1364 m, 107 ± 20 m·min-1 and 1169 ± 260 m respectively. Half-backs, midfielders and half-forwards outperformed full-backs (Effect Size [ES] = 1.03, 1.22 and 2.07 respectively), and full-forwards in Pmet (Effect Size [ES] = 1.70, 2.07 and 1.28 respectively), and HMLD (full-backs: ES = -1.23, -1.37 and -0.84 respectively, and full-forwards: ES = -1.77, -2.00 and -1.38 respectively). Half-backs (ES = -0.60), midfielders (ES = -0.81), and half-forwards (ES = -0.74) experienced a second-half temporal decrement in HMLD. The current investigation demonstrates that metabolic power may increase our understanding of the match-play demands placed on elite hurling players. Coaches may utilize these findings to construct training drills that replicate match-play demands.


Transcriptional regulation of APOBEC3G, a cytidine deaminase that hypermutates human immunodeficiency virus.
Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) is an antiretroviral deoxycytidine deaminase that lethally hypermutates human immunodeficiency virus type 1 (HIV-1) but is itself neutralized by the HIV-1-encoded viral infectivity factor. Accordingly, APOBEC3G occurs specifically in human T lymphocytic cell lines that contain this antiviral defense, including H9. Since the substrate specificities of related cytidine deaminases are strongly influenced by their intracellular quantities, we analyzed the factors that control APOBEC3G expression. The levels of APOBEC3G mRNA and protein were unaffected by treatment of proliferating H9 cells with interferons or tumor necrosis factor-alpha but were enhanced up to 20-fold by phorbol myristate acetate. This induction was mediated at the transcriptional level by a pathway that required activation of the protein kinase Calpha/betaI isozyme (PKC), mitogen-activated protein kinase kinase (MEK) 1 and 2, and extracellular signal-regulated kinase (ERK). Correspondingly, induction of APOBEC3G was blocked by multiple inhibitors that act at diverse steps of this pathway. The PKCalpha/betaI/MEK/ERK pathway also controlled basal levels of APOBEC3G mRNA and protein, which consequently declined when cells were treated with these inhibitors or arrested in the G(0) state of the cell cycle by serum starvation. We conclude that expression of the antiviral APOBEC3G editing enzyme is dynamically controlled by the PKCalpha/betaI/MEK/ERK protein kinase cascade in human T lymphocytes.


Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.
Genome-wide hypothesis-free discovery methods have identified loci that are associated with heavy smoking in adulthood. Research is needed to understand developmental processes that link newly discovered genetic risks with adult heavy smoking. To test how genetic risks discovered in genome-wide association studies of adult smoking influence the developmental progression of smoking behavior from initiation through conversion to daily smoking, progression to heavy smoking, nicotine dependence, and struggles with cessation. A 38-year, prospective, longitudinal study of a representative birth cohort. The Dunedin Multidisciplinary Health and Development Study of New Zealand. The study included 1037 male and female participants. We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in 3 meta-analyses of genome-wide association studies of smoking quantity phenotypes. Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerström Test of Nicotine Dependence), and cessation difficulties were evaluated at 8 assessments spanning the ages of 11 to 38 years. Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that 2 adolescent developmental phenotypes-early conversion to daily smoking and rapid progression to heavy smoking-mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history. Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers.


A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer.
Purpose: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride.Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5 mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression.Results: Forty patients were enrolled. Sixty percent (n = 24) achieved a ≥50% reduction in prostate-specific antigen (PSA). The median time to radiographic progression was 11 months. Nearly all baseline (n = 29 of 31) and posttreatment (n = 16 of 16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n = 10 of 21) of baseline and 42% (n = 5 of 12) of treatment discontinuation specimens. Compared with patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.Conclusions: Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The noncomparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches toward AR inhibition. Clin Cancer Res; 23(4); 935-45. ©2016 AACR.


Frontal lobe dysfunction in Parkinson's disease. The cortical focus of neostriatal outflow.
This study investigates the hypothesis that, as a consequence of Parkinson's disease, disturbed caudate outflow will lead to deficits in cognitive functions dependent upon the integrity of the prefrontal cortex, the cortical focus of caudatofugal signals. Since Parkinson's disease also involves lesions in extra-striatal midbrain cells which reduce the extrinsic supply of dopamine to this cortical region, such functions are at double risk. Forty nondemented parkinsonian patients were drawn from a pool of 100 consecutive patients and matched with 40 normal control subjects according to age, education, IQ, and sex. All patients were quantitatively rated on neurological indices of disease. Neuropsychological assessment of the patient and normal groups included tests of general intelligence, psychomotor skills, memory, visuospatial and executive functions. No global cognitive decline was observed in the parkinsonian group. Moreover, memory and visuospatial abilities were generally intact. A small cluster of deficits emerged, interpreted as reflecting impairment in the ability to spontaneously generate efficient strategies when relying on self-directed task-specific planning. In addition, several tests thought to be sensitive to frontal lobe function distinguished patients with symptoms strongly lateralized to the right versus left side of the body. Deficits in strategic planning were later investigated in relation to severity of disease and to patient attributes including IQ and age, both of which were relevant to performance on specific tasks. Results were compared with previous investigations in parkinsonian patients and discussed from the perspective of both animal and human studies involving damage to the cerebral cortex and basal ganglia. As the prefrontal cortex is thought to play a crucial role in self-directed behavioural planning, the validity of an outflow model in predicting the consequences of caudate nucleus dysfunction was supported.


Nurses' experiences of delivering acute orthopaedic care to patients with dementia.
Nurses who care for acute patients with dementia in a hospital setting report a variety of challenges in regard to meeting the complex needs of their patients. In particular, known barriers to optimal care include a lack of knowledge about dementia, lack of dementia-friendly acute clinical environments, lack of time to care for the individual patient and a prioritised focus on the medical issues that triggered the hospitalisation. Research to date has not specifically focused on nurses' experiences of caring for people with dementia in orthopaedic wards. This study investigates nurses' experiences of caring for people with dementia, in an acute orthopaedic hospital ward setting. Qualitative interviews. This qualitative study employs hermeneutic phenomenological research methods. Eight Danish nurses were interviewed in an orthopaedic ward about their experiences in caring for orthopaedic patients with dementia. Nurses with various levels of expertise were selected for interview so that a full range of nursing experiences could inform the research study. The results of the study revealed two major themes: "Nurse communication and patient information" and "Care compromise", with three and four sub-themes, respectively. These findings are used to illustrate how, and why, nurses' experiences of caring for patients with dementia contribute a discontentment and negative preconceived perception by some nurses towards their acute care of patients with chronic dementia. The results are discussed in the context of Interactional Nursing Practice theory and describe the challenges experienced by acute care orthopaedic nurses who care for patients with dementia. Orthopaedic nurses find it challenging and professionally difficult to provide person-centred care for patients with dementia during an acute orthopaedic hospital admission. Orthopaedic nurses should work to adopt a positive attitude, and person-centred approach, towards dementia care. It is also recommended that the electronic patient record should be supplemented by oral dissemination to some extent, as information, plans of action and knowledge about the care situation for patients with dementia has a tendency to drown in chronological data presentation.


Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review.
To examine biomarkers of methylmercury (MeHg) intake in women and infants from seafood-consuming populations globally and characterize the comparative risk of fetal developmental neurotoxicity. A search was conducted of the published literature reporting total mercury (Hg) in hair and blood in women and infants. These biomarkers are validated proxy measures of MeHg, a neurotoxin found primarily in seafood. Average and high-end biomarkers were extracted, stratified by seafood consumption context, and pooled by category. Medians for average and high-end pooled distributions were compared with the reference level established by a joint expert committee of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). Selection criteria were met by 164 studies of women and infants from 43 countries. Pooled average biomarkers suggest an intake of MeHg several times over the FAO/WHO reference in fish-consuming riparians living near small-scale gold mining and well over the reference in consumers of marine mammals in Arctic regions. In coastal regions of south-eastern Asia, the western Pacific and the Mediterranean, average biomarkers approach the reference. Although the two former groups have a higher risk of neurotoxicity than the latter, coastal regions are home to the largest number at risk. High-end biomarkers across all categories indicate MeHg intake is in excess of the reference value. There is a need for policies to reduce Hg exposure among women and infants and for surveillance in high-risk populations, the majority of which live in low-and middle-income countries.


MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage efferocytosis.
Efferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.


