The tumor suppressor CDKN3 controls mitosis.
Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2(pThr-161) at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.


Ebola virus entry requires the cholesterol transporter Niemann-Pick C1.
Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.


Characteristics of symptomatic reflux episodes in Japanese proton pump inhibitor-refractory non-erosive reflux disease patients.
To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease (NERD) patients. Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance - pH on rabeprazole. The symptom index (SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter. In 14 (40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes (46.7%) than in distal ones (5.7%) (P < 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (38.5%) and distal ones (20.5%) (NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent (31.0%) than in distal reflux ones (3.3%) (P < 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (29.4%) and distal ones (14.3%) (NS). The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy.


Candelabra aloe (Aloe arborescens) in the therapy and prophylaxis of upper respiratory tract infections: traditional use and recent research results.
Aloe arborescens (Candelabra Aloe) has been used in the treatment of upper respiratory tract infections in Central and Eastern European countries for many decades. Originally introduced to support the healing and recovery in cornea transplant patients, aqueous A. arborescens extracts soon became popular in the treatment of upper respiratory tract infections with a focus on toddlers and children. Recent preclinical and clinical data show that immunomodulatory, antiinflammatory, and antiviral effects contribute to its therapeutic efficacy. Based on its well documented, longstanding traditional use and its excellent safety and tolerability, A. arborescens may be considered a valuable addition to the spectrum of herbal medicinal products for the treatment and prophylaxis of upper respiratory tract infections, in particular common cold, in adults and children.


Anticancer and chemosensitizing abilities of cycloviolacin 02 from Viola odorata and psyle cyclotides from Psychotria leptothyrsa.
Cycloviolacin O2 (CyO2), a cyclotide from Viola odorata (Violaceae) has antitumor effects and causes cell death by membrane permeabilization. In the breast cancer line, MCF-7 and its drug resistant subline MCF-7/ADR, the cytotoxic effects of CyO2 (0.2-10 microM) were monitored in the presence and absence of doxorubicin (0.1-5 microM) using cell proliferation assays to establish its chemosensitizing abilities. SYTOX Green assays were Sperformed to verify membrane permeabilization and showed cellular disruption correlates with cyclotide chemosensitization. Fluorescence microscopy studies demonstrated increased cellular internalization of doxorubicin in drug resistant cells when coexposed to CyO2. Interestingly, CyO2 did not produce significant membrane disruption in primary human brain endothelial cells, which suggested cyclotide specificity toward induced pore formation in highly proliferating tumor cells. Furthermore, three novel cyclotides (psyle A, C and E) from Psychotria leptothyrsa (Rubiaceae) were also monitored for cytotoxic activity. The cyclotides displayed potent cytotoxicity (IC50 = 0.64->10 microM), and coexposure to cyclotides significantly enhanced doxorubicin induced toxicity (IC50 = 0.39-0.76 microM). This study documents several cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against drug resistant breast cancer.


Identification of endogenous inhibitory growth factors from a human colon carcinoma cell line.
A line of human colon carcinoma cells, designated MOSER, was established which synthesized tumor-inhibitory factor (TIF) and transforming growth factor (TGF) activity. Both activities were found in serum-free conditioned medium and in cell extracts. The activities coelute on Bio-Gel P-10 in acetic acid, but can be completely separated by reverse-phase high-pressure liquid chromatography. The TIF and TGF activities were acid and heat stable and were sensitive to trypsin and dithiothreitol. MOSER cell TIF prevented the anchorage-independent growth of the more differentiated colon carcinoma cell lines tested but did not affect the less differentiated lines. Using anchorage-dependent growth conditions, the effect of TIF appeared to be noncytotoxic and partially reversible. Purified TGF stimulated the growth of normal rat kidney fibroblasts and the slow-growing CBS colon carcinoma cell line but did not stimulate MOSER cell growth. MOSER cells contain both positive (TGF) and negative (TIF) factors with relative concentrations that may be important parameters in the regulation of cell growth.


Leukopenia and lack of ribavirin predict poor outcomes in patients with haematological malignancies and respiratory syncytial virus infection.
Respiratory syncytial virus (RSV) infection causes morbidity and mortality in cancer patients. However, studies describing this infection in patients with haematological malignancies are scarce. We sought to evaluate the clinical impact of RSV infection on this patient population. We reviewed the records of patients with haematological malignancies and RSV infections cared for at our institution between January 2000 and March 2013. Of the 181 patients, 71 (39%) had AML, ALL or myelodysplastic syndrome, 12 (7%) had CML or CLL, 4 (2%) had Hodgkin lymphoma, 35 (19%) had non-Hodgkin lymphoma and 59 (33%) had multiple myeloma. Most patients [117 (65%)] presented with an upper respiratory tract infection (URTI) and 15 (13%) had a subsequent lower respiratory tract infection (LRTI). The overall LRTI rate was 44% and the 90 day mortality rate was 15%. Multivariable regression analysis showed that having both neutropenia and lymphocytopenia (adjusted OR = 7.17, 95% CI = 1.94-26.53, P < 0.01) and not receiving ribavirin-based therapy during RSV URTI (adjusted OR = 0.03; 95% CI = 0.01-0.11, P < 0.001) were independent risk factors for LRTI. Having both neutropenia and lymphocytopenia at RSV diagnosis was also a risk factor for death at 90 days after RSV diagnosis (adjusted OR = 4.32, 95% CI = 1.24-15.0, P = 0.021). Patients with haematological malignancies and RSV infections, especially those with immunodeficiency, may be at risk of LRTI and death; treatment with ribavirin during RSV URTI may prevent these outcomes.


