ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry.
Interferon stimulated genes (ISGs) target viruses at various stages of their infectious life cycles, including at the earliest stage of viral entry. Here we identify ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) as a gene upregulated by type I IFN treatment in a STAT1-dependent manner. ADAP2 functions as a GTPase-activating protein (GAP) for Arf6 and binds to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and PI(3,4)P2. We show that overexpression of ADAP2 suppresses dengue virus (DENV) and vesicular stomatitis virus (VSV) infection in an Arf6 GAP activity-dependent manner, while exerting no effect on coxsackievirus B (CVB) or Sendai virus (SeV) replication. We further show that ADAP2 expression induces macropinocytosis and that ADAP2 strongly associates with actin-enriched membrane ruffles and with Rab8a- and LAMP1-, but not EEA1- or Rab7-, positive vesicles. Utilizing two techniques--light-sensitive neutral red (NR)-containing DENV and fluorescence assays for virus internalization--we show that ADAP2 primarily restricts DENV infection at the stage of virion entry and/or intracellular trafficking and that incoming DENV and VSV particles associate with ADAP2 during their entry. Taken together, this study identifies ADAP2 as an ISG that exerts antiviral effects against RNA viruses by altering Arf6-mediated trafficking to disrupt viral entry.


Tetrahydrobiopterin and Nitric Oxide Synthase Recouplers.
Generation of nitric oxide (NO) by the nitric oxide synthase (NOS) enzymes plays multiple signalling roles in every organ system, with crucial roles in the cardiovascular system, mediated by endothelial nitric oxide synthase (eNOS, encoded by NOS3) and neuronal nitric oxide synthase (nNOS, encoded by NOS1) in regulation of blood pressure, flow, oxygen delivery and cardiac function. Loss of normal NO-mediated functions in cardiovascular disease state is associated with changes in nitroso-redox signalling that are not dependent solely upon altered NO generation, but increased generation of reactive oxygen species (ROS). The NOS enzymes can also generate ROS, in a catalytic mode whereby the generation of NO from L-arginine is 'uncoupled' from the reduction of molecular oxygen. NOS uncoupling is determined by several factors, including the availability and oxidation state of the required NOS cofactor, tetrahydrobiopterin (BH4). The duality of NOS functions as enzymes that generate both NO and ROS under different regulatory states has emerged as an important pathophysiologic mechanism, and is a potential therapeutic target, via agents that can maintain or restore NOS coupling, for example via effects on BH4 availability.


Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes.
Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.


Expression of hard alpha-keratins in pilomatrixoma, craniopharyngioma, and calcifying odontogenic cyst.
To examine the properties of shadow and ghost cells, 3 kinds of antibodies were raised against human hair proteins and their immunoreactivity was examined in tumors expressing those cells: pilomatrixoma, 14 cases; craniopharyngioma, 17 cases; and calcifying odontogenic cyst (COC), 14 cases. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analyses demonstrated that 2 polyclonal antibodies, PA-HP1 and PA-HP 2, reacted strongly with type I acidic and type II neutral/basic hard alpha-keratins. The other monoclonal antibody, MA-HP1, reacted with type II neutral/basic hard alpha-keratins. Immunohistochemical examination revealed that all 3 antibodies reacted only with the hair shaft in sections of normal skin and dermoid cyst. In all pilomatrixoma cases, 3 antibodies reacted with the cytoplasm of transitional and shadow cells but not with that of basophilic cells. Positive reactions were found only in shadow cells of all 13 adamantinomatous craniopharyngiomas. In all COCs, the antibodies reacted only with ghost cells, not with other epithelial components. Immunoreactivity for phosphothreonine, detected in hard alpha-keratins, also was found in transitional, shadow, and ghost cells. The appearance of shadow or ghost cells might represent differentiation into hair in these 3 kinds of tumors.


Assessment of renal function in mice with unilateral ureteral obstruction using 99mTc-MAG3 dynamic scintigraphy.
Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease. UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys. Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney's peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period. Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.


The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky-Pudlak syndrome and night blindness.
Lysosomes, melanosomes and platelet-dense granules are abnormal in the mouse hypopigmentation mutant pearl. The beta3A subunit of the AP-3 adaptor complex, which likely regulates protein trafficking in the trans - Golgi network/endosomal compartments, was identified as a candidate for the pearl gene by a positional/candidate cloning approach. Mutations, including a large internal tandem duplication and a deletion, were identified in two respective pearl alleles and are predicted to abrogate function of the beta3A protein. Significantly lowered expression of altered beta3A transcripts occurred in kidney of both mutant alleles. The several distinct pearl phenotypes suggest novel functions for the AP-3 complex in mammals. These experiments also suggest mutations in AP-3 subunits as a basis for unique forms of human Hermansky-Pudlak syndrome and congenital night blindness, for which the pearl mouse is an appropriate animal model.


Low serum estradiol levels are related to Mycobacterium avium complex lung disease: a cross-sectional study.
The risk factors for Mycobacterium avium complex lung disease (MAC-LD) are not well known. We hypothesized that low serum estradiol (E2) levels are related to MAC-LD as most patients with MAC-LD are postmenopausal women. This cross-sectional study compared patients with MAC-LD and healthy controls. Study subjects were postmenopausal women aged 65 years or younger. Serum testosterone, dehydroepiandrosterone sulfate (DHEA-S), and E2 levels were measured and categorized as high or low based on median levels. We performed multivariate analysis, receiver operating characteristic (ROC) curve analysis, and age- and body mass index (BMI)-matched subgroup analysis to evaluate the association between low serum E2 levels and MAC-LD. Additionally, using blood samples obtained for other clinical studies, the levels of sex steroid hormones were compared between age- and BMI-matched MAC-LD and bronchiectasis female patients without non-tuberculosis mycobacterial infections (non-NTM BE). Forty-two patients with MAC-LD and 91 healthy controls were included. The median E2 (2.20 pg/mL vs. 15.0 pg/mL, p < 0.001), testosterone (0.230 ng/L vs. 0.250 ng/L, p = 0.005), and DHEA-S (82.5 μg/dL vs. 114.0 μg/dL, p < 0.001) levels were lower in the MAC-LD group than in the control group. Multivariate analysis revealed that low serum E2 (adjusted odds ratio = 34.62, 95% confidence interval = 6.02-199.14) was independently related to MAC-LD, whereas low DHEA-S and testosterone were not. ROC analysis illustrated a strong relationship between low serum E2 levels and MAC-LD (area under the curve = 0.947, 95% confidence interval = 0.899-0.995). Even the age- and BMI-matched subgroup analysis of 17 MAC-LD patients and 17 healthy controls showed lower serum E2 in MAC-LD patients than in healthy controls. Additionally, serum E2 levels of 20 MAC-LD patients were lower than plasma E2 levels of 11 matched non-NTM BE patients (1.79 pg/mL vs. 11.0 pg/mL, p < 0.001). Low serum E2 levels were strongly related to MAC-LD in postmenopausal women.


Basic fibroblast growth factor stimulates corneal endothelial cell growth and endothelial wound healing of human corneas.
To determine the dose response of human recombinant basic fibroblast growth factor (bFGF) on mitogenic activity, and the supplementary role of serum in cultured bovine and human corneal endothelial cells (BCECs, HCECs). To investigate the effect of bFGF on endothelial wound healing of human corneas in vitro. In cell culture, DNA synthesis was assessed by 3H-thymidine incorporation. Wound healing was studied using paired human corneas after mechanical damaging of the endothelium. One cornea was treated with bFGF, and the mate served as control. Wound closure was determined after staining with trypan blue. Endothelial cell density (ECD) was assessed in the closed wound area after alizarin red staining. DNA synthesis was assessed using 3H-thymidine autoradiography. In cell culture, bFGF induced a dose-dependent mitogenic response on BCECs and HCECs. Addition of serum to the culture medium shifted the dose-response curve to considerably lower bFGF concentrations. In organ culture, the time of complete wound closure shortened only marginally (0.5 day) after bFGF treatment (P < 0.01). In the closed wound center, ECD was significantly higher in 1 ng/ml bFGF-treated corneas (686 +/- 134 cells/mm2) than in controls (554 +/- 117 cells/mm2), an increase of +25%. Doses of 0.1 and 10 ng/ml also were effective, but less so than with 1 ng/ml (+11% and +15%, respectively), whereas a dose of 100 ng/ml even had a negative effect (-11%). DNA synthesis was marginally enhanced in bFGF-treated (1 ng/ml) corneas. The maximal effective dose of bFGF producing a BCEC mitogenic response is dependent on serum. In human senior donor corneas, bFGF promotes endothelial wound healing predominantly by stimulation of cell migration.


Impact of caveolin-1 knockout on NANC relaxation in circular muscles of the mouse small intestine compared with longitudinal muscles.
Recently, we showed that caveolin-1 (cav1) knockout mice (Cav1(-/-) mice) have impaired nitric oxide (NO) function in the longitudinal muscle (LM) layer of the small intestine. The defect was a reduced responsiveness of the muscles to NO compensated by an increase in the function of apamin-sensitive, nonadrenergic, noncholinergic (NANC) mediators. In the present study, we examined similarly the effects of cav1 knockout on the relaxation in circular muscle (CM) of the mouse small intestine. CM of Cav1(-/-) mice also showed defective NO function, but less than in LM, as well as more activation of apamin-sensitive NANC mediators. CM of Cav1(-/-) mice, like LM, lacked cav1 but retained small amounts of cav3 and caveolae in the outer CM layer. In addition, we also examined the effects of a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-alpha]quinazolin-1-one (ODQ), on electric field stimulation (EFS)-mediated relaxation in both LM and CM. ODQ had an effect similar to the block of NO synthesis. Moreover, we compared the actions of two NO donors in the LM and CM of control and Cav1(-/-) mice. Similar to LM, CM of Cav1(-/-) mice showed a reduced responsiveness to the NO donors sodium nitroprusside and S-nitroso-N-acetyl penicillamine. However, both ODQ and apamin blocked the inhibitory effects of the NO donors in LM, whereas apamin had no effect in CM. In conclusion, cav1 knockout affects NO function in both LM and CM, but its effects in CM differ significantly.