The Antiproliferative Effect of Moringa oleifera Crude Aqueous Leaf Extract on Human Esophageal Cancer Cells.
Esophageal cancer (EC) is commonly diagnosed in South Africa (SA), with high incidences occurring in SA's black population. Moringa oleifera (MO), a multipurpose tree, is used traditionally for its nutritional and medicinal properties. It has been used for the treatment of a variety of ailments, including cancer. We investigated the antiproliferative effect of MO crude aqueous leaf extract (MOE) on a cancerous esophageal cell line (SNO). SNO cells were exposed to a range of MOE dilutions to evaluate cytotoxicity (MTT assay). Oxidative stress was determined using the TBARS assay. The comet assay was used to assess DNA damage. We then determined cell death mechanisms by measuring phosphatidylserine (PS) externalization (flow cytometry), caspase-3/7 and caspase-9 activities, and adenosine triphosphate (ATP) levels (luminometry). Protein expression of Smac/DIABLO and PARP-1 was determined by western blotting. SNO cells were treated with a range of MOE dilutions to obtain an IC50 value of 389.2 μg/mL MOE (24 h), which was used in all subsequent assays. MOE significantly increased lipid peroxidation (P < .05) and DNA fragmentation (P < .0001) in SNO cells. The induction of apoptosis was confirmed by the increase in PS externalization (P < .0001), caspase-9 (P < .05) and caspase-3/7 (P = .22) activities, and decreased ATP levels (P < .0001). MOE significantly increased both the expression of Smac/DIABLO protein and cleavage of PARP-1, resulting in an increase in the 24-kDa fragment (P < .001). MOE possesses antiproliferative effects on SNO EC cells by increasing lipid peroxidation, DNA fragmentation, and induction of apoptosis.


Anterior Urethroplasty Using a New Tissue Engineered Oral Mucosa Graft: Surgical Techniques and Outcomes.
We investigated whether tissue engineered material may be adopted using standard techniques for anterior urethroplasty. We performed a retrospective multicenter study in patients with recurrent strictures, excluding those with failed hypospadias, lichen sclerosus, traumatic and posterior strictures. A 0.5 cm2 oral mucosa biopsy was taken from the patient cheek and sent to the laboratory to manufacture the graft. After 3 weeks the tissue engineered oral mucosal MukoCell® graft was sent to the hospital for urethroplasty. Four techniques were used, including ventral onlay, dorsal onlay, dorsal inlay and a combined technique. Cystourethrography was performed 1 month postoperatively. Patients underwent clinical evaluation, uroflowmetry and post-void residual urine measurement every 6 months. When the patient showed obstructive symptoms, defined as maximum urine flow less than 12 ml per second, the urethrography was repeated. Patients who underwent further treatment for recurrent stricture were classified as having treatment failure. Of the 38 patients with a median age of 57 years who were included in study the strictures were penile in 3 (7.9%), bulbar in 29 (76.3%) and penobulbar in 6 (15.8%). Median stricture length was 5 cm and median followup was 55 months. Treatment succeeded in 32 of the 38 patients (84.2%) and failed in 15.8%. Success was achieved in 85.7% of ventral onlay, 83.3% of dorsal onlay, 80% of dorsal inlay and 100% of combined technique cases. No local or systemic adverse reactions due to the engineered material were noted. Our findings show that a tissue engineered oral mucosa graft can be implanted using the same techniques suggested for anterior urethroplasty and native oral mucosa, and guaranteeing a similar success rate.


The effect of furazolidone and furaltadone on drug metabolism in rats.
This work examines the effect of oral treatment of rats with the nitrofuran drugs furazolidone (FZ) and furaltadone (F) at doses of 100, 200 and 400 mg/kg for 4 days, or F in the drinking water at concentrations of 0.1, 0.2 and 0.4% w/v for 14 days, on drug metabolism in vivo. FZ at doses of 200 and 400 mg/kg, and F at a dose of 400 mg/kg or at a concentration of 0.4% w/v in water depressed growth and prolonged pentobarbitone-induced sleeping time. Treatment also significantly increased the blood concentration of metronidazole when measured 30 and 40 min after metronidazole administration. Administration of tremorine (25 mg/kg, i.p.) to control vehicle-treated rats produced within 2-3 min tremors, piloerection, profuse salivation, defecation urination and chromodacryorrhesis (red tears). The onset of appearance of these signs was delayed to 7-12 min in rats pretreated with FZ or F (100 mg/kg, 4 days) or cimetidine (50 mg/kg, i.p.) given 45 min earlier. Taken together, these results suggest that FZ and F inhibit drug metabolism in rats. Treatment with these nitrofuran drugs may alter the disposition of certain drugs which may be given concomitantly with them.


5- and 6-glycosylation of transferrin in patients with Alzheimer's disease.
Transferrin is a glycosylated metal-carrying serum protein. One of the biological functions of glycosylation is to regulate the life span of proteins, less glycosylation leading to a faster clearance of a protein from the circulation. In the case of transferrin, this would indirectly also influence iron homeostasis. Higher glycosylation has been demonstrated in patients with Parkinson's disease and rheumatoid arthritis. A genetic variant of transferrin, TfC2, occurs with increased frequency in patients with Alzheimer's disease (AD), rheumatoid arthritis, and other diseases associated with a free radical etiology. Investigations have so far not revealed the reason for the pro-oxidative qualities of TfC2. In this study the glycosylation of Tf in AD (TfC1 homozygotes and TfC1C2 heterozygotes) was compared with alcohol-induced dementia (AID) patients and nondemented, age-matched controls, using isoelectric focusing followed by blotting with anti-Tf antibodies. In TfC1 homozygotes a shift was found toward higher sialylation, but in TfC1C2 heterozygotes the 5- and 6-sialylated bands were less concentrated. The decreased sialalytion found for TfC1C2 heterozygotes, may indicate that the pro-oxidative TfC2 molecules are removed from the circulation at a faster rate than TfC1. This may be of benefit to AD patients having TfC2, but still does not explain why this Tf variant is pro-oxidative.


Early spatial attentional modulation of inputs to the fovea.
Attending to a specific spatial location modulates responsivity of neurons with receptive fields processing that part of the environment. A major outstanding question is whether attentional modulation operates differently for the foveal (central) representation of the visual field than it does for the periphery. Indeed, recent animal electrophysiological recordings suggest that attention differentially affects spatial integration for central and peripheral receptive fields in primary visual cortex. In human electroencephalographic recordings, spatial attention to peripheral locations robustly modulates activity in early visual regions, but it has been claimed that this mechanism does not operate in foveal vision. Here, however, we show clear early attentional modulation of foveal stimulation with the same timing and cortical sources as seen for peripheral stimuli, demonstrating that attentional gain control operates similarly across the entire field of view. These results imply that covertly attending away from the center of gaze, which is a common paradigm in behavioral and electrophysiological studies of attention, results in a precisely timed push-pull mechanism. While the amplitude of the initial response to stimulation at attended peripheral locations is significantly increased beginning at 80 ms, the amplitude of the response to foveal stimulation begins to be attenuated.


Marijuana Use in Epilepsy: The Myth and the Reality.
Marijuana has been utilized as a medicinal plant to treat a variety of conditions for nearly five millennia. Over the past few years, there has been an unprecedented interest in using cannabis extracts to treat epilepsy, spurred on by a few refractory pediatric cases featured in the media that had an almost miraculous response to cannabidiol-enriched marijuana extracts. This review attempts to answer the most important questions a clinician may have regarding the use of marijuana in epilepsy. First, we review the preclinical and human evidences for the anticonvulsant properties of the different cannabinoids, mainly tetrahydrocannabinol (THC) and cannabidiol (CBD). Then, we explore the safety data from animal and human studies. Lastly, we attempt to reconcile the controversy regarding physicians' and patients' opinions about whether the available evidence is sufficient to recommend the use of marijuana to treat epilepsy.


