First Report of Orobanche aegyptiaca Parasitism on Sesame in Iran.
A field survey revealed infestations of broomrape, Orobanche aegyptiaca (syn. Phelipanche aegyptiaca), on sesame (Sesamum indicum L.) plants in the province of Khorasan (36°12'N, 57°39'E, 972 m above sea level) in northeastern Iran in November 2011. About 5% of total sesame fields in this area were infested, and the estimated average yield losses were approximately 30 to 40%. The annual mean air temperature and the average maximum and minimum air temperatures were 17.5, 24.2, and 10.6°C, respectively. In a pot experiment that was also conducted at the Isfahan University of Technology to study the effect of sesame as a trap crop for managing broomrape, a total of 20 genotypes of sesame were infested with broomrape. The infestation of sesame was confirmed by verifying the attachment of the broomrape to the sesame roots. Broomrape plant heights were between 20 and 35 cm, with flowering stems 15 to 20 cm. The stems were erect, usually branched, slender, glandular-pubescent, pale yellowish, and inflorescent rather than lax. Flowers had one bract and two bracteoles. The bracts measured 6 to 8 mm, had ovate lanceolates shorter than the calyces, and filiform, lanceolate bracteoles measuring 8 mm. The calyces measured 10 to 11 mm, and were gamosepalous, entire, whitish, hairy, and glandular. Corollas measured 32 to 35 mm, and were blue violet or sky blue with darker veins and cream proximally, straight or slightly curved, conspicuously infundibuliform in distal parts, and glandular-pubescent with two lips. Stamens were epipetalous, inserted 4 to 5 mm above the corolla base, with filaments hairy below, sparsely so above; anthers were villous or spidery hairy along sutures. Stigma lobes were white. The Botanists Group of the College of Agriculture of IUT confirmed the plants' identity. Sesame has been mentioned before as a trap crop for broomrape (1); however, to our knowledge, this is the first report of broomrape parasitism on sesame in Iran. Reference: (1) B. M. Chittapur et al. Allelopathy J. 8:147, 2001.


[New developments in the treatment of pancreatic cancer].
- The incidence of pancreatic cancer is increasing due to the ageing population among other things, while 5-year survival has improved in the past two decades from 3 to 7%.- In case of biliary obstruction due to pancreatic cancer, biliary drainage before surgery or ablative therapy using a covered metal stent instead of plastic reduces the rate of complications.- In patients with metastasized pancreatic cancer a combination of folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) results in improved survival. Approximately 20% of patients with locally, unresectable pancreatic cancer can undergo surgical resection following treatment with FOLFIRINOX.- The effectiveness of radiofrequency ablation, irreversible electroporation and stereotactic radiotherapy for locally, unresectable pancreatic cancer is currently investigated in multicenter trials.- The effectiveness of neo-adjuvant chemoradiation and minimal invasive surgery in patients with resectable pancreatic cancer is currently investigated in randomized multicenter trials.


The golgin tether giantin regulates the secretory pathway by controlling stack organization within Golgi apparatus.
Golgins are coiled-coil proteins that play a key role in the regulation of Golgi architecture and function. Giantin, the largest golgin in mammals, forms a complex with p115, rab1, GM130, and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), thereby facilitating vesicle tethering and fusion processes around the Golgi apparatus. Treatment with the microtubule destabilizing drug nocodazole transforms the Golgi ribbon into individual Golgi stacks. Here we show that siRNA-mediated depletion of giantin resulted in more dispersed Golgi stacks after nocodazole treatment than by control treatment, without changing the average cisternal length. Furthermore, depletion of giantin caused an increase in cargo transport that was associated with altered cell surface protein glycosylation. Drosophila S2 cells are known to have dispersed Golgi stacks and no giantin homolog. The exogenous expression of mammalian giantin cDNA in S2 cells resulted in clustered Golgi stacks, similar to the Golgi ribbon in mammalian cells. These results suggest that the spatial organization of the Golgi ribbon is mediated by giantin, which also plays a role in cargo transport and sugar modifications.


Emerging Roles of Translational Control in Circadian Timekeeping.
A large part of mammalian physiology and behaviour shows regular daily variations. This temporal organisation is driven by the activity of an endogenous circadian clock, whose molecular basis consists of diurnal waves in gene expression. Circadian transcription is the major driver of these rhythms, yet post-transcriptional mechanisms, some of which occur in response to systemic cues and in a tissue-specific fashion, have central roles in ultimately establishing the oscillatory gene expression programme as well. Regulatory control that occurs at the level of translation is emerging as an important player in the generation and modulation of protein accumulation rhythms. As a mechanism, translation lies at a privileged position to integrate genetically encoded rhythmic signals with other, external and internal stimuli, including nutrient-derived cues. In this review, we summarise our current knowledge of how diurnal control of translation affects both bulk protein levels and gene-specific protein biosynthesis. We discuss mechanisms of regulation, in particular with regard to the complex interplay between circadian cycles and feeding/fasting cycles, as well as emerging roles for upstream open reading frames in clock control.


Restricting dislocation movement in transition metal carbides by phase stability tuning.
A mechanism to enhance hardness in multilayer coatings is proposed. Using the technologically important hard transition metal carbides as prototypes, although the principle is transferable also to other systems, we demonstrate, from first-principles calculations, that by suitable alloying the energy difference between several competing structures in the transition metal carbides is small or tunable. This creates multiphase/polytypic compounds with a random or controllable layer stacking sequence, systems in which the propagation of dislocations can be strongly suppressed by a large number of interfaces between structures with different glide systems, accordingly allowing the possibility of a greatly enhanced hardness. With modern thin-film technologies, it should therefore be possible to deposit such materials that will express multilayer characteristics with only minor changes in the chemical constitution of the material, which is in contrast to conventional superlattices.


Estimating ground-level PM(2.5) concentrations in the southeastern U.S. using geographically weighted regression.
Most of currently reported models for predicting PM(2.5) concentrations from satellite retrievals of aerosol optical depth are global methods without considering local variations, which might introduce significant biases into prediction results. In this paper, a geographically weighted regression model was developed to examine the relationship among PM(2.5), aerosol optical depth, meteorological parameters, and land use information. Additionally, two meteorological datasets, North American Regional Reanalysis and North American Land Data Assimilation System, were fitted into the model separately to compare their performances. The study area is centered at the Atlanta Metro area, and data were collected from various sources for the year 2003. The results showed that the mean local R(2) of the models using North American Regional Reanalysis was 0.60 and those using North American Land Data Assimilation System reached 0.61. The root mean squared prediction error showed that the prediction accuracy was 82.7% and 83.0% for North American Regional Reanalysis and North American Land Data Assimilation System in model fitting, respectively, and 69.7% and 72.1% in cross validation. The results indicated that geographically weighted regression combined with aerosol optical depth, meteorological parameters, and land use information as the predictor variables could generate a better fit and achieve high accuracy in PM(2.5) exposure estimation, and North American Land Data Assimilation System could be used as an alternative of North American Regional Reanalysis to provide some of the meteorological fields.


Dengue virus specific dual HLA binding T cell epitopes induce CD8+ T cell responses in seropositive individuals.
Dengue virus infects an estimated 300 million people each year and even more are at risk of becoming infected as the virus continues to spread into new areas. Despite the increase in viral prevalence, no anti-viral medications or vaccines are approved for treating or preventing infection. CD8+ T cell responses play a major role in viral clearance. Therefore, effective vaccines that induce a broad, multi-functional T cell response with substantial cross-reactivity between all virus serotypes can have major impacts on reducing infection rates and infection related complications. Here, we took an immunoproteomic approach to identify novel MHC class I restricted T cell epitopes presented by dengue virus infected cells, representing the natural and authentic targets of the T cell response. Using this approach we identified 4 novel MHC-I restricted epitopes: 2 with the binding motif for HLA-A24 molecules and 2 with both HLA-A2 and HLA-A24 binding motifs. These peptides were able to activate CD8+ T cell responses in both healthy, seronegative individuals and in seropositive individuals who have previously been infected with dengue virus. Importantly, the dual binding epitopes activated pre-existing T cell precursors in PBMCs obtained from both HLA-A2+ and HLA-A24+ seropositive individuals. Together, the data indicate that these epitopes are immunologically relevant T cell activating peptides presented on infected cells during a natural infection and therefore may serve as candidate antigens for the development of effective multi-serotype specific dengue virus vaccines.