Overview and patient recruitment in the Adult Day Health Care Evaluation Study.
Although Adult Day Health Care (ADHC) is increasingly prominent in the continuum of long-term care services, the results from previous studies of the effects of ADHC are mixed. The objectives of the ADHC Evaluation Study were to determine the effect of ADHC on health status, utilization, and cost of care. The first phase was a randomized controlled trial evaluating ADHC provided directly by the VA. Patients at four medical centers (n = 826) were randomly assigned to receive either ADHC or customary care, and outcomes were compared for the two groups. The second phase was a prospective cohort study evaluating ADHC provided under contract to community agencies in which patients at four additional medical centers (n = 163) were assigned to contract ADHC programs. Outcomes were compared with those of similar patients in the randomized trial. Patients and care givers were assessed at intake and 6 and 12 months after intake. To be admitted to the study, patients must have met one of the following criteria: residence in a nursing home; dependence in ambulation, dressing, or toileting; bowel incontinence; or significant cognitive impairment. Patients at intake demonstrated major impairment in function and high levels of prior use of health care services.


Randomized study between radical surgery and radiotherapy for the treatment of stage IB-IIA cervical cancer: 20-year update.
Stage IB-IIA cervical carcinoma can be equally cured either by radical surgery or radiotherapy (RT). Albeit such policies show the same efficacy, they carry a different morbidity. This is an update after 20 years of a previously published randomized trial of RT vs. surgery in the treatment of stage IB-IIA cervical cancers to assess long-term survival and morbidity and the different pattern of relapse between the 2 modalities. Between September 1986 and December 1991, women referred for a newly diagnosed stage IB and IIA cervical carcinoma were randomized to radical surgery or RT. The primary outcome measures were long-term survival and complications rate. The secondary outcome was recurrence of the disease. Three-hundred forty-three eligible women were randomized: 172 to radical surgery and 171 to external RT. Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease (31 cases) or fatal complications (2 cases). Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280), respectively. As a whole, 94 recurrences (28%) were observed. Median time to relapse was 13.5 (surgery group) and 11.5 months (radiotherapy group) (p=0.100), respectively. Multivariate analysis confirms that risk factors for survival are histotype (p=0.020), tumor diameter (p=0.008), and lymph node status (p<0.001). The results of the present study seem to suggest that there is no treatment of choice for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that the best treatment for the individual patient should take into account clinical factors such as menopausal status, comorbidities, histological type, and tumor diameter.


Detection of four adenovirus serotypes within water-isolated strains of Acanthamoeba in the Canary Islands, Spain.
We surveyed 236 potentially pathogenic Acanthamoeba strains, isolated from water sources in the Canary Islands, for the presence of human adenoviruses (HAdV) using a polymerase chain reaction (PCR)-based typing assay. A total of 34 of these strains were found to be positive for adenovirus belonging to four different HAdV serotypes (HAdV-1, 2, 8, and 37). We found that HAdV-2 was the most frequently encountered serotype amongst the Acanthamoeba strains, and their identification was confirmed by a nested PCR specific for this serotype. We showed that Acanthamoeba genotype T4 was highly associated with serotype HAdV-2, whereas Acanthamoeba genotype T3 was most often associated with adenovirus serotypes related to ocular diseases. Based on these data, we suggest that Acanthamoeba should be considered as a potential reservoir and perhaps even a transmitter of adenoviruses to human and other secondary hosts.


Identification and subcellular localization of a 41 kDa, polyprotein 1ab processing product in human coronavirus 229E-infected cells.
The translation products of the human coronavirus (HCV) 229E open reading frames 1a and 1b, the polyproteins 1a and 1ab, are processed by virus-encoded proteinases. One of the key enzymes in this process is a chymotrypsin-like enzyme, the 3C-like proteinase. In this study we have identified an ORF 1b-encoded, 41 kDa processing product in HCV 229E-infected cells by using a monoclonal antibody with defined specificity. We show that this polypeptide is released from polyprotein 1ab by 3C-like proteinase-mediated cleavage of the peptide bonds Gln-6110/Gly-6111 and Gln-6458/Ser-6459. Also, we have investigated the subcellular localization of the 41 kDa processing product. Immunofluorescence microscopy revealed a punctate, perinuclear distribution of the 41 kDa polypeptide in infected cells and an identical subcellular localization was observed for three additional pp1ab-derived polypeptides. In contrast, the virus nucleocapsid protein showed a homogeneous cytoplasmic localization.