Comparative and population genomic landscape of Phellinus noxius: A hypervariable fungus causing root rot in trees.
The order Hymenochaetales of white rot fungi contain some of the most aggressive wood decayers causing tree deaths around the world. Despite their ecological importance and the impact of diseases they cause, little is known about the evolution and transmission patterns of these pathogens. Here, we sequenced and undertook comparative genomic analyses of Hymenochaetales genomes using brown root rot fungus Phellinus noxius, wood-decomposing fungus Phellinus lamaensis, laminated root rot fungus Phellinus sulphurascens and trunk pathogen Porodaedalea pini. Many gene families of lignin-degrading enzymes were identified from these fungi, reflecting their ability as white rot fungi. Comparing against distant fungi highlighted the expansion of 1,3-beta-glucan synthases in P. noxius, which may account for its fast-growing attribute. We identified 13 linkage groups conserved within Agaricomycetes, suggesting the evolution of stable karyotypes. We determined that P. noxius has a bipolar heterothallic mating system, with unusual highly expanded ~60 kb A locus as a result of accumulating gene transposition. We investigated the population genomics of 60 P. noxius isolates across multiple islands of the Asia Pacific region. Whole-genome sequencing showed this multinucleate species contains abundant poly-allelic single nucleotide polymorphisms with atypical allele frequencies. Different patterns of intra-isolate polymorphism reflect mono-/heterokaryotic states which are both prevalent in nature. We have shown two genetically separated lineages with one spanning across many islands despite the geographical barriers. Both populations possess extraordinary genetic diversity and show contrasting evolutionary scenarios. These results provide a framework to further investigate the genetic basis underlying the fitness and virulence of white rot fungi.


Improving the Accuracy of Flow Cytometric Assessment of Mitochondrial Membrane Potential in Hematopoietic Stem and Progenitor Cells Through the Inhibition of Efflux Pumps.
As cellular metabolism is a key regulator of hematopoietic stem cell (HSC) self-renewal, the various roles played by the mitochondria in hematopoietic homeostasis have been extensively studied by HSC researchers. Mitochondrial activity levels are reflected in their membrane potentials (ΔΨm), which can be measured by cell-permeant cationic dyes such as TMRM (tetramethylrhodamine, methyl ester). The ability of efflux pumps to extrude these dyes from cells can limit their usefulness, however. The resulting measurement bias is particularly critical when assessing HSCs, as xenobiotic transporters exhibit higher levels of expression and activity in HSCs than in differentiated cells. Here, we describe a protocol utilizing Verapamil, an efflux pump inhibitor, to accurately measure ΔΨm across multiple bone marrow populations. The resulting inhibition of pump activity is shown to increase TMRM intensity in hematopoietic stem and progenitor cells (HSPCs), while leaving it relatively unchanged in mature fractions. This highlights the close attention to dye-efflux activity that is required when ΔΨm-dependent dyes are used, and as written and visualized, this protocol can be used to accurately compare either different populations within the bone marrow, or the same population across different experimental models.


A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz.
The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non-genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G>T, c.983T>C, and to a lesser extent, g.15582C>T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C>T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C>T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C>T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels (p=0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries.


Flowering and trichome development share hormonal and transcription factor regulation.
Gibberellins (GAs) and cytokinins (CKs) are plant hormones that act either synergistically or antagonistically during the regulation of different developmental processes. In Arabidopsis thaliana, GAs and CKs overlap in the positive regulation of processes such as the transition from the vegetative to the reproductive phase and the development of epidermal adaxial trichomes. Despite the fact that both developmental processes originate in the rosette leaves, they occur separately in time and space. Here we review how, as genetic and molecular mechanisms are being unraveled, both processes might be closely related. Additionally, this shared genetic network is not only dependent on GA and CK hormone signaling but is also strictly controlled by specific clades of transcription factor families. Some key flowering genes also control other rosette leaf developmental processes such as adaxial trichome formation. Conversely, most of the trichome activator genes, which belong to the MYB, bHLH and C2H2 families, were found to positively control the floral transition. Furthermore, three MADS floral organ identity genes, which are able to convert leaves into floral structures, are also able to induce trichome proliferation in the flower. These data lead us to propose that the spatio-temporal regulation and integration of diverse signals control different developmental processes, such as floral induction and trichome formation, which are intimately connected through similar genetic pathways.


A Path Analysis of Adolescent Athletes' Perceived Stress Reactivity, Competition Appraisals, Emotions, Coping, and Performance Satisfaction.
This study examined a path analysis of adolescent athletes' individual differences in perceived stress reactivity, competition appraisals, emotions, coping, and performance satisfaction. The study aimed to extend an analysis by Nicholls et al. (2012) and further validate the use of the Perceived Stress Reactivity Scale for Adolescent Athletes (PSRS-AA). Adolescent athletes (N = 229, M age = 18.55, SD = 2.40) completed the PSRS-AA followed by a measure of competition appraisals less than 1 h before a competitive event. Within an hour after the competitive event, participants completed a retrospective assessment of emotions, coping strategies, and subjective performance. A path analysis revealed that perceived stress reactivity had direct and indirect effects on the appraisal of higher stressor intensity, lower perceived control, higher perceived threat, negative emotions, and maladaptive coping. Increased threat, positive and negative emotions, and maladaptive coping were associated with performance satisfaction. However, task-orientated coping was not associated with performance satisfaction. The present study enhances and refines the validity of the PSRS-AA for assessing adolescent athletes' perceived stress reactivity. Further strengths and weaknesses of the present study are discussed, along with recommendations for practitioners aiming to support adolescent athletes with high levels of stress reactivity.


The dental office visit as a potential opportunity for diabetes screening: an analysis using NHANES 2003-2004 data.
The bidirectional relationship between periodontitis and diabetes suggests that the dental visit may offer a largely untapped opportunity to screen for undiagnosed diabetes. To better examine this potential opportunity, data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 were used to determine if a larger proportion of patients with periodontal disease as compared with those without periodontitis would be recommended for screening according to American Diabetes Association (ADA) guidelines. The data were also used to determine whether at-risk individuals with periodontitis visited a dental professional recently, so that they could avail themselves of this opportunity for screening, if offered. Data to perform these analyses were collected from 2,923 subjects aged 20 and older who reported that they were never told that they had diabetes, had a periodontal examination, and had sufficient data to compute body mass index. Descriptive statistics, t-tests, and chi-square analyses that compared those with and without periodontitis were extrapolated to the US population. A total of 62.9 percent of those without periodontitis and 93.4 percent of those with periodontal disease met ADA guidelines for diabetes screening. Of those at-risk with periodontal disease, 33.9 percent had seen a dentist in the past 6 months, 50 percent in the past year, and 60.4 percent in the past 2 years. As almost all individuals with periodontitis would have been recommended for diabetes screening, and many at-risk persons with periodontal disease recently visited a dentist, our data suggest that the dental visit provides an important potential venue for this screening.


Early arteriosclerosis and its risk factors in subjects with prediabetes and new-onset diabetes.
We aimed to investigate early arteriosclerosis and its risk factors in populations with prediabetes and new-onset diabetes. A total of 148 participants who did not have diabetes mellitus were assigned to three groups through an oral glucose tolerance test: the normal glucose tolerance (NGT) group; the impaired glucose regulation, also known as prediabetes group and the new-onset type 2 diabetes mellitus group. The insulin resistance index was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). An ELISA was used to determine the level of fibroblast growth factor 21 (FGF21). An arteriosclerosis detector was used to measure the brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). The baPWV, ABI, and FGF21 were used to assess early arteriosclerosis. Significant differences in age, systolic blood pressure (SBP), fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), 2-h insulin (2hINS), and HOMA-IR were found between the NGT group and the prediabetes and new-onset diabetes groups. All of the above, except 2hINS, showed an increasing trend. Moreover, the FGF21 was higher in the new-onset diabetes group than in the NGT group. The baPWV was higher in the new-onset diabetes group than in the other two groups, but no significant difference was noted in the ABI. Age, SBP, diastolic blood pressure, FPG, 2hPG, and FGF21 were positively correlated with the baPWV. In addition, FPG, SBP, FGF21, and HOMA-IR were independent risk factors for the baPWV. Patients with prediabetes and new-onset diabetes may have more significant early arteriosclerosis. The blood glucose level and insulin resistance index may be independent risk factors for early arteriosclerosis.


Bilateral recurrent external obturator muscle hematoma: An unusual cause of pelvic pain in hemophilia.
Following joint hemorrhages, intramuscular hemorrhages are the second most prevalent bleeding pattern in hemophiliac patients. Hematomas of the iliopsoas muscle are a well-known complication of hemophilia; however, obturator muscle hematomas are rare. We herein report a case of spontaneous bleeding of the bilateral external obturator muscles, which occured three times within a period of 9 months in a hemophilia patient with factor VIII inhibitors. To the best of our knowledge, this is the first published case of an obturator externus muscle hematoma in hemophilia. In addition to hip hemarthrosis, iliopsoas hematomas and acute appendicitis, obturator muscle hematoma should be considered as one of the diagnostic alternatives for pelvic pain in hemophiliaψ patients. Magnetic resonance imaging enables rapid diagnosis of obturator muscle hematoma.