Risks of fatal opioid overdose during the first year following nonfatal overdose.
Little is known about risk factors for repeated opioid overdose and fatal opioid overdose in the first year following nonfatal opioid overdose. We identified a national retrospective longitudinal cohort of patients aged 18-64 years in the Medicaid program who received a clinical diagnosis of nonfatal opioid overdose. Repeated overdoses and fatal opioid overdoses were measured with the Medicaid record and the National Death Index. Rates of repeat overdose per 1000 person-years and fatal overdose per 100,000 person-years were determined. Hazard ratios of repeated opioid overdose and fatal opioid overdose were estimated by Cox proportional hazards. Nearly two-thirds (64.8%) of the patients with nonfatal overdoses (total n = 75,556) had filled opioid prescriptions in the 180 days before initial overdose. During the 12 months after nonfatal overdose, the rate of repeat overdose was 295.0 per 1000 person-years and that of fatal opioid overdose was 1154 per 100,000 person-years. After controlling for age, sex, race/ethnicity, and region, the hazard of fatal opioid overdose was increased for patients who had filled a benzodiazepine prescription in the 180 days prior to their initial overdose (HR = 1.71, 95%CI: 1.46-1.99), whose initial overdose involved heroin (HR = 1.57, 95%CI:1.30-1.89), or who required mechanical ventilation at the initial overdose (HR = 1.86, 95%CI = 1.50-2.31). Adults treated for opioid overdose frequently have repeated opioid overdoses in the following year. They are also at high risk of fatal opioid overdose throughout this period, which underscores the importance of efforts to engage and maintain patients in evidence-based opioid treatments following nonfatal overdose.


Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.
The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.


Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.
Although anagrelide is widely used in the treatment of thrombocythemia in myeloproliferative diseases, there is currently limited information on the efficacy and toxicity of its long-term use. This prospective study investigated clinical toxicity and efficacy of anagrelide during two years of treatment. A multicenter, open, phase II study of anagrelide treatment was performed by the Swedish Myeloproliferative Disorder Study Group. The study included 60 patients with thrombocythemia due to myeloproliferative disease, 42 with essential thrombocythemia (ET), 17 with polycythemia vera (PV) and one with myelofibrosis (MF). Complete response (CR), defined as a platelet count <400x10(9)/L in symptomatic patients and < 600x10(9)/L in asymptomatic patients was achieved in 67% of the patients and partial response (PR) in 6%. The response rate was higher in patients with ET than in those with PV (p = 0.05). Primary treatment failure occurred in 27% due to lack of efficacy at a tolerable dose (n=13) or insufficient platelet response without side effects (n=3). In addition, another 14 patients withdrew from treatment before the end of the two-year period due to side effects. Side effects included palpitations (70%), headache (52%), nausea (35%), diarrhea or flatulence (33%), edema (22%) and fatigue (23%). Patients and doctors rated their satisfaction with the anagrelide treatment on a 10-grade scale from 7.6 at 3 months to >9 at 24 months. After two years, 50% (n=30) of the patients continued anagrelide treatment. Side effects and toxic discontinuation rates were higher than in previous studies, probably because this is the first long-term prospective study of the feasibility and toxicity of anagrelide treatment. Nevertheless, anagrelide is a valuable alternative for treatment of thrombocythemia in myeloproliferative disorders for patients who tolerate the drug well.


Disentangling biological effects of primary nanoplastics from dispersion paints' additional compounds.
Microplastic particles (MP) and nanoplastic particles (NP) as persistent anthropogenic pollutants may impact environmental and human health. A relevant potential source of primary MP and NP is water-based dispersion paint which are commonly used in any household. Given the worldwide high application volume of dispersion paint and their diverse material composition MP and NP may enter the environment with unforeseeable consequences. In order to understand the relevance of these MP and NP from paint dispersion we investigated the components of two representative wall paints and analyzed their composition in detail. The different paint components were then investigated for their impact on the model organism Daphnia magna and on a murine cell line. Plastic NP, dissolved polymers, titanium dioxide NPs, and calcium carbonate MPs demonstrated adverse effects in both biological test systems, indicating detrimental consequences of several typical components of wall paints upon release into the environment. The outcome of this study may form the basis for the evaluation of impact on other organisms, environmental transport and impact, other related technical materials and for the development of strategies for the prevention of potential detrimental effects on organisms.


Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons.
The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)-dependent glucose sensing. Mice with inactivation of Glut2-dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation-induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2-deoxy-d-glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed-to-refed transition or following i.p. leptin injection. Sites of central Glut-2 expression were identified by a genetic tagging approach and revealed that glucose-sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2-expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2-dependent glucose-sensing neurons located outside of the arcuate nucleus.


Reducing cardiovascular risk factors in postmenopausal women through a lifestyle change intervention.
The impact of a 6-month lifestyle change intervention on cardiovascular risk factors in obese, sedentary, postmenopausal women was examined. A secondary aim of this investigation was to determine whether the addition of self-control skills training to an empirically supported lifestyle change intervention would result in greater cardiovascular risk reduction. Forty-four women were randomly assigned to receive either a lifestyle change or a lifestyle change with self-control skills intervention. Pretreatment and posttreatment weight loss, body composition, physical activity, cardiorespiratory fitness, diet, blood pressure (BP), blood lipids, and psychosocial functioning were assessed. Also, at 1-year posttreatment, weight loss, body composition, self-reported physical activity, and psychosocial functioning were assessed. The women significantly increased their physical activity (+39.6%) and cardiorespiratory fitness (+13.5%) and reduced their body weight (-6.5%), fat mass (-7.4%), body fat (-2.4%), BP (SBP -6.2%, DBP -9.2%), total cholesterol (-7.4%), triglycerides (-16.5%), and low-density lipoprotein (LDL) cholesterol (9.1%) and improved their diet (p < 0.05). At the 1-year follow-up, women had regained approximately 63% of their posttreatment weight loss (p < 0.05), but had maintained their previous increases in physical activity. Additionally, there were no significant changes in fat free mass, body fat, anxiety, or depression between the end of treatment and 1-year posttreatment. The addition of self-control skills training did not significantly improve cardiovascular risk reduction. Lifestyle change interventions may be an effective means for reducing cardiovascular risk in obese, sedentary, postmenopausal women. However, greater attention should be devoted to the maintenance of these positive lifestyle changes.


Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration.
Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs. The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis. A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H2O2 or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H2O2 and BSO-treated AF cells. Conversely, we showed that TNF-α induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model. A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.


Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer.
The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.


Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging.
Marrow stem cell lines from old donors and those from young controls gave equally rapid rates of colony growth on spleens of irradiated mice. Old and young stem cell lines competed equally well with chromosomally marked marrow stem cells from a young donor in producing cell types that are stimulated by bleeding; old cells competed 70% as well as young in producing cell types stimulated by phytohemagglutinin (PHA) in vitro. After a single serial transplantation, the rates of colony growth declined 1.5- to 2.5-fold, and the ability to compete declined 2- to 4-fold for bleeding-stimulated and 4- to 10-fold for PHA-stimulated cells. Thus, immediate stem cell proliferative capacities decline much more after one serial transplantation than after a lifetime of normal function.


CRMP-2 binds to tubulin heterodimers to promote microtubule assembly.
Regulated increase in the formation of microtubule arrays is thought to be important for axonal growth. Collapsin response mediator protein-2 (CRMP-2) is a mammalian homologue of UNC-33, mutations in which result in abnormal axon termination. We recently demonstrated that CRMP-2 is critical for axonal differentiation. Here, we identify two activities of CRMP-2: tubulin-heterodimer binding and the promotion of microtubule assembly. CRMP-2 bound tubulin dimers with higher affinity than it bound microtubules. Association of CRMP-2 with microtubules was enhanced by tubulin polymerization in the presence of CRMP-2. The binding property of CRMP-2 with tubulin was apparently distinct from that of Tau, which preferentially bound microtubules. In neurons, overexpression of CRMP-2 promoted axonal growth and branching. A mutant of CRMP-2, lacking the region responsible for microtubule assembly, inhibited axonal growth and branching in a dominant-negative manner. Taken together, our results suggest that CRMP-2 regulates axonal growth and branching as a partner of the tubulin heterodimer, in a different fashion from traditional MAPs.