Airway Microbiome and Serum Metabolomics Analysis Identify Differential Candidate Biomarkers in Allergic Rhinitis.
Allergic rhinitis (AR) is a common heterogeneous chronic disease with a high prevalence and a complex pathogenesis influenced by numerous factors, involving a combination of genetic and environmental factors. To gain insight into the pathogenesis of AR and to identity diagnostic biomarkers, we combined systems biology approach to analyze microbiome and serum composition. We collected inferior turbinate swabs and serum samples to study the microbiome and serum metabolome of 28 patients with allergic rhinitis and 15 healthy individuals. We sequenced the V3 and V4 regions of the 16S rDNA gene from the upper respiratory samples. Metabolomics was used to examine serum samples. Finally, we combined differential microbiota and differential metabolites to find potential biomarkers. We found no significant differences in diversity between the disease and control groups, but changes in the structure of the microbiota. Compared to the HC group, the AR group showed a significantly higher abundance of 1 phylum (Actinobacteria) and 7 genera (Klebsiella, Prevotella and Staphylococcus, etc.) and a significantly lower abundance of 1 genus (Pelomonas). Serum metabolomics revealed 26 different metabolites (Prostaglandin D2, 20-Hydroxy-leukotriene B4 and Linoleic acid, etc.) and 16 disrupted metabolic pathways (Linoleic acid metabolism, Arachidonic acid metabolism and Tryptophan metabolism, etc.). The combined respiratory microbiome and serum metabolomics datasets showed a degree of correlation reflecting the influence of the microbiome on metabolic activity. Our results show that microbiome and metabolomics analyses provide important candidate biomarkers, and in particular, differential genera in the microbiome have also been validated by random forest prediction models. Differential microbes and differential metabolites have the potential to be used as biomarkers for the diagnosis of allergic rhinitis.


A successive overrelaxation backpropagation algorithm for neural-network training.
A variation of the classical backpropagation algorithm for neural network training is proposed and convergence is established using the perturbation results of Mangasarian and Solodov. The algorithm is similar to the successive overrelaxation (SOR) algorithm for systems of linear equations and linear complementary problems in using the most recently computed values of the weights to update the values on the remaining arcs.


Biopsychosocial exposure to the COVID-19 pandemic and the relative risk of schizophrenia: Interrupted time-series analysis of a nationally representative sample.
Studies of COVID-19 pandemic biopsychosocial exposure and schizophrenia risk showed contradictory results, were undertaken early in the pandemic, and did not consider lockdowns or COVID-19 infection. Hence, we examined the association between COVID-19 biopsychosocial exposure and incident schizophrenia. An interrupted time-series study design was implemented based on Israeli electronic health records from 2013 to 2021 with national coverage. The period coinciding with the COVID-19 pandemic biopsychosocial exposures from March 2020 to February 2021 was classified as exposed, otherwise unexposed. The effect of the COVID-19 pandemic on incident schizophrenia was quantified by fitting a Poisson regression and modeling the relative risk (RR) and corresponding 95% confidence intervals (CI). Three scenarios were projected from the third lockdown to 10 months to forecast incident schizophrenia rates and their associated 95% prediction intervals (PI). The total population (N = 736,356) yielded 4,310 cases of incident schizophrenia over time. The primary analysis showed that the period exposed to the COVID-19 pandemic was associated with a reduced RR (RR = 0.81, 95% CI = 0.73, 0.91, p < 0.001). This conclusion was supported in 12 sensitivity analyses, including scrutinizing lockdowns and COVID-19 infection status. Two of three forecast scenarios projected an incident increase (6.74, 95% PI = 5.80, 7.84; 7.40, 95% PI = 6.36, 8.60). The reduced risk of schizophrenia during the pandemic suggests no immediate triggering of new onsets either by the virus or the pandemic-induced psychosocial adversities. Once restrictions are lifted, the increased projected presentations have implications for clinicians and healthcare policy.


Interactions of apoptotic cells with macrophages in radiation-induced bystander signaling.
Nontargeted effects that result in ongoing cellular and tissue damage show genotype-dependency in murine models with CBA/Ca, but not C57BL/6, exhibiting sensitivity to induced genomic instability. In vivo, radiation exposure is associated with genotype-dependent macrophage activation, and these cells are a source of bystander signaling involving cytokines and reactive oxygen and nitrogen species. The mechanisms responsible for macrophage activation and production of damaging bystander signals after irradiation are unclear. Macrophages from CBA/Ca exhibit an M1 (proinflammatory) phenotype compared to the M2 (anti-inflammatory) phenotype of C57BL/6 macrophages. Using the murine RAW264.7 macrophage-like cell line, we show that the ability of macrophages to interact with apoptotic cells and their responses to interaction varies significantly according to macrophage phenotype. Nonstimulated and M2 macrophages induce anti-inflammatory markers arginase and TGFβ after engulfment of apoptotic cells. In contrast, M1 macrophages do not induce anti-inflammatory responses, but express the proinflammatory markers NOS2, IL-6, TNFα, superoxide and NO, able to contribute to a damaging microenvironment. Macrophages stimulated with both inflammatory and anti-inflammatory agents prior to exposure to apoptotic cells induce a mixed response. The results indicate a complex cross-talk between macrophages and apoptotic cells and demonstrate that phagocytic clearance of apoptotic cells induced by genotoxic stress can produce microenvironmental responses consistent with the induction of a chromosomal instability phenotype in sensitive CBA/Ca mice with M1 macrophage activation, but not in resistant C57BL/6 mice with M2 macrophage activation. Modulation of macrophage phenotypes may represent a novel approach for reducing the nontargeted effects of radiation.