The developmental trajectory of bipolar disorder.
Bipolar disorder is highly heritable and therefore longitudinal observation of children of affected parents is important to mapping the early natural history. To model the developmental trajectory of bipolar disorder based on the latest findings from an ongoing prospective study of the offspring of parents with well-characterised bipolar disorder. A total of 229 offspring from families in which 1 parent had confirmed bipolar disorder and 86 control offspring were prospectively studied for up to 16 years. High-risk offspring were divided into subgroups based on the parental long-term response to lithium. Offspring were clinically assessed and DSM-IV diagnoses determined on masked consensus review using best estimate procedure. Adjusted survival analysis and generalised estimating equations were used to calculate differences in lifetime psychopathology. Multistate models were used to examine the progression through proposed clinical stages. High-risk offspring had an increased lifetime risk of a broad spectrum of disorders including bipolar disorder (hazard ratio (HR) = 20.89; P = 0.04), major depressive disorder (HR = 17.16; P = 0.004), anxiety (HR = 2.20; P = 0.03), sleep (HR = 28.21; P = 0.02) and substance use disorders (HR = 2.60; P = 0.05) compared with controls. However, only offspring from lithium non-responsive parents developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder and evidence supported a progressive transition through clinical stages, from non-specific psychopathology to depressive and then manic or psychotic episodes. Findings underscore the importance of a developmental approach in conjunction with an appreciation of familial risk to facilitate earlier accurate diagnosis in symptomatic youth.


Activation of human telomerase reverse transcriptase expression by some new symmetrical bis-substituted derivatives of the anthraquinone.
As a part of our program aimed at exploring the biological activity of symmetrical substitution of side chains into the anthracene-9,10-dione chromophore, we have synthesized a series of 1,5-bisthioanthraquinones 2 and 1,5-bisacyloxyanthraquinones 3 that are related to the antitumor agent mitoxantrone. Since the telomerase enzyme is a novel target for potential anticancer therapy and stem cell expansion, we explore the biological effects of these compounds by evaluating their effects on telomerase activity and telomerase expression. Telomerase is required for telomere maintenance and is active in most human cancers and in germinal cells but not in most of the normal human somatic tissues. We found that most of the 1,5-disubstituted anthraquinones did not exhibit inhibitory activity at the concentration ranging from 20 to 30 microM. To facilitate the analysis of the expression of telomerase, we used cancer and normal cell lines that carry secreted alkaline phosphatase (SEAP) gene under the control of human telomerase reverse transcriptase (hTERT). The effects of these compounds on the expression of telomerease were analyzed using the cell-based reporter systems. While most of these compounds did not appear to selectively repress the expression of hTERT in cancer cells, compounds 3a, 3d, and 3i activated hTERT expression in normal cells. The effects of these three compounds on hTERT expression appear to be specific because they did not increase the expression of a CMV promoter-driven SEAP. Thus, in addition to anticancer functions, our finding raises the possibility that these compounds might also have a role in cell immortalization. The application of these anthraquinone derivatives in stem cell research and tissue engineering is also discussed.


The lutein epoxide cycle in higher plants: its relationships to other xanthophyll cycles and possible functions.
Several xanthophyll cycles have been described in photosynthetic organisms. Among them, only two are present in higher plants: the ubiquitous violaxanthin (V) cycle, and the taxonomically restricted lutein epoxide (Lx) cycle, whereas four cycles seem to occur in algae. Although V is synthesised through the β-branch of the carotenoid biosynthetic pathway and Lx is the product of the α-branch; both are co-located in the same sites of the photosynthetic pigment-protein complexes isolated from thylakoids. Both xanthophylls are also de-epoxidised upon light exposure by the same enzyme, violaxanthin de-epoxidase (VDE) leading to the formation of zeaxanthin (Z) and lutein (L) at comparable rates. In contrast with VDE, the reverse reaction presumably catalysed by zeaxanthin epoxidase (ZE), is much slower (or even inactive) with L than with antheraxanthin (A) or Z. Consequently many species lack Lx altogether, and although the presence of Lx shows an irregular taxonomical distribution in unrelated taxa, it has a high fidelity at family level. In those plants which accumulate Lx, variations in ZE activity in vivo mean that a complete Lx-cycle occurs in some (with Lx pools being restored overnight), whereas in others a truncated cycle is observed in which VDE converts Lx into L, but regeneration of Lx by ZE is extremely slow. Accumulation of Lx to high concentrations is found most commonly in old leaves in deeply shaded canopies, and the Lx cycle in these leaves is usually truncated. This seemingly anomalous situation presumably arises because ZE has a low but finite affinity for L, and because deeply shaded leaves are not often exposed to light intensities strong enough to activate VDE. Notably, both in vitro and in vivo studies have recently shown that accumulation of Lx can increase the light harvesting efficiency in the antennae of PSII. We propose a model for the truncated Lx cycle in strong light in which VDE converts Lx to L which then occupies sites L2 and V1 in the light-harvesting antenna complex of PSII (Lhcb), displacing V and Z. There is correlative evidence that this photoconverted L facilitates energy dissipation via non-photochemical quenching and thereby converts a highly efficient light harvesting system to an energy dissipating system with improved capacity to engage photoprotection. Operation of the α- and β-xanthophyll cycles with different L and Z epoxidation kinetics thus allows a combination of rapidly and slowly reversible modulation of light harvesting and photoprotection, with each cycle having distinct effects. Based on the patchy taxonomical distribution of Lx, we propose that the presence of Lx (and the Lx cycle) could be the result of a recurrent mutation in the epoxidase gene that increases its affinity for L, which is conserved whenever it confers an evolutionary advantage.


Spatial Variations in Dengue Transmission in Schools in Thailand.
Dengue is an important neglected tropical disease, with more than half of the world's population living in dengue endemic areas. Good understanding of dengue transmission sites is a critical factor to implement effective vector control measures. A cohort of 1,811 students from 10 schools in rural, semi-rural and semi-urban Thailand participated in this study. Seroconversion data and location of participants' residences and schools were recorded to determine spatial patterns of dengue infections. Blood samples were taken to confirm dengue infections in participants at the beginning and the end of school term. Entomological factors included a survey of adult mosquito density using a portable vacuum aspirator during the school term and a follow up survey of breeding sites of Aedes vectors in schools after the school term. Clustering analyses were performed to detect spatial aggregation of dengue infections among participants. A total of 57 dengue seroconversions were detected among the 1,655 participants who provided paired blood samples. Of the 57 confirmed dengue infections, 23 (40.0%) occurred in students from 6 (6.8%) of the 88 classrooms in 10 schools. Dengue infections did not show significant clustering by residential location in the study area. During the school term, a total of 66 Aedes aegypti mosquitoes were identified from the 278 mosquitoes caught in 50 classrooms of the 10 schools. In a follow-up survey of breeding sites, 484 out of 2,399 water containers surveyed (20.2%) were identified as active mosquito breeding sites. Our findings suggest that dengue infections were clustered among schools and among classrooms within schools. The schools studied were found to contain a large number of different types of breeding sites. Aedes vector densities in schools were correlated with dengue infections and breeding sites in those schools. Given that only a small proportion of breeding sites in the schools were subjected to vector control measures (11%), this study emphasizes the urgent need to implement vector control strategies at schools, while maintaining efforts at the household level.


Quantifying the Effects of Different Neutral Proteases on Human Islet Integrity.
Efficient islet release from the pancreas requires the combination of collagenase, neutral protease (cNP), or thermolysin (TL). Recently, it has been shown that clostripain (CP) may also contribute to efficient islet release from the human pancreas. The aim of this study was to evaluate the impact of these proteases on human islet integrity in a prospective approach. Islets were isolated from the pancreas of 10 brain-dead human organ donors. Purified islets were precultured for 3 to 4 d at 37 °C to ensure that preparations were cleared of predamaged islets, and only integral islets were subjected to 90 min of incubation at 37 °C in Hank's balanced salt solution supplemented with cNP, TL, or CP. The protease concentrations were calculated for a pancreas of 100 g trimmed weight utilizing 120 dimethyl-casein units of cNP, 70,000 caseinase units of TL, or 200 benzoyl-l-arginine-ethyl-ester units of CP (1×). These activities were then increased both 5× and 10×. After subsequent 24-h culture in enzyme-free culture medium, treated islets were assessed and normalized to sham-treated controls. Compared with controls and CP, islet yield was significantly reduced by using the 5× activity of cNP and TL, inducing also fragmentation and DNA release. Viability significantly decreased not until adding the 1× activity of cNP, 5× activity of TL, or 10× activity of CP. Although mitochondrial function was significantly lowered by 1× cNP and 5× TL, CP did not affect mitochondria at any concentration. cNP- and TL-incubated islets significantly lost intracellular insulin already at 1× activity, while the 10× activity of CP had to be added to observe a similar effect. cNP and TL have a similar toxic potency regarding islet integrity. CP also induces adverse effects on islets, but the toxic threshold is generally higher. We hypothesize that CP can serve as supplementary protease to minimize cNP or TL activity for efficient pancreas digestion.