Responses to growth hormone (GH) therapy in short children with normal GH secretion and no bone age delay: an analysis of potential factors affecting their response to rhGH therapy. A controlled study.
Variability still exist about the growth response to growth hormone (GH) therapy in children with idiopathic short stature (ISS). We describe the growth response to rhGH therapy for >2 years in 20 prepubertal children with idiopathic short stature (ISS) and 18 children with GH deficiency (GHD) and compared them with 15 children with ISS who did not receive rhGH therapy. Our study included 35 prepubertal and peripubertal (Tanner 1 and 2) children with short stature (Ht-SDS <-2) and/or Ht-SDS >1SD below their mid parental height SD (MP-Ht-SDS) with slow growth velocity (<-1 SD), with normal peak GH response to provocation tests (15.5±6.5 ng/dl), normal IGF-I SDS (-0.9±0.6), and no bone age delay (± 1 year from chronological age) (ISS). 20 children were treated for 2.5±1.5 years with rhGH 0.05 mg/kg/day and 15 children were not treated with rhGH. 18 children with diagnosis of GHD, diagnosed in the same period, receiving rhGH therapy served as controls. We assessed the linear growth and IGF-I levels of all children for an average of 2 years. Children with ISS on rhGH therapy had a height gain of 0.77 SD in 2 years versus 1.05 SD in GHD children, with significant increase in IGF-I and normal progression of bone age and puberty. Children with ISS who did not receive rhGH had no gain in the changes of Ht-SDS inspite of normal progression of bone age and puberty. The difference between children Ht-SDS and mid-parental height SDS (MP-Ht-SDS) changed significantly from -1.1±3 to -0.3±0.5 in the ISS group and from -1.35±0.5 to -0.3±0.25 in the GHD group, after an average of 2 years of treatment. In the treated ISS group, the Ht-SDS gain was correlated positively with the duration of rhGH therapy (r = 0.82, p<0.0001), negatively with the age at the start of treatment (r = -0.544, p = 0.01), and positively with the bone age (r =-0.44, p = 0.04). The Ht-SDS of children with ISS on rhGH treatment closely approached their MP-Ht-SDS after 2 years of rhGH therapy while those who did not receive rhGH kept the same distance from their MP-Ht-SDS after 2 years. Analysis of possible factors affecting linear growth in children with ISS on rhGH therapy showed that children below 9 years with Ht-SDS <-2.5 SD and those with Ht-SDS >1SD below MP-Ht-SDS grew better on rhGH therapy compared to older children and those with Ht-SDS >-2.5 and were less than 1SD from their MP-HT-SD. Higher doses of rhGH (to keep IGF-I in high normal levels) and longer duration of therapy improved the Ht-SDS gain of these children. We report significant gain in Ht-SDS in prepubertal children with ISS on rhGH therapy and better response in younger children and in those with Ht-SDS > 1 SD below their MP-Ht-SDS.


Semantic priming in the name retrieval of objects and famous faces.
Researchers interested in face processing have recently debated whether access to the name of a known person occurs in parallel with retrieval of semantic-biographical codes, rather than in a sequential fashion. Recently, Schweinberger, Burton, and Kelly (2001) took a failure to obtain a semantic context effect in a manual syllable judgment task on names of famous faces as support for this position. In two experiments, we compared the effects of visually presented categorically related prime words with either objects (e.g. prime: animal; target: dog) or faces of celebrities (e.g. prime: actor; target: Bruce Willis) as targets. Targets were either manually categorized with regard to the number of syllables (as in Schweinberger et al.), or they were overtly named. For neither objects nor faces was semantic priming obtained in syllable decisions; crucially, however, priming was obtained when objects and faces were overtly named. These results suggest that both face and object naming are susceptible to semantic context effects.


Osmosensitivity of transient receptor potential vanilloid 1 is synergistically enhanced by distinct activating stimuli such as temperature and protons.
In animals, body-fluid osmolality is continuously monitored to keep it within a narrow range around a set point (∼300 mOsm/kg). Transient receptor potential vanilloid 1 (TRPV1), a cation channel, has been implicated in body-fluid homeostasis in vivo based on studies with the TRPV1-knockout mouse. However, the response of TRPV1 to hypertonic stimuli has not been demonstrated with heterologous expression systems so far, despite intense efforts by several groups. Thus, the molecular entity of the hypertonic sensor in vivo still remains controversial. Here we found that the full-length form of TRPV1 is sensitive to an osmotic increase exclusively at around body temperature using HEK293 cells stably expressing rat TRPV1. At an ambient temperature of 24°C, a slight increase in the intracellular calcium concentration ([Ca(2+)](i)) was rarely observed in response to hypertonic stimuli. However, the magnitude of the osmosensitive response markedly increased with temperature, peaking at around 36°C. Importantly, the response at 36°C showed a robust increase over a hypertonic range, but a small decrease over a hypotonic range. A TRPV1 antagonist, capsazepine, and a nonspecific TRP channel inhibitor, ruthenium red, completely blocked the increase in [Ca(2+)](i). These results endorse the view that the full-length form of TRPV1 is able to function as a sensor of hypertonic stimuli in vivo. Furthermore, we found that protons and capsaicin likewise synergistically potentiated the response of TRPV1 to hypertonic stimuli. Of note, HgCl(2), which blocks aquaporins and inhibits cell-volume changes, significantly reduced the osmosensitive response. Our findings thus indicate that TRPV1 integrates multiple different types of activating stimuli, and that TRPV1 is sensitive to hypertonic stimuli under physiologically relevant conditions.


Daily Norfloxacin vs. Weekly Ciprofloxacin to Prevent Spontaneous Bacterial Peritonitis: A Randomized Controlled Trial.
For the prevention of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites, norfloxacin 400 mg per day is recommended as a standard regimen. This study aims to investigate whether ciprofloxacin once weekly administration is not inferior to norfloxacin once daily administration for the prevention of SBP. This is an investigator-initiated open-label randomized controlled trial conducted at seven tertiary hospitals in South Korea. Liver cirrhosis patients with ascites were screened, and enrolled in this randomized controlled trial if ascitic protein ≤1.5 g/dL or the presence of history of SBP. Ascitic polymorphonucleated cell count needed to be <250/mm3. Patients were randomly assigned into norfloxacin daily or ciprofloxacin weekly group, and followed-up for 12 months. Primary endpoint was the prevention of SBP. One hundred twenty-four patients met enrollment criteria and were assigned into each group by 1:1 ratio (62:62). Seven patients in the norfloxacin group and five patients in the ciprofloxacin group were lost to follow-up. SBP developed in four patients (4/55) and in three patients (3/57) in each group, respectively (7.3% vs. 5.3%, P = 0.712). The transplant-free survival rates at 1 year were comparable between the groups (72.7% vs. 73.7%, P = 0.970). Incidence of infectious complication, hepatorenal syndrome, hepatic encephalopathy, and variceal bleeding rates were not significantly different (all P = ns). The factors related to survival were models representing underlying liver function. Once weekly ciprofloxacin was as effective as daily norfloxacin for the prevention of SBP in cirrhotic patients with ascites.


Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo.
The antiviral potency of the cytokine IFN-α has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-α-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-α treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated IFN-α/ribavirin (IFN-α/riba) combination therapy. IFN-α/riba therapy decreased HIV-1 viral load by -0.921 (±0.858) log(10) copies/mL in HIV/HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-α/riba treatment in patient-derived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's ρ), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-α/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-α in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.


Augmented visual, auditory, haptic, and multimodal feedback in motor learning: a review.
It is generally accepted that augmented feedback, provided by a human expert or a technical display, effectively enhances motor learning. However, discussion of the way to most effectively provide augmented feedback has been controversial. Related studies have focused primarily on simple or artificial tasks enhanced by visual feedback. Recently, technical advances have made it possible also to investigate more complex, realistic motor tasks and to implement not only visual, but also auditory, haptic, or multimodal augmented feedback. The aim of this review is to address the potential of augmented unimodal and multimodal feedback in the framework of motor learning theories. The review addresses the reasons for the different impacts of feedback strategies within or between the visual, auditory, and haptic modalities and the challenges that need to be overcome to provide appropriate feedback in these modalities, either in isolation or in combination. Accordingly, the design criteria for successful visual, auditory, haptic, and multimodal feedback are elaborated.


Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19.
The complement system augments the humoral immune response, possibly by a mechanism that involves the B lymphocyte membrane receptor, CR2, which binds the C3dg fragment of C3 and triggers several B cell responses in vitro. The present study demonstrates that CR2 associates with a complex of membrane proteins that may mediate signal transduction by ligated CR2. Monoclonal antibodies to CR2 immunoprecipitated from digitonin lysates of Raji B lymphoblastoid cells a membrane complex containing CR2, approximately equimolar amounts of CD19, which is a member of the immunoglobulin superfamily, and three unidentified components: p130, p50, and p20. The complex, which was immunoprecipitated also with anti-CD19, could be dissociated by Nonidet P-40, accounting for its absence in previous studies of CR2. Expression of recombinant CR2 and CD19 in K562 erythroleukemia cells led to formation of a complex that contained not only these two proteins but also p130, p50, and p20, and another component, p14. These unidentified components of the CR2/CD19 complex coimmunoprecipitated with CD19 and not with CR2 from singly transfected cells, indicating primary association with the former. CD19 replicated the capacity of CR2 to interact synergistically with mIgM for increasing free intracellular Ca2+, suggesting that the complex mediates this function of CR2. Therefore, CR2 associates directly with CD19 to become a ligand-binding subunit of a pre-existing signal transduction complex of the B cell that may be representative of a family of membrane protein complexes. This interaction between the complement and immune systems differs from that between immunoglobulin and Clq by involving membrane rather than plasma proteins, and by having complement involved in the afferent phase of the immune response.


Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells.
Phenethyl isothiocyanate (PEITC) from cruciferous vegetables can inhibit the growth of various human cancer cells. In previous studies, we determined that PEITC inhibited the in vitro growth of human glioblastoma GBM 8401 cells by inducing apoptosis, inhibiting migration and invasion, and altering gene expression. Nevertheless, there are no further in vivo reports disclosing whether PEITC can suppress the growth of glioblastoma. Therefore, in this study we investigate the anti-tumor effects of PEITC in a xenograft model of glioblastoma in nude mice. Thirty nude mice were inoculated subcutaneously with GBM 8401 cells. Mice with one palpable tumor were divided randomly into three groups: control, PEITC-10, and PEITC-20 groups treated with 0.1% dimethyl sulfoxide (DMSO), and 10 and 20 μmole PEITC/100 μL PBS daily by oral gavage, respectively. PEITC significantly decreased tumor weights and volumes of GBM 8401 cells in mice, but did not affect the total body weights of mice. PEITC diminished the levels of anti-apoptotic proteins MCL-1 (myeloid cell leukemia 1) and XIAP (X-linked inhibitor of apoptosis protein) in GBM 8401 cells. PEITC enhanced the levels of caspase-3 and Bax in GBM 8401 cells. The growth of glioblastoma can be suppressed by the biological properties of PEITC in vivo. These effects might support further investigations into the potential use of PEITC as an anticancer drug for glioblastoma.


Signal transduction inhibitor therapy for lymphoma.
Current research in lymphoma is focused on two areas of lymphoma biology-the signal transduction pathways used to maintain the growth of malignant lymphocytes and the role of the tumor microenvironment in lymphoma growth and survival. This review focuses on three signaling pathways: the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, the B-cell receptor/spleen tyrosine kinase (BCR/Syk) pathway, and the protein kinase C-beta (PKC-β) pathway, known to be important to lymphoma cells. The mTOR inhibitors temsirolimus and everolimus have demonstrated antitumor activity in all types of lymphoma, the Syk inhibitor fostamatinib has activity in diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and the PKC-β inhibitor enzastaurin is being used as consolidation therapy after remission in diffuse large B-cell lymphoma. This review discusses the biology behind the development of each new agent and the results of initial clinical trials. The goal is to provide the hematologist/oncologist background information on these new agents and understand their current and potential role in the management of patients.


Identification and characterization of hydra metalloproteinase 2 (HMP2): a meprin-like astacin metalloproteinase that functions in foot morphogenesis.
Several members of the newly emerging astacin metalloproteinase family have been shown to function in a variety of biological events, including cell differentiation and morphogenesis during both embryonic development and adult tissue differentiation. We have characterized a new astacin proteinase, hydra metalloproteinase 2 (HMP2) from the Cnidarian, Hydra vulgaris. HMP2 is translated from a single mRNA of 1.7 kb that contains a 1488 bp open reading frame encoding a putative protein product of 496 amino acids. The overall structure of HMP2 most closely resembles that of meprins, a subgroup of astacin metalloproteinases. The presence of a transient signal peptide and a putative prosequence indicates that HMP2 is a secreted protein that requires post-translational processing. The mature HMP2 starts with an astacin proteinase domain that contains a zinc binding motif characteristic of the astacin family. Its COOH terminus is composed of two potential protein-protein interaction domains: an "MAM" domain (named after meprins, A-5 protein and receptor protein tyrosine phosphatase mu) that is only present in meprin-like astacin proteinases; and a unique C-terminal domain (TH domain) that is also present in another hydra metalloproteinase, HMP1, in Podocoryne metalloproteinase 1 (PMP1) of jellyfish and in toxins of sea anemone. The spatial expression pattern of HMP2 was determined by both mRNA whole-mount in situ hybridization and immunofluorescence studies. Both morphological techniques indicated that HMP2 is expressed only by the cells in the endodermal layer of the body column of hydra. While the highest level of HMP2 mRNA expression was observed at the junction between the body column and the foot process, immunofluorescence studies indicated that HMP2 protein was present as far apically as the base of the tentacles. In situ analysis also indicated expression of HMP2 during regeneration of the foot process. To test whether the higher levels of HMP2 mRNA expression at the basal pole related to processes underlying foot morphogenesis, antisense studies were conducted. Using a specialized technique named localized electroporation (LEP), antisense constructs to HMP2 were locally introduced into the endodermal layer of cells at the basal pole of polyps and foot regeneration was initiated and monitored. Treatment with antisense to HMP2 inhibited foot regeneration as compared to mismatch and sense controls. These functional studies in combination with the fact that HMP2 protein was expressed not only at the junction between the body column and the foot process, but also as far apically as the base of the tentacles, suggest that this meprin-class metalloproteinase may be multifunctional in hydra.


Breakthrough Cancer Pain: A Systematic Review of Pharmacologic Management .
Breakthrough cancer pain (BtCP), defined as a transient exacerbation of pain that occurs in conjunction with well-controlled background pain, is a common and burdensome problem in patients with cancer. . The aim of this systematic review is to identify evidence-based pharmacologic modalities for adequate management of BtCP. . PubMed and CINAHL® databases were searched to identify literature regarding pharmacologic strategies for BtCP published from January 2006 to June 2016. These studies were then synthesized by the Oncology Nursing Society Putting Evidence Into Practice pain team. . Forty-four studies provide evidence for the use of opioids for the management of BtCP. Transmucosal immediate-release fentanyl (TIRF) was found to have the most evidence for BtCP. Five studies and guidelines also suggest that oral opioids (not including TIRF products) be dosed proportionally to baseline opioids at 10%-20% of the 24-hour, around-the-clock dose.


Randomized, controlled trial of slow versus rapid feeding volume advancement in preterm infants.
To determine whether infants who are fed initially and advanced at 30 mL/kg per day (intervention) take fewer days to get to full feedings than those who are fed initially and advanced at 20 mL/kg per day (control), without increasing their incidence of feeding complications and necrotizing enterocolitis (NEC). We also examined whether these infants regain birth weight earlier, have fewer days of intravenous fluids, and a have shorter hospital stay. A randomized, controlled, single-center trial was conducted in a Neonatal Intensive Care Unit of a community-based county hospital in Houston, Texas. Infants between 1000 and 2000 g at birth, gestational age < or =35 weeks, and weight appropriate for gestational age were allocated randomly to feedings of expressed human milk or Enfamil formula starting and advanced at either 30 mL/kg per day or 20 mL/kg per day. Infants remained in the study until discharge or development of stage > or =IIA NEC. A total of 155 infants were enrolled: 72 infants in the intervention group and 83 in the control group. Infants in the intervention group achieved full-volume feedings sooner (7 vs 10 days, median), regained birth weight faster (11 vs 13 days, median), and had fewer days of intravenous fluids (6 vs 8 days, median). Three infants in the intervention group and 2 control infants developed NEC for an overall incidence of 3.2% (relative risk: 1.73; 95% confidence interval: 0.30-10.06). Among infants between 1000 and 2000 g at birth, starting and advancing feedings at 30 mL/kg per day seems to be a safe practice and results in fewer days to reach full-volume feedings than using 20 mL/kg per day. This intervention also leads to faster weight gain and fewer days of intravenous fluids.


Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries.
Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.


Utilising non-consensus pathology measurements to improve the diagnosis of oesophageal cancer using a Raman spectroscopic probe.
The application of semi-supervised methodology to improve the classification performance of a Raman spectroscopic probe for the diagnosis of oesophageal cancer is described. It is well known that gold standard histopathology diagnosis can be highly subjective, particularly for diseases which have several stages, such as cancer. A 'consensus' pathology decision can be obtained to ensure a robust gold standard by obtaining a diagnosis from several experts and samples are then only included in standard classification models if they have been assigned the same pathology by all experts. This can result in a significant number of samples that are excluded from the analysis as no consensus was reached. In this work semi-supervised methodology was used to extend Principal Component Analysis followed by Linear Discriminant Analysis (PCA-LDA) to incorporate samples without consensus pathology when discriminating between benign and oesophageal cancer specimens measured using a Raman endoscopic probe ex vivo. We demonstrate that a fully semi-supervised approach improved sensitivity and specificity from 73% and 78% (PCA-LDA) to 78% and 84% (semi-supervised) for discriminating between intestinal metaplasia and dysplasia and from 44% and 66% (PCA-LDA) to 63% and 72% (semi-supervised) when discriminating between intestinal metaplasia and low grade dysplasia.


Development of new targeted therapies for breast cancer.
Clinical application of truly targeted therapy relies on identification of a specific molecular feature (the target) that is biologically relevant, reproducibly measurable and definably correlated with clinical benefit. Ideally the target should be crucial to the tumor's malignant phenotype. The target must be easily measurable in readily obtained clinical samples. Interruption, interference or inhibition of the target should yield a clinical response in a significant proportion of patients whose tumors express the target but in few patients whose tumors do not express the target. As such, targeted therapy offers the twin hopes of maximizing efficacy while minimizing toxicity. A critical review of the hallmarks of malignancy provides a framework for considering potential targets and novel therapeutic interventions. The hallmarks of malignancy include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis, and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionizing radiation or inhibition of estrogen receptor and HER2 growth factor signaling pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial yet therapeutically unimportant, an unlikely paradox.


Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis.
Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. We identified 19 trials including 44,989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3·8 years of follow-up (range 1·0-8·4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]), albuminuria (10% [3-16]), and retinopathy progression (19% [0-34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI -11 to 34]), cardiovascular death (9% [-11 to 26]), total mortality (9% [-3 to 19]), or end-stage kidney disease (10% [-6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group participants, compared with 0·9% in the less intensive treatment group (RR 1·35 [95% CI 0·93-1·97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2·68 [1·21-5·89], p=0·015), but the absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up). Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. National Health and Medical Research Council of Australia.


Affinity proteomic profiling of plasma, cerebrospinal fluid, and brain tissue within multiple sclerosis.
The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.


Factorized Diffusion Map Approximation.
Diffusion maps are among the most powerful Machine Learning tools to analyze and work with complex high-dimensional datasets. Unfortunately, the estimation of these maps from a finite sample is known to suffer from the curse of dimensionality. Motivated by other machine learning models for which the existence of structure in the underlying distribution of data can reduce the complexity of estimation, we study and show how the factorization of the underlying distribution into independent subspaces can help us to estimate diffusion maps more accurately. Building upon this result, we propose and develop an algorithm that can automatically factorize a high dimensional data space in order to minimize the error of estimation of its diffusion map, even in the case when the underlying distribution is not decomposable. Experiments on both the synthetic and real-world datasets demonstrate improved estimation performance of our method over the standard diffusion-map framework.


Prevalence and domains of disability within and outside Appalachian North Carolina: 2013-2016 Behavioral Risk Factor Surveillance System.
The health and social conditions of the Appalachian region generally are poorer than in the US overall, and this gap is widening, suggesting disability may be higher in Appalachia. To describe the prevalence of disability overall and by domain in Appalachian and non-Appalachian regions in North Carolina (NC) and describe the characteristics of people with and without disability in each region. We conducted a cross-sectional study using data from the NC Behavioral Risk Factor Surveillance System from 2013 to 2016 which assessed disability in five domains: vision, cognitive, mobility, self-care, and independent living. We calculated weighted proportions and age- and sex-adjusted prevalence using direct standardization to the 2010 Census. The prevalence of disability in Appalachian NC was significantly higher than in non-Appalachian NC after standardizing by age and sex (26.6% in Appalachia, 24.1% outside Appalachia, p < 0.001). In both regions, mobility disability was most common and self-care disability was least common. People within Appalachia more frequently reported disability in all domains compared to people outside Appalachia. More than one in four adults in Appalachian North Carolina experience disability in at least one domain and one in eight experiences disability in multiple domains. The high prevalence of disability should be considered when planning programs and services across the spectrum of public health. Understanding common disability domains present in populations can inform public health agencies and service providers and help them develop programs and messaging that meet the needs of residents in Appalachia and are accessible to people with disabilities.


Amide Proton Transfer (APT) imaging in tumor with a machine learning approach using partially synthetic data.
Machine learning (ML) has been increasingly used to quantify chemical exchange saturation transfer (CEST) effect. ML models are typically trained using either measured data or fully simulated data. However, training with measured data often lacks sufficient training data, while training with fully simulated data may introduce bias due to limited simulations pools. This study introduces a new platform that combines simulated and measured components to generate partially synthetic CEST data, and to evaluate its feasibility for training ML models to predict amide proton transfer (APT) effect. Partially synthetic CEST signals were created using an inverse summation of APT effects from simulations and the other components from measurements. Training data were generated by varying APT simulation parameters and applying scaling factors to adjust the measured components, achieving a balance between simulation flexibility and fidelity. First, tissue-mimicking CEST signals along with ground truth information were created using multiple-pool model simulations to validate this method. Second, an ML model was trained individually on partially synthetic data, in vivo data, and fully simulated data, to predict APT effect in rat brains bearing 9L tumors. Experiments on tissue-mimicking data suggest that the ML method using the partially synthetic data is accurate in predicting APT. In vivo experiments suggest that our method provides more accurate and robust prediction than the training using in vivo data and fully synthetic data. Partially synthetic CEST data can address the challenges in conventional ML methods.


The serotonin syndrome as a result of mephedrone toxicity.
A 22-year-old male presented to an emergency department by ambulance. His clinical picture included tachycardia, diaphoresis, hypertonia, hyper-reflexia and clonus. The patient became hyperthermic and deteriorated over the next hour. The principal substance ingested was mephedrone and appropriate treatment for the serotonin syndrome resulted in a sustained recovery over 15 h.


Platelet-rich plasma in noninvasive procedures for atrophic acne scars: A systematic review and meta-analysis.
The use of platelet-rich plasma (PRP) combined with noninvasive, nonenergy procedures for atrophic acne scars has shown promise. To date, there has not been a systematic review or meta-analysis of the effectiveness of this therapy. To use meta-analysis to compare Goodman and Baron qualitative scores, patient satisfaction outcomes, and adverse effects in patients undergoing combination procedures with PRP, combination procedures without PRP, and noninvasive monotherapy without PRP in the treatment of patients with atrophic acne scars. The Pubmed and Cochrane library databases were searched for relevant studies published before May 1, 2019. PRISMA guidelines were utilized. Studies that compared the use of PRP in combination with a noninvasive procedure and therapies without PRP for the treatment of atrophic acne scars were included. Cochrane's handbook was utilized to assess the individual biases of the included studies. Publication bias was assessed. A total of 311 participants (153 whole-face participants and 158 split-face participants) were reviewed across eight included studies. Quantitative analysis of 241 participants across six included studies showed a statistically significant reduction in scar severity scores in favor of microneedling or subcision with PRP (P < .001). Combination therapy with intradermal or topical PRP was significantly more effective than monotherapy alone and combination therapy with an adjunct other than PRP (P < .001 and .001, respectively). This systematic review and meta-analysis demonstrated that microneedling or subcision with PRP produced statistically significant improvement in validated outcomes over microneedling or subcision alone.