Comparison of ESWL and ureteroscopic holmium laser lithotripsy in management of ureteral stones.
There are many options for urologists to treat ureteral stones that range from 8 mm to 15 mm, including ESWL and ureteroscopic holmium laser lithotripsy. While both ESWL and ureteroscopy are effective and minimally invasive procedures, there is still controversy over which one is more suitable for ureteral stones. To perform a retrospective study to compare the efficiency, safety and complications using ESWL vs. ureteroscopic holmium laser lithotripsy in management of ureteral stones. Between October 2010 and October 2012, 160 patients who underwent ESWL or ureteroscopic holmium laser lithotripsy at Suzhou municipal hospital for a single radiopaque ureteral stone (the size 8-15 mm) were evaluated. All patients were followed up with ultrasonography for six months. Stone clearance rate, costs and complications were compared. Similarity in stone clearance rate and treatment time between the two procedures; overall procedural time, analgesia requirement and total cost were significantly different. Renal colic and gross hematuria were more frequent with ESWL while voiding symptoms were more frequent with ureteroscopy. Both procedures used for ureteral stones ranging from 8 to 15 mm were safe and minimally invasive. ESWL remains first line therapy for proximal ureteral stones while ureteroscopic holmium laser lithotripsy costs more. To determining which one is preferable depends on not only stone characteristics but also patient acceptance and cost-effectiveness ratio.


Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group.
Previous studies often of short duration have raised concerns that antihypertensive therapy with diuretics and beta-blockers adversely alters levels of other cardiovascular disease risk factors. The Systolic Hypertension in the Elderly Program was a community-based, multicenter, randomized, double-blind, placebo-controlled clinical trial of treatment of isolated systolic hypertension in men and women aged 60 years and older. This retrospective analysis evaluated development of diabetes mellitus in all 4736 participants in the Systolic Hypertension in the Elderly Program, including changes in serum chemistry test results in a subgroup for 3 years. Patients were randomized to receive placebo or treatment with active drugs, with the dose increased in stepwise fashion if blood pressure control goals were not attained: step 1, 12.5 mg of chlorthalidone or 25.0 mg of chlorthalidone; and step 2, the addition of 25 mg of atenolol or 50 mg of atenolol or reserpine or matching placebo. After 3 years, the active treatment group had a 13/4 mm Hg greater reduction in systolic and diastolic blood pressure than the placebo group (both groups, P<.001). New cases of diabetes were reported by 8.6% of the participants in the active treatment group and 7.5% of the participants in the placebo group (P=.25). Small effects of active treatment compared with placebo were observed with fasting levels of glucose (+0.20 mmol/L [+3.6 mg/dL]; P<.01), total cholesterol (+0.09 mmol/L [+3.5 mg/dL]; P<.01), high-density lipoprotein cholesterol (-0.02 mmol/L [-0.77 mg/dL]; P<.01) and creatinine (+2.8 micromol/L [+0.03 mg/dL]; P<.001). Larger effects were seen with fasting levels of triglycerides (+0.9 mmol/L [+17 mg/dL]; P<.001), uric acid (+35 micromol/L [+.06 mg/dL]; P<.001), and potassium (-0.3 mmol/L; P<.001). No evidence was found for a subgroup at higher risk of risk factor changes with active treatment. Antihypertensive therapy with low-dose chlorthalidone (supplemented if necessary) for isolated systolic hypertension lowers blood pressure and its cardiovascular disease complications and has relatively mild effects on other cardiovascular disease risk factor levels.


A novel TGM1 mutation, leading to multiple splicing rearrangements, is associated with autosomal recessive congenital ichthyosis.
Autosomal recessive congenital ichthyosis (ARCI) is a group of rare, clinically heterogeneous skin disorders that affect cornification. ARCI includes lamellar ichthyosis, congenital ichthyosiform erythroderma and harlequin ichthyosis. TGM1 mutations cause > 50% of ARCI cases in the USA. We report two siblings with ARCI. They were found to carry a novel aetiological TGM1 mutation, which leads to the synthesis of multiple abnormal transcripts. These molecules resulted from three independent mechanisms: intron retention, exon skipping and activation of expand cryptic splice sites. Taken together, our findings expand the known TGM1 mutation repertoire, and provide an insight into the molecular mechanisms leading to ARCI phenotypes. These results could be useful for genetic counselling and future potential genotype-phenotype correlations.


Use of novel proteosome inhibitors as a therapeutic strategy in lymphomas current experience and emerging concepts.
Precedent from preclinical experiments coupled with two pivotal phase 2 studies in myeloma has focused attention on a potential role for ubiquitin-proteasome pathway in modulating a number of events that occur commonly in the neoplastic process involving proteins in the regulation of cells cycling, growth and differentiation. This influence is vested in the proteasomes which are large complexes of proteolytic enzymes responsible for degradation of many of these intracellular messengers. Logically interest has centred on molecules having the capacity to influence, by degradation, such molecules and although a number of agents are in development bortezomib is the only one currently in clinical use. Velcade, formerly PS-341, is a novel dipeptide boronic acid capable of reversibly inhibiting the 26S proteasome through a range of activities. The latter are anti-proliferative and proapoptotic with the latter blocking nuclear transcription via NF-kappa B in addition to down regulating adhesion and inhibiting angiogenesis. Additional changes are mediated in protein folding within the endoplasmic reticulum and contribute to cell death. These concepts are given focus by considering their introduction into treatment of lymphoreticular malignancy.


Mortality experience in a polyamide-polyester factory.
Chemical workers have become increasingly concerned about the presence of carcinogens in their occupational environment. As a result, a number of studies of excess cancer mortality have been undertaken in groups of workers with well-characterized exposures. This paper reports the results of one such study carried out in a polyamide-polyester factory in France. A retrospective cohort design was chosen to evaluate the effect of exposure to phthalates, nickel catalyzers, and other chemicals in the work environment. Only a slight excess of cancers, marginally related to exposure category yet not significantly related to length of exposure, was found. The cohort, however, was young but stable, and a continued follow-up is therefore both feasible and justifiable, since it is likely to yield important information about the potential hazards associated with the tergal polymer industry.


What Does Death Preparedness Mean for Family Caregivers of Persons With Dementia?
The purpose of this study was to clarify the concept of death preparedness for family caregivers in dementia. Conceptualization was required to support the assessment, promotion, and operationalization (ie, measurement) of death preparedness through palliative care interventions such as advance care planning. Rodgers evolutionary method of concept analysis was selected to guide this study because of the dynamic nature of death preparedness influenced by context, setting, and time. A comprehensive literature search was conducted. Authors performed constant comparative analysis to identify and interpret surrogate/related concepts, attributes, antecedents, and consequences of death preparedness. Most importantly attributes included (1) knowing and recognizing the symptoms of decline in dementia and what dying looks like; (2) understanding emotions and grief responses; (3) accessing and appraising supports needed to manage and care for dying; (4) organizing affairs and completing tasks in advance; (5) accepting that losses are inevitable and imminent; (6) reflecting on caregiving and finding meaning, "a silver-lining"; and (7) closing, reconciling, and renewing relationship bonds and completing the family member's life. This study contributed a full definition of death preparedness in dementia. Findings aligned with/expanded upon Hebert et al Theoretical Framework of Preparedness for End-of-Life. The use of problem- and emotion-based coping strategies by caregivers with support from health-care providers to promote feelings of death preparedness (including self-efficacy and control) and minimize uncertainty was the implication of this study. Development of a holistic preparedness instrument is underway.


Laser-induced transient grating analysis of dynamics of interaction between sensory rhodopsin II D75N and the HtrII transducer.
The interaction between sensory rhodopsin II (SRII) and its transducer HtrII was studied by the time-resolved laser-induced transient grating method using the D75N mutant of SRII, which exhibits minimal visible light absorption changes during its photocycle, but mediates normal phototaxis responses. Flash-induced transient absorption spectra of transducer-free D75N and D75N joined to 120 amino-acid residues of the N-terminal part of the SRII transducer protein HtrII (DeltaHtrII) showed only one spectrally distinct K-like intermediate in their photocycles, but the transient grating method resolved four intermediates (K(1)-K(4)) distinct in their volumes. D75N bound to HtrII exhibited one additional slower kinetic species, which persists after complete recovery of the initial state as assessed by absorption changes in the UV-visible region. The kinetics indicate a conformationally changed form of the transducer portion (designated Tr*), which persists after the photoreceptor returns to the unphotolyzed state. The largest conformational change in the DeltaHtrII portion was found to cause a DeltaHtrII-dependent increase in volume rising in 8 micros in the K(4) state and a drastic decrease in the diffusion coefficient (D) of K(4) relatively to those of the unphotolyzed state and Tr*. The magnitude of the decrease in D indicates a large structural change, presumably in the solvent-exposed HAMP domain of DeltaHtrII, where rearrangement of interacting molecules in the solvent would substantially change friction between the protein and the solvent.