Cellular and subcellular localization of an Mr 64,000 protein autoantigen in insulin-dependent diabetes.
Antibodies to an Mr 64,000 protein from human or rat islets have been detected at high frequency in newly diagnosed insulin-dependent diabetic patients. In this study, we show that the antigenic and amphiphilic properties of the rat islet Mr 64,000 protein resemble that of the human protein. We have analyzed the expression of the Mr 64,000 protein in populations of pancreatic beta and non-beta cells and in selected rat tissues by immunoprecipitation of [35S]methionine-radiolabeled proteins with sera from diabetic patients or from healthy control individuals. When islet cell populations enriched in beta or non-beta cells were tested for the expression of the Mr 64,000 antigen, the protein was primarily observed in the beta cells. On analyzing preparations of islets, liver, kidney, thyroid, adrenal, pituitary, spleen, and thymus, the protein could only be detected in islets. The protein was also characterized in terms of its subcellular localization by Percoll density gradient centrifugation and was recovered in a fraction enriched in the plasma membrane marker, 5'-nucleotidase. These results are consistent with a beta cell-restricted plasma membrane expression of the protein and support the hypothesis that this protein is a target antigen of beta cell-specific autoimmunity in insulin-dependent diabetes.


PED/PEA-15 controls fibroblast motility and wound closure by ERK1/2-dependent mechanisms.
Cell migration is dependent on the control of signaling events that play significant roles in creating contractile force and in contributing to wound closure. We evaluated wound closure in fibroblasts from mice overexpressing (TgPED) or lacking ped/pea-15 (KO), a gene overexpressed in patients with type 2 diabetes. Cultured skin fibroblasts isolated from TgPED mice showed a significant reduction in the ability to recolonize wounded area during scratch assay, compared to control fibroblasts. This difference was observed both in the absence and in the presence of mytomicin C, an inhibitor of mitosis. In time-lapse experiments, TgPED fibroblasts displayed about twofold lower velocity and diffusion coefficient, as compared to controls. These changes were accompanied by reduced spreading and decreased formation of stress fibers and focal adhesion plaques. At the molecular level, TgPED fibroblasts displayed decreased RhoA activation and increased abundance of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). Inhibition of ERK1/2 activity by PD98059 restored RhoA activation, cytoskeleton organization and cell motility, and almost completely rescued wound closure of TgPED fibroblasts. Interestingly, skin fibroblasts isolated from KO mice displayed an increased wound closure ability. In vivo, healing of dorsal wounds was delayed in TgPED and accelerated in KO mice. Thus, PED/PEA-15 may affect fibroblast motility by a mechanism, at least in part, mediated by ERK1/2.


Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress.
Oxidative stress is a deleterious stressor associated with a plethora of disease and aging manifestations, including neurodegenerative disorders, yet very few factors and mechanisms promoting the neuroprotection of photoreceptor and other neurons against oxidative stress are known. Insufficiency of RAN-binding protein-2 (RANBP2), a large, mosaic protein with pleiotropic functions, suppresses apoptosis of photoreceptor neurons upon aging and light-elicited oxidative stress, and promotes age-dependent tumorigenesis by mechanisms that are not well understood. Here we show that, by downregulating selective partners of RANBP2, such as RAN GTPase, UBC9 and ErbB-2 (HER2; Neu), and blunting the upregulation of a set of orphan nuclear receptors and the light-dependent accumulation of ubiquitylated substrates, light-elicited oxidative stress and Ranbp2 haploinsufficiency have a selective effect on protein homeostasis in the retina. Among the nuclear orphan receptors affected by insufficiency of RANBP2, we identified an isoform of COUP-TFI (Nr2f1) as the only receptor stably co-associating in vivo with RANBP2 and distinct isoforms of UBC9. Strikingly, most changes in proteostasis caused by insufficiency of RANBP2 in the retina are not observed in the supporting tissue, the retinal pigment epithelium (RPE). Instead, insufficiency of RANBP2 in the RPE prominently suppresses the light-dependent accumulation of lipophilic deposits, and it has divergent effects on the accumulation of free cholesterol and free fatty acids despite the genotype-independent increase of light-elicited oxidative stress in this tissue. Thus, the data indicate that insufficiency of RANBP2 results in the cell-type-dependent downregulation of protein and lipid homeostasis, acting on functionally interconnected pathways in response to oxidative stress. These results provide a rationale for the neuroprotection from light damage of photosensory neurons by RANBP2 insufficiency and for the identification of novel therapeutic targets and approaches promoting neuroprotection.


Maternal recall of hypertensive disorders in pregnancy: a systematic review.
Hypertensive disorders in pregnancy are risk markers for future maternal coronary heart disease (CHD). Clinical assessment of a woman's history of pregnancy complications relies on self-report, but the predictive value of maternal recall is unclear. A systematic review was conducted to comprehensively review and critically assess the available literature on maternal recall of hypertensive disorders in pregnancy. The PubMed, EMBASE, and Web of Science databases were searched through August 2012. We included original research articles comparing maternal recall of hypertensive disorders in pregnancy with medical records. Ten studies met eligibility criteria for qualitative analysis and were independently reviewed by two investigators. Recall periods ranged from 48 hours to 30 years. Length of recall did not appear to uniformly affect recall quality. Sensitivity was generally lower and less consistent for gestational hypertension than for preeclampsia. Specificity was >90% for all hypertensive disorders. Determinants of recall accuracy included maternal education and parity. Although maternal recall of hypertensive disorders of pregnancy is specific, low sensitivity and predictive values may limit the clinical utility of asking mothers to recall their history of hypertensive pregnancy complications. Future research on maternal recall of pregnancy complications should be designed to yield predictive values and test recall of disorder subtypes, recurrent complications, and changing recall over time in the same population. The utility of gestation length and offspring birth weight for clinical identification of women whose pregnancy history puts them at increased CHD risk should also be explored.


Carcinoma of the parathyroid.
We report on eight cases of parathyroid carcinoma seen at the Bowman Gray School of Medicine, Winston-Salem, NC, since 1969. Diagnosis of a parathyroid disorder was made on the basis of elevated serum calcium levels and associated disorders such as renal calculi, peptic ulcer disease, pancreatitis, and demineralization of bone. Six of the involved glands were on the left side. In seven patients, the disease was localized to the gland or adjacent structures; one patient had cervical lymph node invasion. Except for the last patient, in whom radical neck dissection and wide excision was done, local excision with adequate margins was the only procedure done. The patient with metastases died of his disease four years later. One patient died of myocardial infarction two years later, but had been normocalcemic in the interval between operation and death, and one patient is hypercalcemic and has had two local recurrences within a 3 1/2 year period. The other five patients are alive and well. The routine use of automated serum level determinations of all hospitalized patients has led to early detection of this malignancy, while it is still a stage I lesion in many instances. On the basis of this material, we conclude that radical neck dissection can no longer be advocated as a routine measure in the treatment of parathyroid carcinoma.


Physiotherapists supporting self-management through health coaching: a mixed methods program evaluation.
To evaluate a program in support of chronic disease self-management (CDSM) that is founded on a health coaching (HC) approach, includes supervised exercise and mindfulness-based stress reduction components and is delivered within a private practice physiotherapy setting. An explanatory mixed method design, framed by theory-based program evaluation, was employed to evaluate an eight-week group-based program. Standardized self-rated and performance measures were evaluated pre- and post intervention. Additionally, participant focus groups were conducted following the intervention period. An inductive thematic approach was undertaken to analyze the qualitative data. Seventeen participants (N = 17) completed the study. Improvements were seen in both self-report and performance outcomes. Participants explained how and why they felt the program was beneficial. Six themes were generated: (1) group dynamic; (2) learning versus doing; (3) holism and comprehensive care; (4) self-efficacy and empowerment; (5) previous solutions versus new management strategies; and (6) healthcare provider support. This study established that a group program in support of CDSM founded on a HC approach demonstrated potential value from participants as well as favorable outcomes. A pragmatic randomized control trial is required to determine efficacy of this intervention.