[Nosocomial Pseudomonas pickettii infection. Danger of the use of ion-exchange resins].
In a recent nosocomial outbreak of Pseudomonas pickettii infection at the general hospital of Corbeil-Essonnes, France, two patients were moderately affected, but two others, who were diabetic, died of septicemia. The infection was transmitted by 0.05% aqueous solutions of chlorhexidine, the treatment of water for these solutions being the cause of contamination. The ion-exchange resin in the deionization cartridges allowed the surviving bacteria in the city water supply to grow while the bacteriological filters downstream only lowered the contamination level. The 0.05% chlorhexidine aqueous solutions failed to prevent growth up to 4 X 10(6) bacteria/ml. P. pickettii is resistant to aminoglycosides and colistine.


Respiratory syncytial virus envelope glycoprotein (G) has a novel structure.
Amino acid sequence of human respiratory syncytial virus envelope glycoprotein (G) was deduced from the DNA sequence of a recombinant plasmid and confirmed by limited amino acid microsequencing of purified 90K G protein. The calculated molecular mass of the protein encoded by the only long open reading frame of 298 amino acids was 32,588 daltons and was somewhat smaller than the 36K polypeptide translated in vitro from mRNA selected by this plasmid. Inspection of the sequence revealed a single hydrophobic domain of 23 amino acids capable of membrane insertion at 41 residues from the N-terminus. There was no N-terminal signal sequence and the hydrophilic N-terminal 20 residues probably represent the cytoplasmic tail of the protein. The N-terminally oriented membrane insertion was somewhat analogous to paramyxovirus hemagglutinin-neuraminidase (HN) and influenza neuraminidase (NA). The protein was moderately hydrophilic and rich in hydroxy-amino acids. It was both N- and O-glycosylated with the latter contributing significantly to the net molecular mass 90K.


Subcellular trafficking of PIN auxin efflux carriers in auxin transport.
The directional transport of the plant hormone auxin is a unique process mediating a wide variety of developmental processes. Auxin movement between cells depends on AUX1/LAX, PGP and PIN protein families that mediate auxin transport across the plasma membrane. The directionality of auxin flow within tissues is largely determined by polar, subcellular localization of PIN auxin efflux carriers. PIN proteins undergo rapid subcellular dynamics that is important for the process of auxin transport and its directionality. Furthermore, various environmental and endogenous signals can modulate trafficking and polarity of PIN proteins and by this mechanism change auxin distribution. Thus, the subcellular dynamics of auxin transport proteins represents an important interface between cellular processes and development of the whole plant. This review summarizes our recent contributions to the field of PIN trafficking and auxin transport regulation.


Combination studies of antifolates with 5-fluorouracil in colon cancer cell lines.
The combined cytotoxic effects of the thymidylate synthase (TS) inhibitors 5-fluorouracil (5FU) and different antifolates were studied in seven colon cancer cell lines. Growth inhibition of the antifolates, Nolatrexed, Raltitrexed, GW1843U89, or MTA in combination with 5FU, was determined and multiple drug effect analysis showed that the drugs acted mostly additively. The only synergistic interaction was found for 5FU and Nolatrexed in the LS174T cell line. Also Raltitrexed and 5FU were slightly synergistic in WiDr/F cells grown at low folate levels, but for the other cell lines grown at high folate levels this combination was more antagonistic. GW1843U89 and 5FU were mainly additive, while 5FU and MTA showed antagonism in WiDr and additivity in LS174T. The effect of the drugs at their target was evaluated by in situ TS inhibition. We observed lower TS activity in all cells when two drugs were used instead of one. Statistical analysis revealed that none of the values of the combinations was higher or lower than could be expected from the product of the effect of single drugs. We concluded that the effects on TS inhibition were additive for all 5FU/antifolate combinations in all cell lines. DNA strand break formation, as a result of TS inhibition, was measured by means of a fluorometric analysis of DNA unwinding. Raltitrexed-induced DNA damage was significantly increased by 5FU in WiDr cells [single agent: 67% double stranded (ds) DNA, combination: 39% ds DNA, P<0.0001]. In LS174T a trend for antagonistic effects was observed for combinations of MTA, GW1843U89, or Raltitrexed and 5FU. The combinations showed additive effects in WiDr/F cells. The overall conclusion of the three assays in each of the cell lines indicated that 5FU and antifolate combinations were predominantly additive in colon cancer cells.