The diagnostic value of motor evoked potentials.
To assess the diagnostic usefulness of motor evoked potentials (MEPs) and to identify the optimal method for calculating the central conduction time. The test results were evaluated in a prospective study of 1023 neurological patients. We evaluated the correlation between clinical and electrophysiological findings, the accuracy, the sensitivity, the percentage of subclinical abnormalities and the false negative rates of MEPs in different neurological disorders. In patients with lower motor neuron involvement, we compared the central conduction time calculated as the difference between the latency of the cortical and magnetic root stimulation responses with that calculated using the F-wave method. The agreement index between electrophysiological and clinical findings was 87%. The overall accuracy of the test was 0.97. The higher sensitivity values were demonstrated in spinal cord disorders (0.85), hereditary spastic paraplegia (0.80) and motor neuron diseases (0.74). The higher percentages of subclinical abnormalities were found in motor neuron disorders (26%) muscular diseases (24%), multiple sclerosis (13.5%) and spinal cord diseases (12.5%). The higher false negative rates were found in sylvian stroke (0.36) and hereditary spastic paraplegia (0.16). Central conduction study using magnetic paravertebral stimulation but not using the F-wave method, resulted in 12% and 10% of false positive values in lower limb multiradiculopathies and in neuropathies, respectively. MEPs represent a highly accurate diagnostic test. MEP clinical value is maximum in motor neuron, muscle and spinal cord diseases. In patients with lower motor neuron involvement, the gold standard for central conduction determination is the F-wave method.


Conserved translatome remodeling in nematode species executing a shared developmental transition.
Nematodes of the genus Caenorhabditis enter a developmental diapause state after hatching in the absence of food. To better understand the relative contributions of distinct regulatory modalities to gene expression changes associated with this developmental transition, we characterized genome-wide changes in mRNA abundance and translational efficiency associated with L1 diapause exit in four species using ribosome profiling and mRNA-seq. We found a strong tendency for translational regulation and mRNA abundance processes to act synergistically, together effecting a dramatic remodeling of the gene expression program. While gene-specific differences were observed between species, overall translational dynamics were broadly and functionally conserved. A striking, conserved feature of the response was strong translational suppression of ribosomal protein production during L1 diapause, followed by activation upon resumed development. On a global scale, ribosome footprint abundance changes showed greater similarity between species than changes in mRNA abundance, illustrating a substantial and genome-wide contribution of translational regulation to evolutionary maintenance of stable gene expression.


Model-based prediction of the patient-specific response to adrenaline.
A model for the cardiovascular and circulatory systems has previously been validated in simulated cardiac and circulatory disease states. It has also been shown to accurately capture the main hemodynamic trends in porcine models of pulmonary embolism and PEEP (positive end-expiratory pressure) titrations at different volemic levels. In this research, the existing model and parameter identification process are used to study the effect of different adrenaline doses in healthy and critically ill patient populations, and to develop a means of predicting the hemodynamic response to adrenaline. The hemodynamic effects on arterial blood pressures and stroke volume (cardiac index) are simulated in the model and adrenaline-specific parameters are identified. The dose dependent changes in these parameters are then related to adrenaline dose using data from studies published in the literature. These relationships are then used to predict the future, patient-specific response to a change in dose or over time periods from 1-12 hours. The results are compared to data from 3 published adrenaline dosing studies comprising a total of 37 data sets. Absolute percentage errors for the identified model are within 10% when re-simulated and compared to clinical data for all cases. All identified parameter trends match clinically expected changes. Absolute percentage errors for the predicted hemodynamic responses (N=15) are also within 10% when re-simulated and compared to clinical data. Clinically accurate prediction of the effect of inotropic circulatory support drugs, such as adrenaline, offers significant potential for this type of model-based application. Overall, this work represents a further clinical, proof of concept, of the underlying fundamental mathematical model, methods and approach, as well as providing a template for using the model in clinical titration of adrenaline in a decision support role in critical care. They are thus a further justification in support of upcoming human clinical trials to validate this model.


The avian cell line AGE1.CR.pIX characterized by metabolic flux analysis.
In human vaccine manufacturing some pathogens such as Modified Vaccinia Virus Ankara, measles, mumps virus as well as influenza viruses are still produced on primary material derived from embryonated chicken eggs. Processes depending on primary cell culture, however, are difficult to adapt to modern vaccine production. Therefore, we derived previously a continuous suspension cell line, AGE1.CR.pIX, from muscovy duck and established chemically-defined media for virus propagation. To better understand vaccine production processes, we developed a stoichiometric model of the central metabolism of AGE1.CR.pIX cells and applied flux variability and metabolic flux analysis. Results were compared to literature dealing with mammalian and insect cell culture metabolism focusing on the question whether cultured avian cells differ in metabolism. Qualitatively, the observed flux distribution of this avian cell line was similar to distributions found for mammalian cell lines (e.g. CHO, MDCK cells). In particular, glucose was catabolized inefficiently and glycolysis and TCA cycle seem to be only weakly connected. A distinguishing feature of the avian cell line is that glutaminolysis plays only a minor role in energy generation and production of precursors, resulting in low extracellular ammonia concentrations. This metabolic flux study is the first for a continuous avian cell line. It provides a basis for further metabolic analyses to exploit the biotechnological potential of avian and vertebrate cell lines and to develop specific optimized cell culture processes, e.g. vaccine production processes.


The situation for female survivors of non-partner sexual violence: A focused enquiry of Somali young women's views, knowledge and opinions.
The aim of the study is to elucidate young women's perceptions of the situation for female survivors of non-partner sexual violence in Somaliland. Young Somali women with diverse backgrounds (n = 25) shared views, knowledge and opinions about non partner sexual violence in focus group discussions held in urban settings. Data was analysed using content analysis. A main category "Bound by culture and community perceptions" with four subcategories comprises the informants' perceptions of non-partner sexual violence among young women in Somaliland. Illuminated is the importance of protecting oneself and the family dignity, a fear of being rejected and mistrusted, how the juridical system exists in the shadow of tradition and potential keys to healthcare support. The study raises awareness of the dilemmas which may be faced by young women subjected to non-partner sexual violence and healthcare providers in the intersection between state and traditional norms. Education is a key when it comes to a young woman considering the use of the services available in a society where traditional problem-solving is relied on parallel to state-based support. State-based functions, communities and families need to work together to provide comprehensive support to young female survivors of non-partner sexual violence in Somaliland.


Comparative anti-inflammatory characterization of wild fruiting body, liquid-state fermentation, and solid-state culture of Taiwanofungus camphoratus in microglia and the mechanism of its action.
Taiwanofungus camphoratus (syn. Antrodia camphorata), a medicinal mushroom in Taiwan, is reputed to provide several therapeutic benefits, but the wild fruiting body is very rare. In this study, we used Taiwanofungus camphoratus extracts from wild fruiting bodies and two types of artificial cultivation (solid-state culture and liquid-state fermentation) to examine their anti-inflammatory effects in microglia cells and their possible roles in protection against neurodegenerative diseases. First, EOC13.31 microglia was treated with various kinds of Taiwanofungus camphoratus extracts and lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) to evaluate the iNOS expression. Western blot and RT-PCR analysis showed that among the various kinds of extracts from wild fruiting bodies, methanol extracts were the most potent inhibitors of iNOS expression. Secondly, the potency of methanol extracts could be ranked as follows: extracts of wild fruiting body>solid-state culture>liquid-state fermentation. To clarify the mechanisms involved, methanol extracts from fruiting body were found to inhibit the phosphorylation of extracellular signal-regulated protein kinases (ERK), c-Jun NH2-terminal protein kinases (JNK) and signal transducer and activator of transcription-1 (STAT-1) induced by LPS/IFN-gamma. Methanol extracts from fruiting body also inhibited NF-kappaB activation through the prevention of inhibitor kappaB (IkappaB) degradation. Moreover, methanol extracts from wild fruiting body inhibited both the iNOS and cyclooxygenase-2 (COX-2) expression induced by beta-amyloid in microglia in a dose-dependent manner. In an animal model, we confirmed that methanol extracts from fruiting bodies were able to suppress ear edema, indicating that they have anti-inflammatory activity in vivo. These results suggest that Taiwanofungus camphoratus exhibits an anti-inflammatory activity that might contribute to the prevention of neurodegenerative diseases.


Human prion protein cDNA: molecular cloning, chromosomal mapping, and biological implications.
A human complementary DNA whose protein product is considered to be the major component of scrapie-associated fibrils in Creutzfeldt-Jakob disease, kuru, and Gerstmann-Straussler syndrome has been identified and characterized. The extensive homology of this gene sequence to the hamster PrP 27- to 30-kilodalton prion protein complementary DNA clone, and its existence as a single copy in the human genome, leads to the conclusion that this is the human prion gene. This human prion gene has been mapped to human chromosome 20, negating a direct link between the prion protein and Down's syndrome or the amyloid of Alzheimer's disease.