Towards a whole-genome sequence for rye (Secale cereale L.).
We report on a whole-genome draft sequence of rye (Secale cereale L.). Rye is a diploid Triticeae species closely related to wheat and barley, and an important crop for food and feed in Central and Eastern Europe. Through whole-genome shotgun sequencing of the 7.9-Gbp genome of the winter rye inbred line Lo7 we obtained a de novo assembly represented by 1.29 million scaffolds covering a total length of 2.8 Gbp. Our reference sequence represents nearly the entire low-copy portion of the rye genome. This genome assembly was used to predict 27 784 rye gene models based on homology to sequenced grass genomes. Through resequencing of 10 rye inbred lines and one accession of the wild relative S. vavilovii, we discovered more than 90 million single nucleotide variants and short insertions/deletions in the rye genome. From these variants, we developed the high-density Rye600k genotyping array with 600 843 markers, which enabled anchoring the sequence contigs along a high-density genetic map and establishing a synteny-based virtual gene order. Genotyping data were used to characterize the diversity of rye breeding pools and genetic resources, and to obtain a genome-wide map of selection signals differentiating the divergent gene pools. This rye whole-genome sequence closes a gap in Triticeae genome research, and will be highly valuable for comparative genomics, functional studies and genome-based breeding in rye.


Some aspects of sodium movement across porcine aortic walls in vitro.
1. Sodium movement across the porcine aortic arch in vitro is greater from the intimal to the medial surface than in the reverse direction. 2. A short-circuit current can be measured across the aortic arch and the calculated energy is greater than the energy required to support the net outward sodium movement, suggesting the possibility of active transport of other ions. 3. Net sodium movement is not significantly altered by an adverse gradient on the outside (medial side) but is reduced by a gradient in the opposite direction. 4. Sodium retention within the tissue is increased by a gradient on the medial side. 5. The movement of [14C]inulin is greater from the medial to the intimal surface, suggesting greater porosity on the medial side. A slight rise in both total tissue fluid and extracellular fluid occurred when the sodium concentration on the medial side of the preparation was increased. This did not occur with the sodium concentration increased on the intimal side. The changes were only significant statistically for total tissue fluid. 6. The short-circuit current can be enhanced by adrenaline and reduced by a variety of beta-adrenoreceptor-blocking agents. 7. It appears that aortic tissue can actively transport sodium and it is suggested that this mechanism could play a part in blood pressure control.


Encapsidation of free host DNA by simian virus 40: a simian virus 40 pseudovirus.
Under specified growth conditions, simian virus 40 encapsidated host DNA in a noncircular form free of viral DNA. Two bands of virus particles were present in cesium chloride equilibrium density centrifugation. The host DNA species contained in the upper band was of a lower molecular weight than the DNA present in the mature virus in the lower band.


L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway.
As a natural analogue of glutamate, l-theanine is the unique amino acid derivative in green tea. Although its underlining mechanisms are not yet clear, it has been suggested that l-theanine treatment may prove beneficial to patients with neurodegenerative diseases. In this study, we investigated the neuroprotective effect and its mechanism of l-theanine in an in vitro model of Alzheimer's disease by using the human APP (Swedish mutation) transgenic SH-SY5Y cell. Amyloid beta (Abeta) neurotoxicity was triggered by l-glutamate in this cell line. Additionally, l-theanine significantly attenuated l-glutamate-induced apoptosis at similar levels to those seen with the NMDA receptor inhibitor MK-801 in the stably expressing APP Swedish mutation SH-SY5Y cells which over-generated Abeta. Meanwhile, the activation of c-Jun N-terminal kinase and caspase-3 induced by l-glutamate was suppressed by l-theanine. We also found that cells treated with l-theanine showed decreased production of nitric oxide resulting from the down-regulated protein levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). These results indicate that the inhibition of the NMDA subtype of glutamate receptors and its related pathways is the crucial point of the neuroprotective effect of l-theanine in the cell model. Thus, our present study supports the notion that l-theanine may provide effective prophylaxis and treatment for Alzheimer's disease.


A 3-D kinematic analysis of gliding in a flying snake, Chrysopelea paradisi.
Flying snake species (Chrysopelea) locomote through the air despite a lack of appendages or any obvious external morphological specialization for flight. Here photogrammetric techniques were used to investigate C. paradisi's aerial trajectory in three dimensions. Two videocameras arranged in stereo were used to record head, midpoint and vent landmarks on snakes that jumped from a horizontal branch at a height of 9.62 m and landed in an open field. The coordinates of these landmarks were reconstructed in three dimensions and used to analyze patterns of position, glide angle and speed concurrently with changes in body posture in 14 glide sequences from different individuals. C. paradisi's trajectory was composed of a ballistic dive followed by a shallowing phase in which the path became more horizontal; for most glide trials, no equilibrium phase was observed. In the ballistic dive, the snake changed posture from generally straight to a wide 'S' shape in planview and began aerial undulation. Shortly after the ballistic dive, the snake's speed transitioned from an initial acceleration to stable or to a different rate of increase or decrease. Aerial undulation, in which high-amplitude traveling waves pass posteriorly down the body, was a prominent locomotor behavior. In mid-glide, this undulation occurred with the anterior body oriented approximately parallel with the ground and the posterior body cycling up and down in the vertical plane. The body angle of attack for the anterior body for one trial was 20-40 degrees . Snakes traveled a horizontal distance of 10.14+/-2.69 m (mean +/-s.d.) while reaching an airspeed of 10.0+/-0.9 m s(-1), sinking speed of 6.4+/-0.8 m s(-1) and horizontal speed of 8.1+/-0.9 m s(-1). The glide path shallowed at a rate of 20+/-6 degrees s(-1) and reached a minimum glide angle of 28+/-10 degrees , with a minimum recorded glide angle of 13 degrees . C. paradisi are surprisingly good gliders given their unconventional locomotor style, with performance characteristics that rival or surpass more familiar gliding taxa such as flying squirrels. As in other gliders, C. paradisi is potentially capable of using aerial locomotion to move effectively between trees, chase aerial prey, or avoid predators.


CellCognition: time-resolved phenotype annotation in high-throughput live cell imaging.
Fluorescence time-lapse imaging has become a powerful tool to investigate complex dynamic processes such as cell division or intracellular trafficking. Automated microscopes generate time-resolved imaging data at high throughput, yet tools for quantification of large-scale movie data are largely missing. Here we present CellCognition, a computational framework to annotate complex cellular dynamics. We developed a machine-learning method that combines state-of-the-art classification with hidden Markov modeling for annotation of the progression through morphologically distinct biological states. Incorporation of time information into the annotation scheme was essential to suppress classification noise at state transitions and confusion between different functional states with similar morphology. We demonstrate generic applicability in different assays and perturbation conditions, including a candidate-based RNA interference screen for regulators of mitotic exit in human cells. CellCognition is published as open source software, enabling live-cell imaging-based screening with assays that directly score cellular dynamics.


Clinical probe utilizing surface enhanced Raman scattering.
Conventional Raman scattering is a well-known technique for detecting and identifying complex molecular samples. In surface enhanced Raman scattering, a nanorough metallic surface close to the sample enormously enhances the Raman signal. In previous work, the metallic surface was a thin layer of gold deposited on a rough transparent epoxy substrate. The advantage of the clear substrate was that the Raman signal could be obtained by passing light through the substrate, on to opaque samples simply placed against its surface. In this work, a commercially available Raman spectrometer was coupled to a distant probe. Raman signals were obtained from the surface, and from the interior, of a solid specimen located more than 1 m away from the spectrometer. The practical advantage of this arrangement is that it opens up surface enhanced Raman spectrometry to a clinical environment, with a patient simply sitting or lying near the spectrometer.


Maintaining and improving the oral health of young children.
Oral health is an integral part of the overall health of children. Dental caries is a common and chronic disease process with significant short- and long-term consequences. The prevalence of dental caries for the youngest of children has not decreased over the past decade, despite improvements for older children. As health care professionals responsible for the overall health of children, pediatricians frequently confront morbidity associated with dental caries. Because the youngest children visit the pediatrician more often than they visit the dentist, it is important that pediatricians be knowledgeable about the disease process of dental caries, prevention of the disease, and interventions available to the pediatrician and the family to maintain and restore health.