Photobiomodulation improves the frontal cognitive function of older adults.
The frontal lobe hypothesis of age-related cognitive decline suggests that the deterioration of the prefrontal cortical regions that occurs with aging leads to executive function deficits. Photobiomodulation (PBM) is a newly developed, noninvasive technique for enhancing brain function, which has shown promising effects on cognitive function in both animals and humans. This randomized, sham-controlled study sought to examine the effects of PBM on the frontal brain function of older adults. Thirty older adults without a neuropsychiatric history performed cognitive tests of frontal function (ie, the Eriksen flanker and category fluency tests) before and after a single 7.5-minute session of real or sham PBM. The PBM device consisted of three separate light-emitting diode cluster heads (633 and 870 nm), which were applied to both sides of the forehead and posterior midline, and delivered a total energy of 1349 J. Significant group (experimental, control) × time (pre-PBM, post-PBM) interactions were found for the flanker and category fluency test scores. Specifically, only the older adults who received real PBM exhibited significant improvements in their action selection, inhibition ability, and mental flexibility after vs before PBM. Our findings support that PBM may enhance the frontal brain functions of older adults in a safe and cost-effective manner.


Nephrolithiasis and Risk of Incident Bone Fracture.
Higher urine calcium is a common feature of calcium nephrolithiasis and may be associated with lower bone mineral density in individuals with kidney stones. However previous population based studies of kidney stones and the risk of bone fracture demonstrate conflicting results. We examined independent associations between a history of kidney stones and incident fracture. We performed prospective studies using data from the Nurses' Health Study of 107,001 women with 32 years of followup and the Health Professionals Follow-up Study of 50,982 men with 26 years of followup. We excluded premenopausal women, men younger than 45 years and individuals who reported osteoporosis at baseline. Study outcomes were incident wrist (distal radius) or incident hip (proximal femur) fracture due to low or moderate trauma. Cox proportional hazards regression was used to adjust for multiple factors, including age, race, body mass index, thiazide use, supplemental calcium and dietary intakes. There were 4,940 wrist and 2,391 hip fractures in women, and 862 wrist and 747 hip fractures in men. All fractures were incident. The multivariable adjusted relative risk of incident wrist fracture in participants with a history of kidney stones compared to participants without kidney stones was 1.18 (95% CI 1.04-1.34) in women and 1.21 (95% CI 1.00-1.47) in men. The pooled multivariable adjusted relative risk of wrist fracture was 1.20 (95% CI 1.08-1.33). The multivariable adjusted relative risk of incident hip fracture in participants with kidney stones was 0.96 (95% CI 0.80-1.14) in women and 0.92 (95% CI 0.74-1.14) in men. The pooled multivariable adjusted relative risk of hip fracture was 0.94 (95% CI 0.82-1.08). Nephrolithiasis is associated with a significantly higher risk of incident wrist but not hip fracture in women and men.


[Patients with a chronic recurring psychosis in general practice: the need for close follow-up].
Three patients, a man aged 45, and two women aged 48 and 51 years, were suffering from chronic recurring psychoses for which they were taking medication. Their general practitioner was alerted to signals of psychotic relapse by the first patient himself and for the other two patients by the next of kin. The first two patients decided to discontinue their medication, one because he wanted to live 'a normal life' and the other because she thought the medication made her gain weight. The third patient had a psychic decompensation because her son had decided to live on his own and because she had also moved. The first two patients were successfully treated by restoring their medication, although the second patient also had to be referred to a psychiatrist. The third patient had lost confidence in the general practitioner, and was eventually admitted to a psychiatric clinic for treatment. Nowadays, increasing numbers of chronic psychiatric patients are living outside of hospitals. The adequate response of general practitioners to psychotic relapse in such patients warrants regular contact to evaluate the patient's network and to detect a relapse in an early phase. A proactive attitude and being adequately informed by locum general practitioners are also important. The extent to which the patient cooperates will depend upon the quality of the patient/general practitioner relationship.


The long-term impact of wheelchair delivery on the lives of people with disabilities in three countries of the world.
Lack of access to mobility for people with disabilities, particularly in less- resourced settings, continues to be widespread. Despite challenges to wheelchair delivery, the benefits to health, employment, social integration and life satisfaction are apparent. Previous studies have explored the impact of receiving a wheelchair on the lives of the users through cross-sectional or short-term longitudinal analysis. The current study was undertaken to evaluate whether previously reported changes were sustained after 30 months of use, and whether results varied between two differing models of a wheelchair. One hundred and ninety-one subjects from Peru, Uganda and Vietnam received one of two models of wheelchair provided by the Free Wheelchair Mission. Using interviews to record survey results, data were collected at the time the wheelchair was received and following 12 and 30 months of use. Variables of overall health, employment, income and travel were explored through non-parametric analysis. There was a significant improvement in overall health and distance travelled after 12 months, but these changes were no longer significant by 30 months (Friedman test for overall change, p = 0.000). Employment status showed a small but significant increase at 12 and 30 months (Cochran's Q, p = 0.000). Reported income increased slowly, becoming significantly different at 30 months (Friedman test, p = 0.033). There was no association between the model of wheelchair received and the incidence of pressure ulcers, pain or maintenance required. There was higher satisfaction with the GEN_2 wheelchair at 12 months (p = 0.004), but this difference was not apparent by 30 months. Overall wheelchair satisfaction and maintenance levels were favourable. While overall health status, and distance travelled into the community fluctuated over time, receipt of one of two models of a wheelchair in less-resourced settings of the world appears to have a positive sustained impact on employment and income. Further investigations should be carried out to confirm these results and explore the factors responsible for fluctuating variables. This study affirms the importance of long-term follow-up of outcomes associated with wheelchair distribution in less-resourced environments.