Valence asymmetries in the human amygdala: task relevance modulates amygdala responses to positive more than negative affective cues.
Organisms must constantly balance appetitive needs with vigilance for potential threats. Recent research suggests that the amygdala may play an important role in both of these goals. Although the amygdala plays a role in processing motivationally relevant stimuli that are positive or negative, negative information often appears to carry greater weight. From a functional perspective, this may reflect the fact that threatening stimuli generally require action, whereas appetitive stimuli can often be safely ignored. In this study, we examine whether amygdala activation to positive stimuli may be more sensitive to task goals than negative stimuli, which are often related to self-preservation concerns. During fMRI, participants were presented with two images that varied on valence and extremity and were instructed to focus on one of the images. Results indicated that negative stimuli elicited greater amygdala activity regardless of task relevance. In contrast, positive stimuli only led to a relative increase in amygdala activity when they were task relevant. This suggests that the amygdala may be more responsive to negative stimuli regardless of their relevance to immediate goals, whereas positive stimuli may only elicit amygdala activity when they are relevant to the perceivers' goals. This pattern of valence asymmetry in the human amygdala may help balance approach-related goal pursuit with chronic self-preservation goals.


CD14 and complement crosstalk and largely mediate the transcriptional response to Escherichia coli in human whole blood as revealed by DNA microarray.
Systemic inflammation like in sepsis is still lacking specific diagnostic markers and effective therapeutics. The first line of defense against intruding pathogens and endogenous damage signals is pattern recognition by e.g., complement and Toll-like receptors (TLR). Combined inhibition of a key complement component (C3 and C5) and TLR-co-receptor CD14 has been shown to attenuate certain systemic inflammatory responses. Using DNA microarray and gene annotation analyses, we aimed to decipher the effect of combined inhibition of C3 and CD14 on the transcriptional response to bacterial challenge in human whole blood. Importantly, combined inhibition reversed the transcriptional changes of 70% of the 2335 genes which significantly responded to heat-inactivated Escherichia coli by on average 80%. Single inhibition was less efficient (p<0.001) but revealed a suppressive effect of C3 on 21% of the responding genes which was partially counteracted by CD14. Furthermore, CD14 dependency of the Escherichia coli-induced response was increased in C5-deficient compared to C5-sufficient blood. The observed crucial distinct and synergistic roles for complement and CD14 on the transcriptional level correspond to their broad impact on the inflammatory response in human blood, and their combined inhibition may become inevitable in the early treatment of acute systemic inflammation.


Health insurance coverage and prescription contraceptive use among young women at risk for unintended pregnancy.
This study investigates the relationships between health insurance coverage and prescription contraceptive use among women 18-24 years of age at risk for unintended pregnancy. Data from the 2002 National Survey of Family Growth were analyzed. The sample comprised 1049 women 18-24 years of age at risk for unintended pregnancy. Multivariate logistic regression analysis was employed to examine the likelihood of prescription contraceptive use (1) between uninsured women versus ones with private insurance, Medicaid or another form of government insurance and (2) between those who had consistent versus inconsistent insurance coverage, after adjusting for a range of sociodemographic and sexual health factors. Twenty percent of the participants were uninsured and over 30% had inconsistent coverage. Only 55% were currently using prescription contraceptives. In multivariate analyses, young women with private insurance or Medicaid were more likely than the uninsured to use prescription contraceptives. No significant differences in prescription contraceptive use were found between other forms of government insurance and uninsurance or between consistent and inconsistent coverage. Access to comprehensive health insurance should be considered one strategy to address the high rates of unintended pregnancy among this vulnerable population.


A new, highly precise measurement technology for the in vitro evaluation of the accuracy of digital imaging data.
Three-dimensional radiological imaging data play an increasingly role in planning, simulation, and navigation in oral and maxillofacial surgery. The aim of this study was to establish a new, highly precise, in vitro measurement technology for the evaluation of the geometric accuracy down to the micrometric range of digital imaging data. A macerated human mandible was scanned optically with an industrial, non-contact, white light scanner, and a three-dimensional (3D) model was obtained, which served as a master model. The mandible was then scanned 10 times by cone beam computed tomography (CBCT), and the generated 3D surface bone model was virtually compared with the master model. To evaluate the accuracy of the CBCT scans, the standard deviation and the intraclass coefficient were determined. A total of 19 measurement points in 10 CBCT scans were investigated, and showed an average value of 0.2676 mm with a standard deviation of 0.0593 mm. The standard error of the mean was 0.0043 mm. The intraclass correlation coefficient (ICC) within the 10 CBCT scans was 0.9416. This highly precise measuring technology was demonstrated to be appropriate for the evaluation of the accuracy of digital imaging data, down to the micrometric scale. This method is able to exclude human measurement errors, as the software calculates the superimposition and deviation. Thus inaccuracies caused by measurement errors can be avoided. This method provides a highly precise determination of deviations of different CBCT parameters and 3D models for surgical, navigational, and diagnostic purposes. Thus, surgical procedures and the post-operative outcomes can be precisely simulated to benefit the patient.


Distinct transcriptional changes in donor kidneys upon brain death induction in rats: insights in the processes of brain death.
Brain death affects hormone regulation, inflammatory reactivity and hemodynamic stability. In transplant models, donor organs retrieved from brain dead (BD) rats suffer from increased rates of primary non-function and lower graft survival. To unravel the mechanisms behind brain death we have performed DNA microarray studies with kidney-derived RNA from normo- and hypotensive BD rats, corresponding with optimal and marginal BD donors, respectively. In kidneys from normotensive donors 63 genes were identified as either up- (55) or down-regulated (8), while 90 genes were differentially expressed (67 up-regulated) in hypotensive BD donor kidneys. Most genes were categorized in different functional groups: metabolism/transport (including the down-regulated water channel Aqp-2), inflammation/coagulation (containing the largest number (16) of up-regulated genes including selectins, Il-6, alpha- and beta-fibrinogen), cell division/fibrosis (including KIM-1 involved in tubular regeneration) and defense/repair (with the cytoprotective genes HO-1, Hsp70, MnSOD2). Also, genes encoding transcription factors (including immediate early genes as Atf-3, Egr-1) and proteins involved in signal transduction (Pik3r1) were identified. Summarizing, the use of DNA microarrays has clarified parts of the process of brain death: Brain-death-induced effects ultimately lead, via activation of transcription factors and signal transduction cascades, to differential expression of different "effector" genes. Not only deleterious processes such as inflammation and fibrosis occur in brain dead donor kidneys but genes involved in protection and early repair processes are activated as well. These findings can be used to introduce specific cytoprotective interventions in the brain dead donor to better maintain or even increase organ viability.


Continental Survey of Access to Diagnostic Tools and Endovascular Management of Aneurysmal Subarachnoid Hemorrhage in Africa.
Rationale: Interventional neurovascular procedures are effective in lowering the burden of mortality and complications resulting from aneurysmal subarachnoid hemorrhage (aSAH). Despite the wide uptake of interventional neurovascular procedures in high-income countries, access to care in low- and middle-income countries remains limited, and little is known about accessibility in Africa. In this survey, we decided to assess access to diagnostic tools and treatment of aSAH in Africa. Methodology: A Google form e-survey was distributed to African neurosurgery centers accepting responses from January 4th to March 21st 2021. Data on accessibility to diagnostic tools, treatment methodologies, and interventional neuroradiology personnel in African centers were collected. Ninety five percent confidence intervals were computed for each variable. Results: Data was received from 36 neurosurgical centers in 16 African countries (16/54, 30%). Most centers were public institutions. Ninety four percent of the centers had the necessary resources for a lumbar puncture (LP) and a laboratory for the diagnosis of aSAH. Most centers had at least one computed tomography (CT) scanner, 81% of the centers had access to CT angiography and some had access to conventional angiography. Forty seven percent of the centers could obtain a head CT within 2 h of presentation in an emergency. Sixty one percent of centers provided clipping of intracranial aneurysms whilst only 22% of centers could perform the endovascular treatment. Sixty four percent of centers did not have an endovascular specialist. Conclusion: This survey highlights health inequity in access to endovascular treatment for aSAH. Lack of diagnostic tools to identify an aneurysm and a shortfall of qualified endovascular specialists are prime reasons for this. Our findings can inform health system strengthening policies including the acquisition of equipment and capacity building in Africa.


EasyPCC: Benchmark Datasets and Tools for High-Throughput Measurement of the Plant Canopy Coverage Ratio under Field Conditions.
Understanding interactions of genotype, environment, and management under field conditions is vital for selecting new cultivars and farming systems. Image analysis is considered a robust technique in high-throughput phenotyping with non-destructive sampling. However, analysis of digital field-derived images remains challenging because of the variety of light intensities, growth environments, and developmental stages. The plant canopy coverage (PCC) ratio is an important index of crop growth and development. Here, we present a tool, EasyPCC, for effective and accurate evaluation of the ground coverage ratio from a large number of images under variable field conditions. The core algorithm of EasyPCC is based on a pixel-based segmentation method using a decision-tree-based segmentation model (DTSM). EasyPCC was developed under the MATLAB® and R languages; thus, it could be implemented in high-performance computing to handle large numbers of images following just a single model training process. This study used an experimental set of images from a paddy field to demonstrate EasyPCC, and to show the accuracy improvement possible by adjusting key points (e.g., outlier deletion and model retraining). The accuracy (R² = 0.99) of the calculated coverage ratio was validated against a corresponding benchmark dataset. The EasyPCC source code is released under GPL license with benchmark datasets of several different crop types for algorithm development and for evaluating ground coverage ratios.