Development of a search filter for identifying studies completed in primary care.
Identifying articles relevant to primary care is challenging for busy clinicians. Setting specific search strategies can be used to help clinicians find pertinent studies in a timely fashion. To develop search filters for identifying research studies of relevance to primary care in MEDLINE (OvidSP). We conducted a search of MEDLINE (OvidSP) for articles published in five core medical journals at five yearly intervals. We identified a gold standard set of primary care relevant articles which was divided into two subsets. The first subset was used to identify frequently occurring words and phrases through textual analysis. Search filters were developed from these words and phrases and internally validated against records in the second subset. We evaluated the filters performance in a search for articles on two common primary care conditions in MEDLINE (OvidSP). Of the 12 045 articles retrieved, 9028 records were reviewed, of which 371 articles were relevant to primary care (gold standard). When the search filters generated from textual analysis were internally validated, filter specificity peaked at 99% with 60% sensitivity, 67% precision and 97% accuracy. When evaluated against a set of articles on two common primary care conditions, the best performing combination search filter specificity maximized at 99.7% with sensitivity reaching 15% (precision 90%; accuracy 89%). The best performing combination search filter works well in reducing the number of irrelevant papers retrieved in a MEDLINE (OvidSP) search if a busy clinician needs to focus on research relevant to primary care.


Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904.
The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study. Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 50 mg/m(2) on days 1 and 15 (arm A); gemcitabine 1,500 mg/m(2) at a rate of 10 mg/m(2)/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m(2) with docetaxel 40 mg/m(2) on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m(2) with irinotecan 100 mg/m(2) on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival. Results Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens. Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.


Sources of NADPH in yeast vary with carbon source.
Production of NADPH in Saccharomyces cerevisiae cells grown on glucose has been attributed to glucose-6-phosphate dehydrogenase (Zwf1p) and a cytosolic aldehyde dehydrogenase (Ald6p) (Grabowska, D., and Chelstowska, A. (2003) J. Biol. Chem. 278, 13984-13988). This was based on compensation by overexpression of Ald6p for phenotypes associated with ZWF1 gene disruption and on the apparent lethality resulting from co-disruption of ZWF1 and ALD6 genes. However, we have found that a zwf1Delta ald6Delta mutant can be constructed by mating when tetrads are dissected on plates with a nonfermentable carbon source (lactate), a condition associated with expression of another enzymatic source of NADPH, cytosolic NADP+-specific isocitrate dehydrogenase (Idp2p). We demonstrated previously that a zwf1Delta idp2Delta mutant loses viability when shifted to medium with oleate or acetate as the carbon source, apparently because of the inadequate supply of NADPH for cellular antioxidant systems. In contrast, the zwf1Delta ald6Delta mutant grows as well as the parental strain in similar shifts. In addition, the zwf1Delta ald6Delta mutant grows slowly but does not lose viability when shifted to culture medium with glucose as the carbon source, and the mutant resumes growth when the glucose is exhausted from the medium. Measurements of NADP(H) levels revealed that NADPH may not be rapidly utilized in the zwf1Delta ald6Delta mutant in glucose medium, perhaps because of a reduction in fatty acid synthesis associated with loss of Ald6p. In contrast, levels of NADP+ rise dramatically in the zwf1Delta idp2Delta mutant in acetate medium, suggesting a decrease in production of NADPH reducing equivalents needed both for biosynthesis and for antioxidant functions.


Cardiovascular autonomic control in patients undergoing left ventricular assist device (LVAD) support and pharmacologic therapy.
The objective of the study is to determine cardiac autonomic control in patients undergoing assessment for and/or LVAD therapy. Heart rate variability (HRV) was measured in 17 explanted LVAD, 17 implanted LVAD and 23 NYHA III-IV classified chronic heart failure (CHF) patients and ten healthy matched controls under three conditions: supine free breathing, standing and supine controlled breathing. Five measures of HRV were assessed: mean R-R interval (mR-R), high frequency (HF) and low frequency (LF) spectral power, LF in normalised units (LFnu), and LF to HF (LF:HF) ratio. Repeat measures ANOVA showed significant (p < 0.05) differences in HRV between all three conditions within groups. Lower values were observed in CHF for LF(in log natural units) compared with explanted patients (-1.4 [95% CI -2.6 to -0.7], p = 0.04) and controls (-2.1 [-3.5 to -0.7], p = 0.001) and for LF:HF compared with implanted patients under paced breathing conditions (z = -2.7, p = 0.007) and controls in standing (z = -2.9, p = 0.004) and paced breathing conditions (z = -2.3, p = 0.02). However, no significant differences were seen between explanted, implanted and control groups under any condition. Patients implanted with an LVAD and explanted from a LVAD following myocardial recovery demonstrate a more normal dynamic response to autonomic stimuli and have a lower HRV risk profile compared to CHF patients.


The application of precisely controlled functional electrical stimulation to the shoulder, elbow and wrist for upper limb stroke rehabilitation: a feasibility study.
Functional electrical stimulation (FES) during repetitive practice of everyday tasks can facilitate recovery of upper limb function following stroke. Reduction in impairment is strongly associated with how closely FES assists performance, with advanced iterative learning control (ILC) technology providing precise upper-limb assistance. The aim of this study is to investigate the feasibility of extending ILC technology to control FES of three muscle groups in the upper limb to facilitate functional motor recovery post-stroke. Five stroke participants with established hemiplegia undertook eighteen intervention sessions, each of one hour duration. During each session FES was applied to the anterior deltoid, triceps, and wrist/finger extensors to assist performance of functional tasks with real-objects, including closing a drawer and pressing a light switch. Advanced model-based ILC controllers used kinematic data from previous attempts at each task to update the FES applied to each muscle on the subsequent trial. This produced stimulation profiles that facilitated accurate completion of each task while encouraging voluntary effort by the participant. Kinematic data were collected using a Microsoft Kinect, and mechanical arm support was provided by a SaeboMAS. Participants completed Fugl-Meyer and Action Research Arm Test clinical assessments pre- and post-intervention, as well as FES-unassisted tasks during each intervention session. Fugl-Meyer and Action Research Arm Test scores both significantly improved from pre- to post-intervention by 4.4 points. Improvements were also found in FES-unassisted performance, and the amount of arm support required to successfully perform the tasks was reduced. This feasibility study indicates that technology comprising low-cost hardware fused with advanced FES controllers accurately assists upper limb movement and may reduce upper limb impairments following stroke.


Proposed "Exposure And Symptom Triage" (EAST) Tool to Assess Radiation Exposure After a Nuclear Detonation.
ABSTRACTOne of the biggest medical challenges after the detonation of a nuclear device will be implementing a strategy to assess the severity of radiation exposure among survivors and to triage them appropriately. Those found to be at significant risk for radiation injury can be prioritized to receive potentially lifesaving myeloid cytokines and to be evacuated to other communities with intact health care infrastructure prior to the onset of severe complications of bone marrow suppression. Currently, the most efficient and accessible triage method is the use of sequential complete blood counts to assess lymphocyte depletion kinetics that correlate with estimated whole-body dose radiation exposure. However, even this simple test will likely not be available initially on the scale required to assess the at-risk population. Additional variables such as geographic location of exposure, sheltering, and signs and symptoms may be useful for initial sorting. An interdisciplinary working group composed of federal, state, and local public health experts proposes an Exposure And Symptom Triage (EAST) tool combining estimates of exposure from maps with clinical assessments and single lymphocyte counts if available. The proposed tool may help sort survivors efficiently at assembly centers near the damage and fallout zones and enable rapid prioritization for appropriate treatment and transport. (Disaster Med Public Health Preparedness. 2018; 12: 386-395).


Dairy consumption and CVD: a systematic review and meta-analysis.
Inverse associations between dairy consumption and CVD have been reported in several epidemiological studies. Our objective was to conduct a meta-analysis of prospective cohort studies of dairy intake and CVD. A comprehensive literature search was conducted to identify studies that reported risk estimates for total dairy intake, individual dairy products, low/full-fat dairy intake, Ca from dairy sources and CVD, CHD and stroke. Random-effects meta-analyses were used to generate summary relative risk estimates (SRRE) for high v. low intake and stratified intake dose-response analyses. Additional dose-response analyses were performed. Heterogeneity was examined in sub-group and sensitivity analyses. In total, thirty-one unique cohort studies were identified and included in the meta-analysis. Several statistically significant SRRE below 1.0 were observed, namely for total dairy intake and stroke (SRRE=0·91; 95% CI 0·83, 0·99), cheese intake and CHD (SRRE=0·82; 95% CI 0·72, 0·93) and stroke (SRRE=0·87; 95% CI 0·77, 0·99), and Ca from dairy sources and stroke (SRRE=0·69; 95% CI 0·60, 0·81). However, there was little evidence for inverse dose-response relationships between the dairy variables and CHD and stroke after adjusting for within-study covariance. The results of this meta-analysis of prospective cohort studies have shown that dairy consumption may be associated with reduced risks of CVD, although additional data are needed to more comprehensively examine potential dose-response patterns.