Unexpected diversity in the mobilome of a Pseudomonas aeruginosa strain isolated from a dental unit waterline revealed by SMRT Sequencing.
The Gram-negative bacterium Pseudomonas aeruginosa is found in several habitats, both natural and human-made, and is particularly known for its recurrent presence as a pathogen in the lungs of patients suffering from cystic fibrosis, a genetic disease. Given its clinical importance, several major studies have investigated the genomic adaptation of P. aeruginosa in lungs and its transition as acute infections become chronic. However, our knowledge about the diversity and adaptation of the P. aeruginosa genome to non-clinical environments is still fragmentary, in part due to the lack of accurate reference genomes of strains from the numerous environments colonized by the bacterium. Here, we used PacBio long-read technology to sequence the genome of PPF-1, a strain of P. aeruginosa isolated from a dental unit waterline. Generating this closed genome was an opportunity to investigate genomic features that are difficult to accurately study in a draft genome (contigs state). It was possible to shed light on putative genomic islands, some shared with other reference genomes, new prophages, and the complete content of insertion sequences. In addition, four different group II introns were also found, including two characterized here and not listed in the specialized group II intron database.


Red, Yellow, Green, and Blue Amplified Spontaneous Emission and Lasing Using Colloidal CdSe Nanoplatelets.
There have been multiple demonstrations of amplified spontaneous emission (ASE) and lasing using colloidal semiconductor nanocrystals. However, it has been proven difficult to achieve low thresholds suitable for practical use of nanocrystals as gain media. Low-threshold blue ASE and lasing from nanocrystals is an even more challenging task. Here, we show that colloidal nanoplatelets (NPLs) with electronic structure of quantum wells can produce ASE in the red, yellow, green, and blue regions of the visible spectrum with low thresholds and high gains. In particular, for blue-emitting NPLs, the ASE threshold is 50 μJ/cm(2), lower than any reported value for nanocrystals. We then demonstrate red, yellow, green, and blue lasing using NPLs with different thicknesses. We find that the lateral size of NPLs does not show any strong effect on the Auger recombination rates and, correspondingly, on the ASE threshold or gain saturation. This observation highlights the qualitative difference of multiexciton dynamics in CdSe NPLs and other quantum-confined CdSe materials, such as quantum dots and rods. Our measurements of the gain bandwidth and gain lifetime further support the prospects of colloidal NPLs as solution-processed optical gain materials.


Measuring the Difference Between Parental Alienation and Parental Estrangement: The PARQ-Gap.
Parental alienation (rejection of a parent without legitimate justification) and realistic estrangement (rejection of a parent for a good reason) are generally accepted concepts among mental health and legal professionals. Alienated children, who were not abused, tend to engage in splitting and lack ambivalence with respect to their parents; estranged children, who were maltreated, usually perceive their parents in an ambivalent manner. The hypothesis of this study was that a psychological test-the Parental Acceptance-Rejection Questionnaire (PARQ)-will help to distinguish severely alienated from nonalienated children. The PARQ, which was used to identify and quantify the degree of splitting for each participant, was administered to 45 severely alienated children and 71 nonalienated children. The PARQ-Gap score-the difference between each child's PARQ: Father score and PARQ: Mother score-was introduced and defined in this research. Using a PARQ-Gap score of 90 as a cut point, this test was 99% accurate in distinguishing severely alienated from nonalienated children. This research presents a way to distinguish parental alienation from other reasons for contact refusal. The PARQ-Gap may be useful for both clinicians and forensic practitioners in evaluating children of separating and divorced parents when there is a concern about the possible diagnosis of parental alienation.


Role of cortical tension in bleb growth.
Blebs are spherical membrane protrusions often observed during cell migration, cell spreading, cytokinesis, and apoptosis, both in cultured cells and in vivo. Bleb expansion is thought to be driven by the contractile actomyosin cortex, which generates hydrostatic pressure in the cytoplasm and can thus drive herniations of the plasma membrane. However, the role of cortical tension in bleb formation has not been directly tested, and despite the importance of blebbing, little is known about the mechanisms of bleb growth. In order to explore the link between cortical tension and bleb expansion, we induced bleb formation on cells with different tensions. Blebs were nucleated in a controlled manner by laser ablation of the cortex, mimicking endogenous bleb nucleation. Cortical tension was modified by treatments affecting the level of myosin activity or proteins regulating actin turnover. We show that there is a critical tension below which blebs cannot expand. Above this threshold, the maximal size of a bleb strongly depends on tension, and this dependence can be fitted with a model of the cortex as an active elastic material. Together, our observations and model allow us to relate bleb shape parameters to the underlying cellular mechanics and provide insights as to how bleb formation can be biochemically regulated during cell motility.


Serum triglyceride and risk of coronary heart disease, stroke, and total mortality in Japanese-American men.
The role of serum triglyceride as a risk factor for coronary heart disease (CHD), stroke, and total mortality was examined in men of Japanese ancestry who were 45 to 78 years old. During the first 10 years following a baseline nonfasting triglyceride determination, there were 490 incidence cases of CHD in 7615 men at risk. Average annual incidence rates were 2.1 times higher in men with nonfasting values above the 75th percentile (279 mg/dl) than in those under the 25th percentile (129 mg/dl, p less than 0.001). This association largely disappeared when associations of triglyceride with other CHD risk factors were accounted for. Fasting triglycerides were measured in a representative sample of 1729 men part-way through the study. With an average follow-up of 5.7 years there were 72 new CHD cases in this group with the risk for men in the top quartile (above 195 mg/dl) being 1.9 times higher than for those in the bottom quartile (below 94 mg/dl). This gradient was of borderline significance (p less than 0.10) and completely disappeared in a multivariate analysis which included HDL and other factors. It appears that the association of triglyceride with CHD in this cohort is of a noncausal nature. Triglycerides were not predictive of stroke or of total mortality in these men.


Cognitive Training in Parkinson's Disease.
Cognitive impairment is now widely accepted as a fundamental aspect of Parkinson's disease (PD). Given the prevalence of cognitive impairment and the associated impact on well-being, evidence-based interventions are needed. However, while research is continually accumulating in order to better understand the pathology and trajectory of cognitive changes, treatment options lag behind. Nonpharmacological approaches are of particular interest in this group, given the typical polypharmacy already present in PD patients. In this regard, cognitive training (CT) is a relatively new and prominent therapeutic option with accumulating scientific support and increasing public awareness. Research has now established benefits across many different populations, and trials investigating the use of CT specifically in PD are becoming more common. We offer a brief summary of CT and its efficacy in PD samples to date, as well as discuss areas requiring further exploration in this group. Crucially, we suggest that CT should be supported as a research priority in PD, given both proven and potential benefits as a noninvasive and well-tolerated behavioral intervention for cognitive impairment.


Breathlessness in COPD: linking symptom clusters with brain activity.
Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain-behaviour-breathlessness links. We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared with the high symptom burden group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). This is the largest functional neuroimaging study of COPD to date, and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multimodal models of breathlessness in identifying behavioural phenotypes and for advancing understanding of differences in breathlessness burden.


How Much of What We Learn in Virtual Reality Transfers to Real-World Navigation?
Past studies suggest that learning a spatial environment by navigating on a desktop computer can lead to significant acquisition of spatial knowledge, although typically less than navigating in the real world. Exactly how this might differ when learning in immersive virtual interfaces that offer a rich set of multisensory cues remains to be fully explored. In this study, participants learned a campus building environment by navigating (1) the real-world version, (2) an immersive version involving an omnidirectional treadmill and head-mounted display, or (3) a version navigated on a desktop computer with a mouse and a keyboard. Participants first navigated the building in one of the three different interfaces and, afterward, navigated the real-world building to assess information transfer. To determine how well they learned the spatial layout, we measured path length, visitation errors, and pointing errors. Both virtual conditions resulted in significant learning and transfer to the real world, suggesting their efficacy in mimicking some aspects of real-world navigation. Overall, real-world navigation outperformed both immersive and desktop navigation, effects particularly pronounced early in learning. This was also suggested in a second experiment involving transfer from the real world to immersive virtual reality (VR). Analysis of effect sizes of going from virtual conditions to the real world suggested a slight advantage for immersive VR compared to desktop in terms of transfer, although at the cost of increased likelihood of dropout. Our findings suggest that virtual navigation results in significant learning, regardless of the interface, with immersive VR providing some advantage when transferring to the real world.