Improving the Impact and Implementation of Disaster Education: Programs for Children Through Theory-Based Evaluation.
A main weakness in the evaluation of disaster education programs for children is evaluators' propensity to judge program effectiveness based on changes in children's knowledge. Few studies have articulated an explicit program theory of how children's education would achieve desired outcomes and impacts related to disaster risk reduction in households and communities. This article describes the advantages of constructing program theory models for the purpose of evaluating disaster education programs for children. Following a review of some potential frameworks for program theory development, including the logic model, the program theory matrix, and the stage step model, the article provides working examples of these frameworks. The first example is the development of a program theory matrix used in an evaluation of ShakeOut, an earthquake drill practiced in two Washington State school districts. The model illustrates a theory of action; specifically, the effectiveness of school earthquake drills in preventing injuries and deaths during disasters. The second example is the development of a stage step model used for a process evaluation of What's the Plan Stan?, a voluntary teaching resource distributed to all New Zealand primary schools for curricular integration of disaster education. The model illustrates a theory of use; specifically, expanding the reach of disaster education for children through increased promotion of the resource. The process of developing the program theory models for the purpose of evaluation planning is discussed, as well as the advantages and shortcomings of the theory-based approaches.


Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis.
Acute gastrointestinal infections due to rotaviruses and other enteric pathogens are major causes of morbidity and mortality in infants and young children throughout the world. Breast-feeding can reduce the rate of serious gastroenteritis in infants; however, the degrees of protection offered against rotavirus infection vary in different populations. The mechanisms associated with milk-mediated protection against viral gastroenteritis have not been fully elucidated. We have isolated a macromolecular component of human milk that inhibits the replication of rotaviruses in tissue culture and prevents the development of gastroenteritis in an animal model system. Purification of the component indicates that the antiviral activity is associated with an acidic fraction (pI = 4.0-4.6), which is free of detectable immunoglobulins. Furthermore, high levels of antiviral activity are associated with an affinity-purified complex of human milk mucin. Deglycosylation of the mucin complex results in the loss of antiviral activity. Further purification indicated that rotavirus specifically binds to the milk mucin complex as well as to the 46-kD glycoprotein component of the complex. Binding to the 46-kD component was substantially reduced after chemical hydrolysis of sialic acid. We have documented that human milk mucin can bind to rotavirus and inhibit viral replication in vitro and in vivo. Variations in milk mucin glycoproteins may be associated with different levels of protection against infection with gastrointestinal pathogens.


Screening in silico predicted remotely acting NF1 gene regulatory elements for mutations in patients with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1), a neuroectodermal disorder, is caused by germline mutations in the NF1 gene. NF1 affects approximately 1/3,000 individuals worldwide, with about 50% of cases representing de novo mutations. Although the NF1 gene was identified in 1990, the underlying gene mutations still remain undetected in a small but obdurate minority of NF1 patients. We postulated that in these patients, hitherto undetected pathogenic mutations might occur in regulatory elements far upstream of the NF1 gene. In an attempt to identify such remotely acting regulatory elements, we reasoned that some of them might reside within DNA sequences that (1) have the potential to interact at distance with the NF1 gene and (2) lie within a histone H3K27ac-enriched region, a characteristic of active enhancers. Combining Hi-C data, obtained by means of the chromosome conformation capture technique, with data on the location and level of histone H3K27ac enrichment upstream of the NF1 gene, we predicted in silico the presence of two remotely acting regulatory regions, located, respectively, approximately 600 kb and approximately 42 kb upstream of the NF1 gene. These regions were then sequenced in 47 NF1 patients in whom no mutations had been found in either the NF1 or SPRED1 gene regions. Five patients were found to harbour DNA sequence variants in the distal H3K27ac-enriched region. Although these variants are of uncertain pathological significance and still remain to be functionally characterized, this approach promises to be of general utility for the detection of mutations underlying other inherited disorders that may be caused by mutations in remotely acting regulatory elements.


A systematic review of stenting and angioplasty of symptomatic extracranial vertebral artery stenosis.
Extracranial vertebral artery stenosis (ECVAS) is common among patients with ischemic stroke. Despite the limited knowledge of the natural history of patients with symptomatic vertebral disease, endovascular revascularization techniques are now utilized in clinical practice. We sought to determine the risk of endovascular treatment for ECVAS with a systematic review of the literature. A search strategy was used using the terms "stenting," "vertebral," "ostium," "origin," and "extracranial" through Medline. All articles were reviewed along with their references to determine the risk and durability of endovascular treatment. A total of 27 articles were identified that met inclusion criterion, with a total of 980 of 993 patients treated with stents. The majority of patients (56%) were noted to have contralateral vertebral artery stenosis or occlusion and 92% were symptomatic at the time of treatment. A total of 11 patients (1.1%) experienced a stroke and 8 (0.8%) experienced a transient ischemic attack within 30 days of the procedure. Drug-eluting stents were associated with lower restenosis rates (11%) compared to bare metal stents (30%) at a mean of 24 months of follow-up. Stenting and angioplasty of ECVAS appear to have a low rate of periprocedural stroke or transient ischemic attack and restenosis rates that may not be as high as suspected. Given the frequency of ECVAS as an etiology for ischemic stroke, future studies aimed at determining efficacy of this treatment modality relative to medical therapy would be of benefit to clinicians caring for these patients.


Leaky channels make weak muscles.
Mutations in the skeletal muscle voltage-gated calcium channel (CaV1.1) have been associated with hypokalemic periodic paralysis, but how the pathogenesis of this disorder relates to the functional consequences of mutations was unclear. In this issue of the JCI, Wu and colleagues recapitulate the disease by generating a novel knock-in CaV1.1 mutant mouse and use this model to investigate the cellular and molecular features of pathogenesis. They demonstrated an aberrant muscle cell current conducted through the CaV1.1 voltage-sensor domain (gating pore current) that explains an abnormally depolarized muscle membrane and the failure of muscle action potential firing during challenge with agents known to provoke periodic paralysis. Their work advances understanding of molecular and cellular mechanisms underlying an inherited channelopathy.


Assessing the psychological health of captive and wild apes: a response to Ferdowsian et al. (2011).
As many studies of cognition and behavior involve captive animals, assessing any psychological impact of captive conditions is an important goal for comparative researchers. Ferdowsian and colleagues (2011) sought to address whether captive chimpanzees show elevated signs of psychopathology relative to wild apes. They modified a checklist of diagnostic criteria for major depression and posttraumatic stress disorder in humans, and applied these criteria to various captive and wild chimpanzee populations. We argue that measures derived from human diagnostic criteria are not a powerful tool for assessing the psychological health of nonverbal animals. In addition, we highlight certain methodological drawbacks of the specific approach used by Ferdowsian and colleagues (2011). We propose that research should (1) focus on objective behavioral criteria that account for species-typical behaviors and can be reliably identified across populations; (2) account for population differences in rearing history when comparing how current environment impacts psychological health in animals; and (3) focus on how changes in current human practices can improve the well-being of both captive and wild animals.


Cholecystokinin release from the rat caudate-putamen, cortex and hippocampus is increased by activation of the D1 dopamine receptor.
Studies were undertaken to examine the role of dopamine in the regulation of cholecystokinin (CCK) release in slices of the rat caudate-putamen (CP), a region where both neuroactive substances are abundant yet not extensively colocalized. It was found that dopamine, acting through a D1 dopamine receptor, is a major factor regulating CCK release in this tissue. Haloperidol and the selective D1 antagonist, SKF 83566, but not the D2 antagonist, sulpiride, inhibited potassium-evoked release from CP slices. Apomorphine enhanced both basal and potassium-evoked release, an effect which was reversed by (+/-)SKF 83566, but not by sulpiride. The D1 agonist, (+)SKF 38393, displayed agonist and antagonist activity in this system, whereas the D2 agonist, quinpirole, had no effect. Depletion of endogenous dopamine by pretreatment of animals with alpha-methyl-para-tyrosine decreased potassium-induced release by 45%, and in these animals, haloperidol no longer inhibited release. These dopaminergic agents altered CCK release in cortex and hippocampus in a similar fashion, although those tissues were less sensitive to their effects. These results suggest that dopamine, acting through D1 receptors, increases CCK release in CP, cortex and hippocampus. The results of previous studies showing that phorbol esters increase CCK release and that occupation of D1 receptors increases phosphoinositol turnover make it possible to hypothesize that dopamine, acting through D1 receptors, is increasing CCK release by increasing phosphoinositol turnover. Further studies will be required to verify this hypothesis and to determine whether dopamine is acting directly or indirectly to modulate CCK release.


Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine.
We report five cases of restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) that were probably associated with olanzapine. The first patient showed a good response to olanzapine, but the RLS symptoms associated with olanzapine resulted in poor long-term compliance, eventually leading to frequent relapse of psychotic symptoms. The second patient exhibited sudden PLMS following olanzapine injection. The third patient had been suffering from serious akathisia while on risperidone, and was cured after switching to olanzapine, but thereafter the patient suffered from RLS at nighttime. The fourth patient showed RLS symptoms that were initially caused by a 20-mg daily olanzapine dosage and were later mitigated when olanzapine was reduced and ropinirole was administered. The fifth patient exhibited paraesthesia and agitation caused by olanzapine that was misdiagnosed as psychotic agitation. Increasing the olanzapine dosage severely aggravated the symptoms of RLS. Antipsychotic-induced RLS and PLMS are not well-recognized side effects of antipsychotics, with the symptoms often misdiagnosed as psychotic agitation. These cases also suggest that the occurrence of RLS can cause noncompliance with antipsychotics in psychiatric patients, and thus aggravate their psychotic symptoms.