From forest to farm: systematic review of cultivar feeding by chimpanzees--management implications for wildlife in anthropogenic landscapes.
Crop-raiding is a major source of conflict between people and wildlife globally, impacting local livelihoods and impeding conservation. Conflict mitigation strategies that target problematic wildlife behaviours such as crop-raiding are notoriously difficult to develop for large-bodied, cognitively complex species. Many crop-raiders are generalist feeders. In more ecologically specialised species crop-type selection is not random and evidence-based management requires a good understanding of species' ecology and crop feeding habits. Comprehensive species-wide studies of crop consumption by endangered wildlife are lacking but are important for managing human-wildlife conflict. We conducted a comprehensive literature search of crop feeding records by wild chimpanzees (Pan troglodytes), a ripe-fruit specialist. We assessed quantitatively patterns of crop selection in relation to species-specific feeding behaviour, agricultural exposure, and crop availability. Crop consumption by chimpanzees is widespread in tropical Africa. Chimpanzees were recorded to eat a considerable range of cultivars (51 plant parts from 36 species). Crop part selection reflected a species-typical preference for fruit. Crops widely distributed in chimpanzee range countries were eaten at more sites than sparsely distributed crops. We identified 'high' and 'low' conflict crops according to their attractiveness to chimpanzees, taking account of their importance as cash crops and/or staple foods to people. Most (86%) high conflict crops were fruits, compared to 13% of low conflict crops. Some widely farmed cash or staple crops were seldom or never eaten by chimpanzees. Information about which crops are most frequently consumed and which are ignored has enormous potential for aiding on-the-ground stakeholders (i.e. farmers, wildlife managers, and conservation and agricultural extension practitioners) develop sustainable wildlife management schemes for ecologically specialised and protected species in anthropogenic habitats. However, the economic and subsistence needs of local people, and the crop-raiding behaviour of sympatric wildlife, must be considered when assessing suitability of particular crops for conflict prevention and mitigation.


The impact of aminopyrene trisulfonate (APTS) label in acceptor glycan substrates for profiling plant pectin β-galactosyltransferase activities.
Aminopyrene trisulfonate (APTS)-labelled disaccharides are demonstrated to serve as readily accessible acceptor substrates for galactosyltransferase activities present in Arabidopsis microsome preparations. The reductive amination procedure used to install the fluorophore results in loss of the ring structure of the reducing terminal sugar unit, such that a single intact sugar ring is present, attached via an alditol tether to the aminopyrene fluorophore. The configuration of the alditol portion of the labelled acceptor, as well as the position of alditol galactosylation, substantially influence the ability of compounds to serve as Arabidopsis galactosyltransferase acceptor substrates. The APTS label exhibits an unexpected reaction-promoting effect that is not evident for structurally similar sulfonated aromatic fluorophores ANDS and ANTS. When APTS-labelled β-(1 → 4)-Gal3 was employed as an acceptor substrate with Arabidopsis microsomes, glycan extension generated β-(1 → 4)-galactan chains running to beyond 60 galactose residues. These studies demonstrate the potential of even very short glycan-APTS probes for assessing plant galactosyltransferase activities and the suitability CE-LIF for CAZyme profiling.


Nasal cancer in the Northamptonshire boot and shoe industry.
A survey of the incidence of nasal cancer in Northamptonshire during the period 1953 to 1967 is reported. Of the 46 patients with nasal cancer ascertained during the 15-year period 21 (19 males and 2 females) had been employed at some time in the boot and shoe industry. Five other cases diagnosed either before 1953 or after 1967 in persons who had worked in the boot and shoe industry in Northamptonshire were ascertained from various sources.The incidence of nasal cancer (all histological types considered together) was significantly higher in male boot and shoe operatives in Northamptonshire than in males of all occupational classes in the Cancer Register areas selected for comparison and in males working in other occupations in Northamptonshire. The excess incidence has recently given rise to the occurrence of between 1 and 2 new cases per annum in the Northamptonshire boot and shoe industry.The cases within the Northamptonshire industry occurred almost entirely in the relatively small number of workers who are exposed to the dust of the materials used in the manufacture of footwear.Possibly there are two carcinogenic factors in the industry-one related to the production of nasal adenocarcinoma, and the other to squamous and possibly other types of carcinoma in the nasal cavity and sinuses. This requires further study. Our best estimate of the latent period for the adenocarcinoma cases was 54.6 years, which is substantially longer than for the patients with squamous, transitional, and anaplastic tumours (41.7 years). We have no evidence to answer the question whether the facts are still present in the industrial environment, though undoubtedly the standards of hygiene in the industry has improved substantially since these men were first exposed.There is probably an increased risk of nasal adenocarcinoma in the footwear repairing industry, but this requires further study. Our evidence suggests that snuff taking should be considered as a possible contributory factor in both industrial and non-industrial nasal cancer.A survey of the footwear manufacturing and repairing industry is recommended regarding cancer of the respiratory tract. Further attempts should be made to minimize the inhalation of dust. The case for the prescription of nasal cancer in the footwear industry should be considered.


Two-Year Whey Protein Supplementation Did Not Enhance Muscle Mass and Physical Function in Well-Nourished Healthy Older Postmenopausal Women.
Protein may play a role in preventing muscle loss with aging. To our knowledge, there have been no long-term randomized controlled trials to examine the effects of increased dietary protein intake on muscle health in community-dwelling older women. In this study, we evaluated the effects of whey protein supplementation on muscle mass and physical function in community-dwelling older Australian women. In this 2 y randomized, double-blind, placebo-controlled trial, women aged 70-80 y (mean 74.3 ± 2.7 y) were randomly assigned to either a high protein drink containing 30 g of whey protein (n = 109) or a placebo drink containing 2.1 g protein (n = 110) daily. Dual-energy X-ray absorptiometry appendicular skeletal muscle mass, upper arm and calf (38% tibia) muscle cross-sectional area, physical function including hand grip strength, lower limb muscle strength and Timed Up and Go test, and 24 h urinary nitrogen were measured at baseline, 1 y, and 2 y. A total of 196 women with at least one follow-up measurement were included in this analysis. Baseline mean BMI was 26.7 ± 3.9 kg/m(2) and protein intake was 76 ± 17 g/d (1.1 ± 0.3 g · kg body weight(-1) · d(-1)). A mean increase in protein intake of ∼ 20 g/d in the protein group was confirmed by the estimates from 24 h urinary nitrogen. Over the 2 y in both groups there was a significant decrease in the upper arm (mean ± SE: -5.59 ± 0.75 cm(2)) and calf (-0.77 ± 0.11 cm(2)) muscle area, as well as hand grip strength (-1.30 ± 0.3 kg) (all P < 0.05), but appendicular skeletal muscle mass did not change significantly. There were no significant effects of the protein intervention on any of the muscle mass or physical function measures (all P > 0.05) at 1 and 2 y. This study showed that in protein-replete, healthy, ambulant, postmenopausal older women, 30 g/d of extra protein did not improve the maintenance of muscle mass or physical function despite evidence of deterioration in muscle measurements in the upper limb. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN012607000163404.


Prevalence of Leptospira spp. in wild brown rats (Rattus norvegicus) on UK farms.
Wild brown rats (Rattus norvegicus) are frequently implicated in the carriage and spread of Leptospira spp. Wild brown rats (n = 259) were trapped from 11 UK farms and tested for Leptospira spp. using a number of diagnostic tests. The prevalence of leptospiral infection was low, but there was variation in the results obtained with the different diagnostic tests. Estimates of prevalence ranged between 0% by silver-staining of tissues, 1% by the microscopic agglutination test, 4% by the enzyme-linked immunosorbent assay, 4% by culture, and 8% by fluorescent antibody technique. In total, 37 (14%) rats were positive by at least one of the tests, which contrasts with the frequently reported prevalences of 50-70% for wild rats in the UK. Serovar bratislava was a prevalent as icterohaemorrhagiae, although it was present only on farms with larger rat populations.