A DFT study on the aldol condensation reaction on MgO in the process of ethanol to 1,3-butadiene: understanding the structure-activity relationship.
Using periodic density functional theory calculations, the aldol condensation of acetaldehyde to 3-hydroxybutanal over dehydroxylated MgO surfaces with and without structure defects was investigated. Compared with the C-C coupling step, the enolization step via proton transfer of the α-hydrogen of acetaldehyde to the MgO surface or the proton back-transfer step to form the desired 3-hydroxybutanal has a higher energy barrier, indicating that the proton transfer process is the key step for the aldol condensation on MgO. To highlight the effect of water, we also calculated the proton transfer steps in the presence of water and studied the reaction pathways over the partially hydroxylated MgO surface. The results show that water can participate in the proton back-transfer step by donating a proton to the alkoxide anion to form the 3-hydroxybutanal, thus reducing the activation energy; the surface OH groups induce a lowering of the activation energy barriers for the overall reaction. The results of the electronic structure analysis indicate that a strong Lewis acid-weak/medium base pair may have the best performance for aldol condensation, such as Mg3C-O4C-D produced by divacancy defects and Mg4C-O2CH produced by the dissociative adsorption of water. A strong Lewis acid generated by low-coordinated Mg2+ can adsorb and stabilize the acetaldehyde molecule near the catalyst surface which is beneficial for the abstraction of an α-proton from an acetaldehyde molecule, and a medium or weak Brønsted base is favorable for the proton back-transfer step.


Single molecule magnet behaviors of Zn4Ln2 (Ln = DyIII, TbIII) complexes with multidentate organic ligands formed by absorption of CO2 in air through in situ reactions.
In this work, we report the syntheses, crystal structures and magnetic properties of three novel Zn-Ln mixed metal complexes, namely [Zn4Dy2(L1)2(L2)2(N3)2]Cl2·2H2O (1), [Zn4Tb2(L1)2(L2)2(Cl)2][ZnN3Cl3]·2H2O (2), and [Zn4Gd2(L1)2(L2)2(Cl)2][ZnN3Cl3]·2H2O (3), in which L12- and L23- were formed from the ligand L [L = N1,N3-bis(3-methoxysalicylidene)diethylenetriamine] through in situ reactions. Interestingly, carbon dioxide in air was absorbed in the process of forming carbamate ligand L23-; this can be ascribed to the insertion of CO2 into M-N amide bonds. Moreover, 1 and 2 represent the first series of 3d-4f SMMs containing carbamate ligands by fixation of CO2 in air. Single-crystal X-ray diffraction analyses reveal that the crystal structures of 1 and 2 are anion-dependent, i.e., the apical positions of the two ZnII ions in 1 and 2 are occupied by an N atom of N3- and by Cl-, respectively. However, the topologies of 2 and 3 are similar. Two ZnII ions and one LnIII (Ln = Dy (1), Tb (2) and Gd (3)) form nearly linear trinuclear [Zn2Ln] units which are double-bridged by two L23- ligands. Magnetic studies reveal that two complexes show single molecule magnet behavior under a direct current (dc) field, with effective energy barriers (Ueff) of 30.66(5) K for 1 and 8.87(3) K for 2. Ab initio calculations reveal that the DyIII ions in 1 and the TbIII ions in 2 are axial in nature; however, a difference in the tunnel splitting of 1 and 2 leads to variation in the magnetization blockades of the two complexes. Theoretical calculations also indicate that the directions of the main magnetic axes severely deviate from the coordination atoms of the first spheres of DyIII and TbIII in 1 and 2; thus further results in poor SMM behavior of the two complexes.


Allergic rhinitis.
Allergic rhinitis is a common disorder that is strongly linked to asthma and conjunctivitis. It is usually a long-standing condition that often goes undetected in the primary-care setting. The classic symptoms of the disorder are nasal congestion, nasal itch, rhinorrhea and sneezing. A thorough history, physical examination and allergen skin testing are important for establishing the diagnosis of allergic rhinitis. Second-generation oral antihistamines and intranasal corticosteroids are the mainstay of treatment. Allergen immunotherapy is an effective immune-modulating treatment that should be recommended if pharmacologic therapy for allergic rhinitis is not effective or is not tolerated, or if chosen by the patient. This article provides an overview of the pathophysiology, diagnosis, and appropriate management of this disorder.


Clinical evidences on the antiviral properties of macrolide antibiotics in the COVID-19 era and beyond.
Macrolides are a large group of antibiotics characterised by the presence of a macro-lactone ring of variable size. The prototype of macrolide antibiotics, erythromycin was first produced by Streptomyces and associated species more than half a century ago; other related drugs were developed. These drugs have been shown to have several pharmacological properties: in addition to their antibiotic activity, they possess some anti-inflammatory properties and have been also considered against non-bacterial infections. In this review, we analysed the available clinical evidences regarding the potential anti-viral activity of macrolides, by focusing on erythromycin, clarithromycin and azithromycin. Overall, there is no significant evidences so far that macrolides might have a direct benefit on most of viral infections considered in this review (RSV, Influenza, coronaviruses, Ebola and Zika viruses). However, their clinical benefit cannot be ruled out without further and focused clinical studies. Macrolides may improve the clinical course of viral respiratory infections somehow, at least through indirect mechanisms relying on some and variable anti-inflammatory and/or immunomodulatory effects, in addition to their well-known antibacterial activity.


Correct dosing of artemether-lumefantrine for management of uncomplicated malaria in rural Tanzania: do facility and patient characteristics matter?
Use of artemisinin-based combination therapy (ACT), such as artemether-lumefantrine (AL), requires a strict dosing schedule that follows the drugs' pharmacokinetic properties. The quality of malaria case management was assessed in two areas in rural Tanzania, to ascertain patient characteristics and facility-specific factors that influence correct dosing of AL for management of uncomplicated malaria. Exit interviews were conducted with patients attending health facilities for initial illness consultation. Information about health workers' training and supervision visits was collected. Health facilities were inventoried for capacity and availability of medical products related to care of malaria patients. The outcome was correct dosing of AL based on age and weight. Logistic regression was used to assess health facility factors and patient characteristics associated with correct dosing of AL by age and weight. A total of 1,531 patients were interviewed, but 60 pregnant women were excluded from the analysis. Only 503 (34.2%) patients who received AL were assessed for correct dosing. Most patients who received AL (85.3%) were seen in public health facilities, 75.7% in a dispensary and 91.1% in a facility that had AL in stock on the survey day. Overall, 92.1% (463) of AL prescriptions were correct by age or weight; but 85.7% of patients received correct dosing by weight alone and 78.5% received correct dosing by age alone. In multivariate analysis, patients in the middle dosing bands in terms of age or weight, had statistically significant lower odds of correct AL dosing (p < 0.05) compared to those in the lowest age or weight group. Other factors such as health worker supervision and training on ACT did not improve the odds of correct AL dosing. Although malaria treatment guidelines indicate AL dosing can be prescribed based on age or weight of the patient, findings from this study show that patients within the middle age and weight dosing bands were least likely to receive a correct dose by either measure. Clinicians should be made aware of AL dosing errors for patients aged three to 12 years and advised to use weight-based prescriptions whenever possible.


Calculation of Organ Doses for a Large Number of Patients Undergoing CT Examinations.
The objective of our study was to develop an automated calculation method to provide organ dose assessment for a large cohort of pediatric and adult patients undergoing CT examinations. We adopted two dose libraries that were previously published: the volume CT dose index-normalized organ dose library and the tube current-exposure time product (100 mAs)-normalized weighted CT dose index library. We developed an algorithm to calculate organ doses using the two dose libraries and the CT parameters available from DICOM data. We calculated organ doses for pediatric (n = 2499) and adult (n = 2043) CT examinations randomly selected from four health care systems in the United States and compared the adult organ doses with the values calculated from the ImPACT calculator. The median brain dose was 20 mGy (pediatric) and 24 mGy (adult), and the brain dose was greater than 40 mGy for 11% (pediatric) and 18% (adult) of the head CT studies. Both the National Cancer Institute (NCI) and ImPACT methods provided similar organ doses (median discrepancy < 20%) for all organs except the organs located close to the scanning boundaries. The visual comparisons of scanning coverage and phantom anatomies revealed that the NCI method, which is based on realistic computational phantoms, provides more accurate organ doses than the ImPACT method. The automated organ dose calculation method developed in this study reduces the time needed to calculate doses for a large number of patients. We have successfully used this method for a variety of CT-related studies including retrospective epidemiologic studies and CT dose trend analysis studies.