A self-powered brain-linked biosensing electronic-skin for actively tasting beverage and its potential application in artificial gustation.
A new self-powered brain-linked biosensing electronic-skin (e-skin) for detecting pH value and alcoholicity of beverages has been realized based on polydimethysiloxane/polypyrrole (PDMS/Ppy) nanostructures. This e-skin (linking brain and transmitting signal to the specific encephalic region) can work as an artificial gustation system for gustatory perception substitution without an external electricity source. The sensing units on the e-skin can efficiently convert mechanical energy (human motion) into triboelectric impulse. The triboelectric output can be influenced by pH value and alcohol concentration in common beverages (acidic, alkaline or alcoholic drinks), which can be treated as the bio-chemical sensing signal. The bio-chemical sensing behavior arises from the triboelectrification/bio-chemical-sensing coupling effect. The biosensing e-skin is simply linked to the brain of a mouse at the primary motor cortex area, and the inputting signal can take part in the mouse perception, thus realizing behavior interventions, e.g., shaking of legs. This study provides a novel approach for developing artificial gustation e-skin and self-powered brain-machine interaction system with low cost.


Drinking, drugs and driving in Ireland: more evidence for action.
To examine the prevalence of drug positivity among drivers suspected of driving under the influence of an intoxicant, and consequently apprehended by the police in Ireland. 2000 specimens were selected for drug analysis, 1000 with results under the limit for alcohol and 1000 over the limit. The limit for alcohol is 80 mg/100 ml in blood and 107 mg/100 ml in urine. Seven drugs/drug classes were examined; amphetamines, methamphetamines, benzodiazapines, cannabinoids, cocaine, opiates and methadone. 331 (33.1%) of the drivers under the legal limit for alcohol tested positive for one or more of the relevant drugs, and the corresponding figures of drivers over the limit was 142 (14.2%; p<0.001). Using weighted analysis, this corresponds to 15.7% (95% confidence interval (CI) 13.5% to 18.1%) of all tested drivers (15.8% in men and 14.5% in women). Among drivers who had minimal blood alcohol levels, 67.9% (95% CI 61.2% to 74.1%) were taking at least one type of drug. The prevalence of taking drugs reduced steadily as alcohol concentrations increased, but still remained as high as 11.1% (95% CI 8.3% to 14.6%) for drivers with blood alcohol concentrations >200 mg/100 ml. Being under the limit for alcohol, stopped in a city area, stopped between 6 am and 4 pm, or 4 pm and 9 pm, and being of a younger age were each independently associated with drug positivity. There are immediate implications for the evidential breath alcohol program and for checkpoints; in the event of a nil or low alcohol reading being obtained, a separate blood or urine specimen should be sought for analysis, which is currently non-routine.


Effects of the Addition of a Dual Task to a Supervised Physical Exercise Program on Older Adults' Cognitive Performance.
The purpose of this study was to investigate the effects of the addition of a dual task to multicomponent training on cognition of active older adults. Eighty physically active older adults were divided into an intervention group (IG) and a control group (CG). Both groups performed multicomponent training over 12 weeks. The IG simultaneously performed exercises and cognitive tasks. The Mini-Mental State Examination, the Montreal Cognitive Assessment, and the Clock Drawing Test were used for cognitive assessments. The Timed Up and Go Test associated with a cognitive task was used for dual-task assessment. Significant interactions were not observed between groups in terms of the cognitive variables or the dual-task performance. An interaction was observed only for Timed Up and Go Test performance, which was better in the CG than in the IG. Active older adults showed no improvement in cognition following the addition of the dual task to the multicomponent training.


Signs of Imminent Dying and Change in Symptom Intensity During Pharmacological Treatment in Dying Nursing Home Patients: A Prospective Trajectory Study.
To investigate whether it is possible to determine signs of imminent dying and change in pain and symptom intensity during pharmacological treatment in nursing home patients, from day perceived as dying and to day of death. Prospective, longitudinal trajectory trial. Forty-seven nursing homes within 35 municipalities of Norway. A total of 691 nursing home patients were followed during the first year after admission and 152 were assessed carefully in their last days of life. Time between admission and day of death, and symptom severity by Edmonton symptom assessment system (ESAS), pain (mobilization-observation-behavior-intensity-dementia-2), level of dementia (clinical dementia rating scale), physical function (Karnofsky performance scale), and activities of daily living (physical self-maintenance scale). Twenty-five percent died during the first year after admission. Increased fatigue (logistic regression, odds ratio [OR] 1.8, P = .009) and poor appetite (OR 1.2, P = .005) were significantly associated with being able to identify the day a person was imminently dying, which was possible in 61% of the dying (n = 82). On that day, the administration of opioids, midazolam, and anticholinergics increased significantly (P < .001), and was associated with amelioration of symptoms, such as pain (mixed-models linear regression, 60% vs 46%, P < .001), anxiety (44% vs 31%, P < .001), and depression (33% vs 15%, P < .001). However, most symptoms were still prevalent at day of death, and moderate to severe dyspnea and death rattle increased from 44% to 53% (P = .040) and 8% to 19% (P < .001), respectively. Respiratory symptoms were not associated with opioids or anticholinergics. Pharmacological treatment ameliorated distressing symptoms in dying nursing home patients; however, most symptoms, including pain and dyspnea, were still common at day of death. Results emphasize critical needs for better implementation of guidelines and staff education. ClinicalTrials.govNCT01920100.


Functional network centrality in obesity: A resting-state and task fMRI study.
Obesity is associated with structural and functional alterations in brain areas that are often functionally distinct and anatomically distant. This suggests that obesity is associated with differences in functional connectivity of regions distributed across the brain. However, studies addressing whole brain functional connectivity in obesity remain scarce. Here, we compared voxel-wise degree centrality and eigenvector centrality between participants with obesity (n=20) and normal-weight controls (n=21). We analyzed resting state and task-related fMRI data acquired from the same individuals. Relative to normal-weight controls, participants with obesity exhibited reduced degree centrality in the right middle frontal gyrus in the resting-state condition. During the task fMRI condition, obese participants exhibited less degree centrality in the left middle frontal gyrus and the lateral occipital cortex along with reduced eigenvector centrality in the lateral occipital cortex and occipital pole. Our results highlight the central role of the middle frontal gyrus in the pathophysiology of obesity, a structure involved in several brain circuits signaling attention, executive functions and motor functions. Additionally, our analysis suggests the existence of task-dependent reduced centrality in occipital areas; regions with a role in perceptual processes and that are profoundly modulated by attention.


The perivitelline space-forming capacity of mouse oocytes is associated with meiotic competence.
Although mouse oocytes progressively acquire meiotic competence during their growth in the ovaries, only half of full-grown oocytes can accomplish meiosis. Two types of full-grown oocytes have been reported on the basis of their chromatin configuration, the surrounded-nucleolus (SN) type and the non-surrounded-nucleolus (NSN) type. Therefore, full-grown oocytes collected from the ovaries of adult animals comprise a heterogeneous population; some oocytes are meiotically incompetent (NSN-type), and some are competent (SN-type). In the present study, we found that full-grown oocytes could be classified into two groups using the criterion of formation of the perivitelline space (PVS) after culture with 3-isobutyl-1-methylxanthine (IBMX) for 1 h. In oocytes with a PVS, actin-filled processes within zona pellucidae originating from cumulus cells were reduced, while they were rich in oocytes without a PVS, suggesting that a reduction in these processes contributes to PVS formation. PVS formation was highly correlated with meiotic competence and SN-type configuration. The results of this study demonstrate that PVS formation is a useful criterion for easily distinguishing between SN- and NSN-type oocytes, without injury to the cells.


Social Consequences of Ebola Containment Measures in Liberia.
In the Ebola Virus Disease (EVD) outbreak in Liberia, two major emergency disease-control measures were cremation of bodies and enforcement of quarantine for asymptomatic individuals suspected of being in contact with a positive case. Enforced by State-related actors, these were promoted as the only method to curtail transmissions as soon as possible. However, as with other harsh measures witnessed by Liberian citizens, in many cases those measures elicited uncontrolled negative reactions within the communities (stigma; fear) that produced, in some cases, the opposite effect of that intended. The research has been conducted in two phases, for a total of 8 weeks. Ethnography of local practices was carried out in 7 neighbourhoods in Monrovia and 5 villages in Grand Cape Mount County in Liberia. 45 Focus Group Discussions (432 participants) and 30 semi-structured interviews sustained the observing participation. Randomly selected people from different social layers were targeted. The principal investigator worked with the help of two local assistants. Perceptions and practices were both analysed. Participants stressed how cremation perpetuated the social breakdown that started with the isolation for the sickness. Socio-economical divides were created by inequitable management of the dead: those who could bribe the burial teams obtained a burial in a private cemetery or the use of Funeral Homes. Conversely, those in economic disadvantage were forced to send their dead for cremation. State-enforced quarantine, with a mandatory prohibition of movement, raised condemnation, strengthened stigmatization and created serious socio-economic distress. Food was distributed intermittently and some houses shared latrines with non-quarantined neighbours. Escapes were also recorded. Study participants narrated how they adopted local measures of containment, through local task forces and socially-rooted control of outsiders. They also stressed how information that was not spread built up rumours and suspicion. Populations experiencing an epidemic feel a high degree of social insecurity, in addition to the health hazards. Vertical and coercive measures increase mistrust and fear, producing a counter-productive effect in the containment of the epidemic. On the other hand, local communities show a will to be engaged and a high degree of flexibility in participating to the epidemic response. Efforts in the direction of awareness and community involvement could prove to be better strategy to control the epidemic and root the response on social participation.