Evaluation of genome similarities using the non-decimated wavelet transform.
The wavelets have become increasingly popular in the field of bioinformatics due to their capacity in multiresolution analysis and space-frequency localization; the latter particularity is acquired due to a moving window that runs through the analyzed space. As a feature, they have a better ability to capture hidden components of biological data and an efficient link between biological systems and the mathematical objects used to describe them. The decomposition of signals/sequences at different levels of resolution allows obtaining distinct characteristics in each level. The energy (variance) obtained at each level provides a new set of information that can be used to search similarities between sequences. We show that the behavior of GC-content sequence can be succinctly described regarding the non-decimated wavelet transform, and we indicate how this characterization can be used to improve clustering of the similar strains of the genome of the Mycobacterium tuberculosis, having a very efficient level of detail. The clustering analysis using the energy obtained at each level of the analyzed sequences was essential to verify the dissimilarity of the sequences.


On a notion of simplicial depth.
For a distribution F on R(p) and a point x in R(p) the simplicial depth D(x), which is the probability that x be inside a random simplex whose vertices are p + 1 independent observations from F, is introduced. D(x) can be viewed as a measure of depth of the point x relative to F, and its empirical version gives rise to a natural ordering of the data points from the center outward. This ordering provides an approach for detecting outliers in a multivariate data cloud and leads to the introduction of affine equivariant multivariate generalizations of the univariate sample median and L-statistics. This sample median is shown to be consistent for the center of any angularly symmetric distribution.


Structural basis for ligand binding and specificity in adrenergic receptors: implications for GPCR-targeted drug discovery.
Crystal structures of engineered human beta 2-adrenergic receptors (ARs) in complex with an inverse agonist ligand, carazolol, provide three-dimensional snapshots of the disposition of seven transmembrane helices and the ligand-binding site of an important G protein-coupled receptor (GPCR). As expected, beta 2-AR shares substantial structural similarities with rhodopsin, the dim-light photoreceptor of the rod cell. However, although carazolol and the 11- cis-retinylidene moiety of rhodopsin are situated in the same general binding pocket, the second extracellular (E2) loop structures are quite distinct. E2 in rhodopsin shows beta-sheet structure and forms part of the chromophore-binding site. In the beta 2-AR, E2 is alpha-helical and seems to be distinct from the receptor's active site, allowing a potential entry pathway for diffusible ligands. The structures, together with extensive structure-activity relationship (SAR) data from earlier studies, provide insight about possible structural determinants of ligand specificity and how the binding of agonist ligands might alter receptor conformation. We review key features of the new beta 2-AR structures in the context of recent complementary work on the conformational dynamics of GPCRs. We also report 600 ns molecular dynamics simulations that quantified beta 2-AR receptor mobility in a membrane bilayer environment and show how the binding of an agonist ligand, adrenaline (epinephrine), causes conformational changes to the ligand-binding pocket and neighboring helices.


Extensive sharing of chloroplast haplotypes among European birches indicates hybridization among Betula pendula, B. pubescens and B. nana.
Extensive sharing of chloroplast haplotypes among the silver birch, Betula pendula Roth., the downy birch, B. pubescens Ehrh., and the dwarf birch, B. nana L., was discovered using polymerase chain reaction-restriction fragment length polymporphism markers. The geographical component of the genetic variation was stronger than the species component: the species were not significantly different while 11% of the variation could be attributed to differentiation between the two main regions studied, Scandinavia and western Russia. All haplotypes occurring in more than 2% of the individuals were shared among the species and the introgression ratios were quite large: 0.79 between B. pubescens and B. pendula and 0.67 between B. pubescens and B. nana. The data also indicate that B. pendula individuals are more similar to sympatric B. pubescens than to B. pendula individuals from nearby forests. However, this trend is not as pronounced when B. pubescens is considered, suggesting that introgression is not symmetrical. The haplotype sharing among the three Betula species is most likely caused by hybridization and subsequent cytoplasmic introgression.