Referral pattern of patients received at the national referral hospital: challenges in low income countries.
To examine the medical referral pattern of patients received at the Muhimbili National Hospital (MNH) in order to inform the process of strengthening the referral system. The study design was a prospective study conducted at MNH during a 10-week study period from January to March 2004. The study sample consisted of patients referred to MNH. Of the 11,412 patients seen, 72.5% were self-referrals. More than 70% of the patients seen required admission, though not necessarily at tertiary level. Only 0.8% came from outside the Dar es Salaam region. More than 70% of the patients seen required admission. Surgical services were required by 66.8% of patients, with obstetric conditions being most prominent (24.6% of all patients). For those who were formally referred from other health services, lack of expertise and equipment were the most common reasons given for referral (96.3%). Efforts to improve referral systems in low-income countries require that the primary and secondary level hospitals services be strengthened and increased so as to limit inappropriate use of national referral hospitals.


Working well: a systematic scoping review of the Indigenous primary healthcare workforce development literature.
Strong and effective workforce models are essential for improving comprehensive Indigenous primary healthcare service (PHC) provision to Indigenous peoples in Canada, Australia, New Zealand and the USA (CANZUS nations). This review systematically scoped the literature for studies that described or evaluated models and systems that support the sustainability, capacity or growth of the Indigenous PHC workforce to provide effective PHC provision. Eleven databases, 10 websites and clearinghouses, and the reference lists of 5 review articles were searched for relevant studies from CANZUS nations published in English from 2000 to 2017. A process of thematic analysis was utilised to identify key conditions, strategies and outcomes of Indigenous PHC workforce development reported in the literature. Overall, 28 studies were found. Studies reported enabling conditions for workforce development as government funding and appropriate regulation, support and advocacy by professional organisations; community engagement; PHC leadership, supervision and support; and practitioner Indigeneity, motivation, power equality and wellbeing. Strategies focused on enhancing recruitment and retention; strengthening roles, capacity and teamwork; and improving supervision, mentoring and support. Only 12/28 studies were evaluations, and these studies were generally of weak quality. These studies reported impacts of improved workforce sustainability, workforce capacity, resourcing/growth and healthcare performance improvements. PHCs can strengthen their workforce models by bringing together healthcare providers to consider how these strategies and enabling conditions can be improved to meet the healthcare and health needs of the local community. Improvement is also needed in the quality of evidence relating to particular strategies to guide practice.


Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.
Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity.


Long human CHGA flanking chromosome 14 sequence required for optimal BAC transgenic "rescue" of disease phenotypes in the mouse Chga knockout.
Chromogranin A (CHGA) plays a catalytic role in formation of catecholamine storage vesicles and also serves as precursor to the peptide fragment catestatin, a catecholamine secretory inhibitor whose expression is diminished in the hypertensive individuals. We previously reported the hypertensive, hyperadrenergic phenotype of Chga-/- knockout (KO) mice and rescue by the human ortholog. In the present study, we compare two humanized CHGA mouse models. Into the Chga null background, by bacterial artificial chromosome transgenesis human CHGA transgene has been introduced. Both lines have the complete approximately 12 kbp CHGA gene integrated stably in the genome but have substantial differences in CHGA expression, as well as consequent sympathochromaffin biochemistry and physiology. A mouse model with longer-insert HumCHGA31 displays integration encompassing not only CHGA but also long human flanking sequences. This is in contrast to mouse model HumCHGA19 with limited flanking human sequence co-integrated. As a consequence, HumCHGA19 mice have normal though diminished pattern of spatial expression of CHGA, and 14-fold lower circulating CHGA, with failure to rescue KO phenotypes to normalcy. In the longer-insert HumCHGA31 mice, catecholamine secretion, exaggerated responses to environmental stress, and hypertension were all alleviated. Promoter regions of the transgenes in both HumCHGA19 and HumCHGA31 display minimal CpG methylation, weighing against differential "position effects" of integration, and thus suggesting that lack of cis elements required for optimal CHGA expression occurs in HumCHGA19 mice. Such "humanized" CHGA mouse models may be useful in probing the physiological consequences of variation in CHGA expression found in humans, with consequences for susceptibility to hypertension and cardiovascular disease.


Adaptive Empathy: A Model for Learning Empathic Responses in Response to Feedback.
Empathy is usually deployed in social interactions. Nevertheless, common measures and examinations of empathy study this construct in isolation from the person in distress. In this article we seek to extend the field of examination to include both empathizer and target to determine whether and how empathic responses are affected by feedback and learned through interaction. Building on computational approaches in feedback-based adaptations (e.g., no feedback, model-free and model-based learning), we propose a framework for understanding how empathic responses are learned on the basis of feedback. In this framework, adaptive empathy, defined as the ability to adapt one's empathic responses, is a central aspect of empathic skills and can provide a new dimension to the evaluation and investigation of empathy. By extending existing neural models of empathy, we suggest that adaptive empathy may be mediated by interactions between the neural circuits associated with valuation, shared distress, observation-execution, and mentalizing. Finally, we propose that adaptive empathy should be considered a prominent facet of empathic capabilities with the potential to explain empathic behavior in health and psychopathology.


Childhood abuse and neglect in relation to the presence and persistence of psychotic and depressive symptomatology.
The association between childhood trauma and psychotic and depressive symptomatology is well established. However, less is known about the specificity and course of these symptoms in relation to childhood trauma. In a large sample (n = 2765) of patients with psychosis (n = 1119), their siblings (n = 1057) and controls (n = 589), multivariate (mixed-effects) regression analyses with multiple outcomes were performed to examine the association between childhood trauma and psychotic and depressive symptomatology over a 3-year period. A dose-response relationship was found between childhood trauma and psychosis. Abuse was more strongly associated with positive symptoms than with negative symptoms whereas the strength of the associations between neglect and positive and negative symptoms was comparable. In patients, similar associations between childhood trauma and psychotic or depressive symptoms were found, and in siblings and controls, stronger associations were found between trauma and depressive symptomatology. Childhood trauma was not related to a differential course of symptoms over a 3-year time period. In congruence with earlier work, our findings suggest that childhood trauma, and abuse in particular, is associated with (subthreshold) psychosis. However, childhood trauma does not seem to be associated with a differential course of symptoms, nor does it uniquely heighten the chance of developing (subthreshold) psychotic symptomatology. Our results indicate that trauma may instead contribute to a shared vulnerability for psychotic and depressive symptoms.


The regulatory role of the tetrapeptide AcSDKP in skin and hair physiology and the prevention of ageing effects in these tissues--a potential cosmetic role.
The naturally occurring tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) recognized as a potent angiogenic factor was shown recently to contribute to the repair of cutaneous injuries. In the current article, we report the ability of AcSDKP to exert a beneficial effect on normal healthy skin and scalp and to compensate for the ageing process. In vitro AcSDKP at 10⁻¹¹-10⁻⁷ M significantly stimulates the growth of human keratinocytes, fibroblasts and follicle dermal papilla cells. Moreover, it enhances the growth of human epidermal keratinocyte progenitor and stem cells as shown in a clonogenic survival assay. Topical treatment of ex vivo cultured skin explants with 10⁻⁵ M AcSDKP increases the thickness of the epidermis and upregulates the synthesis of keratins 14 and 19, fibronectin, collagen III and IV as well as the glycoaminoglycans (GAGs). In the ex vivo-cultured hair follicles, AcSDKP promotes hair shaft elongation and induces morphological and molecular modifications matching the criteria of hair growth. Furthermore, AcSDKP at 10⁻¹¹-10⁻⁷ M was shown to improve epidermal barrier, stimulating expression of three protein components of tight junctions (claudin-1, occludin, ZO-1) playing an important role in connecting neighbouring cells. This tetrapeptide exercises also activation of SIRT1 implicated in the control of cell longevity. Indeed, a two-fold increase in the synthesis of SIRT1 by cultured keratinocytes was observed in the presence of 10⁻¹¹-10⁻⁷ M AcSDKP. In conclusion, these findings provide convincing evidence of the regulatory role of AcSDKP in skin and hair physiology and suggest a cosmetic use of this natural tetrapeptide to prevent skin ageing and hair loss and to promote the cutaneous regeneration and hair growth.