Sectional matrix: Step-by-step directions for their clinical use.
The sectional matrix is the best way to achieve a strong contact point in Class II restorations with composite resin in the posterior dental sector. The pre-wedging is essential to get a separation between teeth which avoid the matrix deformation during its insertion. This article describes the clinical technique for restoring Class II cavities using a sectional matrix.


Hydroxyl radical generation by an extracellular low-molecular-weight substance and phenol oxidase activity during wood degradation by the white-rot basidiomycete Trametes versicolor.
One-electron oxidation activity, as measured by ethylene generation from 2-keto-4-thiomethylbutyric acid, phenol oxidase activity, and the generation of hydroxyl radical were examined in cultures of the lignin-degrading white-rot basidiomycete fungus, Trametes (Coriolus) versicolor. The activity levels of specific lignin-degrading enzymes and cellulases, as well as the rate of wood degradation, also were examined. The fungus secreted a low-molecular-weight substance (M(r) 1000-5000) that catalyzed a redox reaction between molecular oxygen and an electron donor, to produce the hydroxyl radical via hydrogen peroxide. During wood decay, T. versicolor also produced significant amounts of laccase and lignin peroxidase, carboxymethyl cellulase, and Avicelase. The roles of the hydroxyl radical, phenol oxidases, and cellulases in wood degradation by white-rot fungi are discussed. That the hydroxyl radical produced by the low-molecular-weight substance secreted by T. versicolor results in new phenolic substructures on the lignin polymer, making it susceptible to attack by laccase or manganese peroxidase is suggested.


Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor.
The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.


Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.
Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract. We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression. HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63). These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.


STRSeq: A catalog of sequence diversity at human identification Short Tandem Repeat loci.
The STR Sequencing Project (STRSeq) was initiated to facilitate the description of sequence-based alleles at the Short Tandem Repeat (STR) loci targeted in human identification assays. This international collaborative effort, which has been endorsed by the ISFG DNA Commission, provides a framework for communication among laboratories. The initial data used to populate the project are the aggregate alleles observed in targeted sequencing studies across four laboratories: National Institute of Standards and Technology (N=1786), Kings College London (N=1043), University of North Texas Health Sciences Center (N=839), and University of Santiago de Compostela (N=944), for a total of 4612 individuals. STRSeq data are maintained as GenBank records at the U.S. National Center for Biotechnology Information (NCBI), which participates in a daily data exchange with the DNA DataBank of Japan (DDBJ) and the European Nucleotide Archive (ENA). Each GenBank record contains the observed sequence of a STR region, annotation ("bracketing") of the repeat region and flanking region polymorphisms, information regarding the sequencing assay and data quality, and backward compatible length-based allele designation. STRSeq GenBank records are organized within a BioProject at NCBI (https://www.ncbi.nlm.nih.gov/bioproject/380127), which is sub-divided into: commonly used autosomal STRs, alternate autosomal STRs, Y-chromosomal STRs, and X-chromosomal STRs. Each of these categories is further divided into locus-specific BioProjects. The BioProject hierarchy facilitates access to the GenBank records by browsing, BLAST searching, or ftp download. Future plans include user interface tools at strseq.nist.gov, a pathway for submission of additional allele records by laboratories performing population sample sequencing and interaction with the STRidER web portal for quality control (http://strider.online).


Genetic influences on the central nervous system depressant and membrane-disordering actions of ethanol and sodium valproate.
The effects of the two central nervous system (CNS) depressant drugs ethanol and sodium valproate were compared using two pairs of mouse lines that had been selected from a heterogeneous stock for differential sensitivity to ethanol. The LS/SS lines differ in sensitivity to ethanol-induced sedation, and the WSP/WSR lines differ in the severity of their withdrawal convulsions after chronic ethanol treatment. We used these lines to test the hypothesis that ethanol and valproate act by the same mechanism. CNS depressant action was assessed by determining the brain drug concentration at which the mice lost their ability to balance on a stationary wooden dowel. LS mice were about twice as sensitive as SS mice to valproate-induced ataxia, in agreement with their reported relative sensitivity to ethanol. The WSR and WSP mice did not differ significantly in sensitivity to ethanol or valproate in this test. The intrinsic order and sensitivity to disordering of synaptosomal plasma membranes prepared from the four lines were measured using fluorescence polarization with the probe 1,6-diphenyl-1,3,5-hexatriene and EPR spectroscopy with 5-doxylstearic acid. No differences in the intrinsic membrane order of the four lines were detected with either technique. The sensitivities of the membranes from the four lines to ethanol- or valproate-induced disordering were not significantly different when measured by fluorescence polarization, but EPR spectroscopy revealed line differences in disordering sensitivity that correlated with the relative sensitivity of the four lines to the CNS depressant action of these drugs. These studies show that genetic factors modulate sensitivity to ethanol and valproate in a similar manner both in vivo and in vitro, suggesting that these drugs act by the same membrane-disordering mechanism.


The Nimrod transmembrane receptor Eater is required for hemocyte attachment to the sessile compartment in Drosophila melanogaster.
Eater is an EGF-like repeat transmembrane receptor of the Nimrod family and is expressed in Drosophila hemocytes. Eater was initially identified for its role in phagocytosis of both Gram-positive and Gram-negative bacteria. We have deleted eater and show that it appears to be required for efficient phagocytosis of Gram-positive but not Gram-negative bacteria. However, the most striking phenotype of eater deficient larvae is the near absence of sessile hemocytes, both plasmatocyte and crystal cell types. The eater deletion is the first loss of function mutation identified that causes absence of the sessile hemocyte state. Our study shows that Eater is required cell-autonomously in plasmatocytes for sessility. However, the presence of crystal cells in the sessile compartment requires Eater in plasmatocytes. We also show that eater deficient hemocytes exhibit a cell adhesion defect. Collectively, our data uncovers a new requirement of Eater in enabling hemocyte attachment at the sessile compartment and points to a possible role of Nimrod family members in hemocyte adhesion.


Modeling developmental changes in yo-yo intermittent recovery test level 1 in elite pubertal soccer players.
To model the development of soccer-specific aerobic performance, assessed by the Yo-Yo Intermittent Recovery Test Level 1 in 162 elite pubertal soccer players, age 11-14 y at baseline. Longitudinal multilevel modeling analyses comprised predictors related to growth (chronological age, body size [height and weight] and composition [fat mass, fat-free mass]), and motor coordination [3 KÖrperkoordination Test für Kinder subtests: jumping sideways, moving sideways, backward balancing] and estimated biological-maturation groups (earliest [<percentile 33] and latest maturers [>percentile 66]). The best-fitting model on soccer-specific aerobic performance could be expressed as -3639.76 + 369.86 × age + 21.38 × age² + 9.12 × height - 29.04 × fat mass + 0.06 × backward balance. Maturity groups had a negligible effect on soccer-specific aerobic performance (-45.32 ± 66.28; P > .05). The current study showed that the development of aerobic performance in elite youth soccer is related to growth and muscularity and emphasized the importance of motor coordination in the talent-identification and -development process. Note that biological maturation was excluded from the model, which might endorse the homogeneity in estimated biological-maturation status in the current elite pubertal soccer sample.


Biotic mechanisms of community stability shift along a precipitation gradient.
Understanding how biotic mechanisms confer stability in variable environments is a fundamental quest in ecology, and one that is becoming increasingly urgent with global change. Several mechanisms, notably a portfolio effect associated with species richness, compensatory dynamics generated by negative species covariance and selection for stable dominant species populations can increase the stability of the overall community. While the importance of these mechanisms is debated, few studies have contrasted their importance in an environmental context. We analyzed nine long-term data sets of grassland species composition to investigate how two key environmental factors, precipitation amount and variability, may directly influence community stability and how they may indirectly influence stability via biotic mechanisms. We found that the importance of stability mechanisms varied along the environmental gradient: strong negative species covariance occurred in sites characterized by high precipitation variability, whereas portfolio effects increased in sites with high mean annual precipitation. Instead of questioning whether compensatory dynamics are important in nature, our findings suggest that debate should widen to include several stability mechanisms and how these mechanisms vary in importance across environmental gradients.


Population rate-coding predicts correctly that human sound localization depends on sound intensity.
Human sound localization is an important computation performed by the brain. Models of sound localization commonly assume that sound lateralization from interaural time differences is level invariant. Here we observe that two prevalent theories of sound localization make opposing predictions. The labelled-line model encodes location through tuned representations of spatial location and predicts that perceived direction is level invariant. In contrast, the hemispheric-difference model encodes location through spike-rate and predicts that perceived direction becomes medially biased at low sound levels. Here, behavioral experiments find that softer sounds are perceived closer to midline than louder sounds, favoring rate-coding models of human sound localization. Analogously, visual depth perception, which is based on interocular disparity, depends on the contrast of the target. The similar results in hearing and vision suggest that the brain may use a canonical computation of location: encoding perceived location through population spike rate relative to baseline.