Solid-state DNA sizing by atomic force microscopy.
Atomic force microscopy (AFM) allows rapid, accurate, and reproducible visualization of DNA adsorbed onto solid supports. The images reflect the lengths of the DNA molecules in the sample. Here we propose a solid-state DNA sizing (SSDS) method based on AFM as an analytical method for high-throughput applications such as finger-printing, restriction mapping, +/- screening, and genotyping. For this process, the sample is first deposited onto a solid support by adsorption from solution. It is then dried and imaged under ambient conditions by AFM. The resulting images are subjected to automated determination of the lengths of the DNA molecules on the surface. The result is a histogram of sizes that is similar to densitometric scans of DNA samples separated on gels. A direct comparison of SSDS with agarose gel electrophoresis for +/- screening shows that it produces equivalent results. Advantages of SSDS include reduced sample size (i.e., lower reagent costs), rapid analysis of single samples, and potential for full automation using available technology. The high sensitivity of the method also allows the number of polymerase chain reaction cycles to be reduced to 15 or less. Because the high signal-to-noise ratio of the AFM allows for direct visualization of DNA-binding proteins, different DNA conformations, restriction enzymes, and other DNA modifications, there is potential for dramatically improving the information content in this type of analysis.


Carbon dioxide concentration dictates alternative methanogenic pathways in oil reservoirs.
Deep subsurface formations (for example, high-temperature oil reservoirs) are candidate sites for carbon capture and storage technology. However, very little is known about how the subsurface microbial community would respond to an increase in CO2 pressure resulting from carbon capture and storage. Here we construct microcosms mimicking reservoir conditions (55 °C, 5 MPa) using high-temperature oil reservoir samples. Methanogenesis occurs under both high and low CO2 conditions in the microcosms. However, the increase in CO2 pressure accelerates the rate of methanogenesis to more than twice than that under low CO2 conditions. Isotope tracer and molecular analyses show that high CO2 conditions invoke acetoclastic methanogenesis in place of syntrophic acetate oxidation coupled with hydrogenotrophic methanogenesis that typically occurs in this environment (low CO2 conditions). Our results present a possibility of carbon capture and storage for enhanced microbial energy production in deep subsurface environments that can mitigate global warming and energy depletion.


Microwaves from GSM mobile telephones affect 53BP1 and gamma-H2AX foci in human lymphocytes from hypersensitive and healthy persons.
The data on biologic effects of nonthermal microwaves (MWs) from mobile telephones are diverse, and these effects are presently ignored by safety standards of the International Commission for Non-Ionizing Radiation Protection (ICNIRP). In the present study, we investigated effects of MWs of Global System for Mobile Communication (GSM) at different carrier frequencies on human lymphocytes from healthy persons and from persons reporting hypersensitivity to electromagnetic fields (EMFs). We measured the changes in chromatin conformation, which are indicative of stress response and genotoxic effects, by the method of anomalous viscosity time dependence, and we analyzed tumor suppressor p53-binding protein 1 (53BP1) and phosphorylated histone H2AX (gamma-H2AX), which have been shown to colocalize in distinct foci with DNA double-strand breaks (DSBs), using immunofluorescence confocal laser microscopy. We found that MWs from GSM mobile telephones affect chromatin conformation and 53BP1/gamma-H2AX foci similar to heat shock. For the first time, we report here that effects of MWs from mobile telephones on human lymphocytes are dependent on carrier frequency. On average, the same response was observed in lymphocytes from hypersensitive and healthy subjects.


Systemic sclerosis-associated interstitial pneumonia: evaluation of pulmonary function over a five-year period.
To evaluate alterations in pulmonary function in patients with systemic sclerosis-associated interstitial pneumonia over a five-year period. This was a longitudinal study involving 35 nonsmoking patients with systemic sclerosis and without a history of lung disease. At the first evaluation, performed at the time of the diagnosis of interstitial pneumonia, the patients were submitted to HRCT, spirometry, and measurement of DLCO. The patients were subdivided into two groups by the presence or absence of honeycombing on the HRCT scans. Approximately five years after the first evaluation, the patients were submitted to spirometry and measurement of DLCO only. Of the 35 patients, 34 were women. The mean age was 47.6 years. The mean time between the two evaluations was 60.9 months. Honeycombing was detected on the HRCT scans in 17 patients. In the sample as a whole, five years after the diagnosis, FVC, FEV₁ and DLCO significantly decreased (81.3 ± 18.2% vs. 72.1 ± 22.2%; 79.9 ± 17.8% vs. 72.5 ± 20.6%; and 74.0 ± 20.5% vs. 60.7 ± 26.8%, respectively; p = 0.0001 for all), and the FEV₁/FVC ratio significantly increased (98.5 ± 7.2% vs. 101.9 ± 7.8%; p = 0.008). In the same period, FVC, FEV₁, and DLCO values were significantly lower in the patients with honeycombing on the HRCT scans than in those without (p = 0.0001). In systemic sclerosis-associated interstitial lung disease, the detection of honeycombing on HRCT is crucial to predicting accelerated worsening of pulmonary function.