Super-resolution and reconstruction of sparse sub-wavelength images.
We show that, in contrast to popular belief, sub-wavelength information can be recovered from the far-field of an optical image, thereby overcoming the loss of information embedded in decaying evanescent waves. The only requirement is that the image is known to be sparse, a specific but very general and wide-spread property of signals which occur almost everywhere in nature. The reconstruction method relies on newly-developed compressed sensing techniques, which we adapt to optical super-resolution and sub-wavelength imaging. Our approach exhibits robustness to noise and imperfections. We provide an experimental proof-of-principle by demonstrating image recovery at a spatial resolution 5-times higher than the finest resolution defined by a spatial filter. The technique is general, and can be extended beyond optical microscopy, for example, to atomic force microscopes, scanning-tunneling microscopes, and other imaging systems.


Eight different viral agents in childhood acute gastroenteritis.
Viral gastroenteritis is the most frequent cause of acute gastroenteritis (AGE) of childhood. The aim of this study was to determine the prevalence of viral agents including astrovirus, rotavirus, adenovirus, enterovirus, norovirus, parechovirus, Aichivirus and sapovirus in children with AGE in a pediatric Turkish population. Fecal specimens of 240 children with AGE were investigated by polymerase chain reaction, and viral agents were identified in 131 (54.6%) samples. The distribution of viral agents was as follows: 56 (42.8%) norovirus, 44 (33.6%) rotavirus, 29 (22.1%) enterovirus, 21 (16.0%) adenovirus, 21 (16.0%) parechovirus, 5 (3.8%) sapovirus and 1 (0.8%) Aichivirus. Single and multiple viral agents were detected in 38.8% and 15.8% of patients, respectively. The duration of hospitalization was longer in children with multiple viral agents than in those infected with a single viral agent (p<0.001). While the highest rate of rotavirus infection was detected in winter, the highest rate of norovirus was found in the summer. In conclusion, norovirus and rotavirus are the most frequent causes of childhood AGE in our country.


Managing Poststroke Fatigue Using Telehealth: A Case Report.
The objective of this study was to examine the effectiveness of delivering Managing Fatigue: A Six-Week Course for Energy Conservation via telehealth for a 70-yr-old man with poststroke fatigue (PSF). For this pilot case study, a questionnaire developed by the authors and the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a were used for screening. The study was implemented via teleconference over an 8-wk period. The Fatigue Impact Scale (FIS) and the Canadian Occupational Performance Measure (COPM) were used to gather pretest and posttest data. After the participant completed the course, decreased fatigue impact was noted on the FIS, and modestly improved occupational performance and satisfaction were evidenced by the COPM. For this single participant experiencing PSF, performance and satisfaction on the COPM guardedly improved and fatigue impact decreased after participation in the energy conservation course offered by teleconference, a form of telehealth delivery. Further research is recommended with larger sample sizes.


The pattern of injury in fatal pedal cycle accidents and the possible benefits of cycle helmets.
To establish the number of fatal pedal cycle accidents occurring in the Sheffield and Barnsley area, UK, and to investigate the possible benefits of helmet wearing by cyclists. All medicolegal investigations into fatal road traffic accidents in the areas of Sheffield and Barnsley (total population 757,300) were reviewed to identify cases in which pedal cyclists had died. The necropsy reports of the cases were compared with those of an equal number of controls (pedestrians and motor vehicle occupants) which were matched by sex, age and year of death. 28 deaths occurred in the last 15 years giving a mortality of 0.25/100,000 per annum, which is lower than the rate for the UK as a whole (0.43/100,000), but in five cases the accidents which eventually led to death occurred outside the area under study. These deaths represented 3.3% of road traffic deaths between 1979 and 1993. Over 80% of both cases and controls had severe head injuries, but the controls had suffered more fatal injuries to other parts of the body. None of the cyclists had worn helmets and, in order to assess the maximum possible benefit of helmet wearing, it was assumed that a helmet would have saved all those who only had head injuries. It was found that helmets might have saved 14 lives in 15 years. A similar calculation based on the controls suggests that if all pedestrians and vehicle occupants had worn helmets, 175 lives might have been saved in the same period. There is no justification for compelling cyclists to wear helmets without taking steps to improve the safety of all road users.


Selective inhibition of adenylyl cyclase type V by the dopamine D3 receptor.
Despite a great deal of research, the second messenger coupling of the dopamine D3 receptor has not yet been clearly established. The closely related D2 and D4 receptors have been shown to inhibit adenylyl cyclase activity in a variety of cell types, but the D3 receptor has little or no effect on this second messenger system. We now demonstrate that when the D3 receptor and adenylyl cyclase type V are coexpressed in 293 cells, the agonist quinpirole causes 70% inhibition of forskolin-stimulated cAMP levels. This effect seems to be selective for this adenylyl cyclase isoform because the D3 receptor does not inhibit adenylyl cyclase types I or VI and only weakly stimulates adenylyl cyclase type II. In contrast, the D2 receptor inhibits cAMP accumulation in 293 cells in the absence of cotransfected adenylyl cyclases and stimulates adenylyl cyclase type II to a greater extent than the D3 receptor. The inhibition of adenylyl cyclase type V by the D3 receptor is sensitive to pertussis toxin, suggesting the involvement of G proteins of the Gi family. Guanosine-5'-O-(3-thio)triphosphate binding studies indicate that the D3 receptor weakly activates all three Gialpha subunits, whereas the D2 receptor activates these G proteins to a substantially greater extent. However, despite its relative inability to promote G protein activation, the D3 receptor is capable of substantial and consistent inhibition of adenylyl cyclase type V. The robust second messenger coupling of the D3 receptor in a heterologous system with defined components provides a system for further studies of the function of this receptor and should facilitate the development and characterization of new D3 receptor ligands.


Differential role for CD277 as a co-regulator of the immune signal in T and NK cells.
The human butyrophilin (BTN) 3 or CD277 molecules belong to the B7 family members and are expressed in various immune cells such as T and NK cells. Here, we show that CD277 triggering considerably enhances TCR-induced cytokine production and cell proliferation, even when another co-stimulatory molecule, CD28, is engaged. These CD277-induced additive functional effects are in accordance with the detection of early T-cell activation events such as TCR-induced cell signaling being increased upon CD277 engagement. However, we found that CD277 triggering is not involved in CD16- or NKp46-induced NK cell activation. BTN3/CD277 comprises three structurally related members, BTN3A1, BTN3A2 and BTN3A3. CD277 antibodies recognize all isoforms and we describe a differential expression of BTN3 isoforms between T and NK cells that could explain differential CD277 functions between T and NK cells. Our results show that, while T cells express all BTN3/CD277 transcripts, NK cells express mostly BTN3A2, which lacks the B30.2 intracellular domain. Furthermore, NKp30-induced cytokine production is decreased by the specific engagement of BTN3A2, but not by BTN3A1 triggering. Thus, we provide new insights into the CD277 co-stimulatory pathway that may differentially participate in the regulation of various cell-mediated immune responses.


Evaluation of allicin for the treatment of experimentally induced subacute lead poisoning in sheep.
Garlic (Allium sativum) is known to reduce lead toxicity in some species of animals. The objective of this study was to evaluate the efficacy of allicin, one of the most active components of garlic, in the treatment of subacute lead intoxication in sheep. Nine female sheep weighing 25-29 kg orally received a daily dose of 80 mg/kg body weight of lead acetate for 5 days. The animals were then assigned into two groups. Group 1 did not receive any further treatment and was used as the control group and group 2 was treated orally by 2.7 mg/kg body weight of allicin twice daily for 7 days. Within one day following allicin treatment, group 2 blood lead levels were significantly lower than that in group 1 (mean of 616.9 microg/l and 290.02 microg/l, respectively; P < 0.05). Also, allicin treatment significantly reduced kidney lead content and considerably reduced bone and ovary lead contents. These results suggest that allicin might have some therapeutic effects on lead poisoning.


Advancing Long-Term Care Science Through Using Common Data Elements: Candidate Measures for Care Outcomes of Personhood, Well-Being, and Quality of Life.
To support the development of internationally comparable common data elements (CDEs) that can be used to measure essential aspects of long-term care (LTC) across low-, middle-, and high-income countries, a group of researchers in medicine, nursing, behavioral, and social sciences from 21 different countries have joined forces and launched the Worldwide Elements to Harmonize Research in LTC Living Environments (WE-THRIVE) initiative. This initiative aims to develop a common data infrastructure for international use across the domains of organizational context, workforce and staffing, person-centered care, and care outcomes, as these are critical to LTC quality, experiences, and outcomes. This article reports measurement recommendations for the care outcomes domain, focusing on previously prioritized care outcomes concepts of well-being, quality of life (QoL), and personhood for residents in LTC. Through literature review and expert ranking, we recommend nine measures of well-being, QoL, and personhood, as a basis for developing CDEs for long-term care outcomes across countries. Data in LTC have often included deficit-oriented measures; while important, reductions do not necessarily mean that residents are concurrently experiencing well-being. Enhancing measurement efforts with the inclusion of these positive LTC outcomes across countries would facilitate international LTC research and align with global shifts toward healthy aging and person-centered LTC models.


Face/On: Multi-Modal Haptic Feedback for Head-Mounted Displays in Virtual Reality.
While the real world provides humans with a huge variety of sensory stimuli, virtual worlds most of all communicate their properties by visual and auditory feedback due to the design of current head mounted displays (HMDs). Since HMDs offer sufficient contact area to integrate additional actuators, prior works utilised a limited amount of haptic actuators to integrate respective information about the virtual world. With the Face/On prototype complex feedback patterns are introduced that combine a high number of vibration motors with additional thermal sources to transport multi-modal and spatial information. A pre-study determining the boundaries of the feedbacks' intensities as well as a user study showing a significant increase of presence and enjoyment validate Face/On's approach.