Associations between social support, prevalent symptoms and health-related quality of life in Chinese women undergoing treatment for breast cancer: a cross-sectional study using structural equation modelling.
There is little in the literature exploring the inter-relationship of social support, prevalent symptoms and health-related quality of life (HRQoL) among breast cancer patients. This study examines the inter-relationships among the three variables using the 'Theory of Unpleasant Symptoms' as a framework. 279 Chinese breast cancer patients undergoing treatment were recruited for face-to-face interviews. The instruments used were Chinese versions of the Brief Fatigue Inventory, Brief Pain Inventory, Hospital Anxiety and Depression Scales, Medical Outcomes Study Social Support Survey and Functional Assessment of Cancer Therapy for Breast Cancer. Goodness-of-fit and misfit indices were obtained for the final model (SRMR = 0.034, robust RMSEA = 0.051 and robust CFI = 0.981), and the results showed that social support had large total effects on social/family (total effect = 0.704, P < 0.05) and functional well-being (total effect = 0.450, P < 0.05), but a minimal effect on the breast cancer scale (total effect = 0.036, P > 0.05). The inter-relationships among the three variables give us a better understanding of breast cancer patients' experience and provide guidance for developing effective strategies to improve their HRQoL and relieving unpleasant symptoms.


Service utilization for lifetime mental disorders in U.S. adolescents: results of the National Comorbidity Survey-Adolescent Supplement (NCS-A).
Mental health policy for youth has been constrained by a paucity of nationally representative data concerning patterns and correlates of mental health service utilization in this segment of the population. The objectives of this investigation were to examine the rates and sociodemographic correlates of lifetime mental health service use by severity, type, and number of DSM-IV disorders in the National Comorbidity Survey-Adolescent Supplement. Face-to-face survey of mental disorders from 2002 to 2004 using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview in a nationally representative sample of 6,483 adolescents 13 to 18 years old for whom information on service use was available from an adolescent and a parent report. Total and sector-specific mental health service use was also assessed. Approximately one third of adolescents with mental disorders received services for their illness (36.2%). Although disorder severity was significantly associated with an increased likelihood of receiving treatment, half of adolescents with severely impairing mental disorders had never received mental health treatment for their symptoms. Service rates were highest in those with attention-deficit/hyperactivity disorder (59.8%) and behavior disorders (45.4%), but fewer than one in five affected adolescents received services for anxiety, eating, or substance use disorders. Comorbidity and severe impairment were strongly associated with service utilization, particularly in youth with behavior disorders. Hispanic and non-Hispanic Black adolescents were less likely than their White counterparts to receive services for mood and anxiety disorders, even when such disorders were associated with severe impairment. Despite advances in public awareness of mental disorders in youth, a substantial proportion of young people with severe mental disorders have never received specialty mental health care. Marked racial disparities in lifetime rates of mental health treatment highlight the urgent need to identify and combat barriers to the recognition and treatment of these conditions.


Cloning of miniature pig HIF-1alpha and its responses to immunosuppressive agents.
Miniature pigs are worth notice as candidate donors for xenotransplantation. However, donor organs are inevitably subjected to hypoxia, which causes vascular endothelial dysfunction. In this respect, hypoxia-inducible factor 1alpha (HIF-1alpha), the key factor for hypoxic adaptation, should be expressed in grafts. However, some immunosuppressive drugs have been reported to suppress HIF-1alpha in rat cells. Here, we first identified the cDNA and protein structures of miniature pig HIF-1alpha, and next investigated the effects of cyclosporine and FK506 on HIF-1alpha expression in endothelial cells of miniature pig. Thus, we conclude that FK506, rather than cyclosporine, may be recommended for xenotransplantation using miniature pig organs.


Combination treatment in the rehabilitation of visuo-spatial neglect.
Visuo-spatial neglect predicts longer hospitalization, poorer recovery of motor skills and greater functional limitation. The aim of the present study was to analyze whether the combined administration of computerized cognitive rehabilitation with right hemifield eye-patching in patients with left spatial neglect following a right hemisphere stroke is more effective than computerized cognitive rehabilitation applied in isolation. Randomized clinical trial conducted in 28 patients. These were grouped into two experimental groups: single treatment group (ST) (n= 15) and combined treatment group (CT) (n= 13). All received an average of 15 one-hour sessions of computerized cognitive rehabilitation using the Guttmann, NeuroPersonalTrainer® telerehabilitation platform. Those patients in the TC group performed the sessions wearing a visual device with which the right hemifield of each eye was occluded. Following treatment, both the ST and the TC group showed improvements in neuropsychological examination protocol although there were no differences pre- and post-treatment on the functional scale in either group. Likewise, no statistically significant differences were observed in intergroup comparison. The results from this study indicate that combination treatment is not more effective than rehabilitation applied in isolation.


Validity of Preoperative Clinical Findings to Identify Dental Pulp Status: A National Dental Practice-Based Research Network Study.
Endodontic diagnostic tests are often used clinically to assess pulp status as a basis for the diagnosis and determination of whether root canal treatment (RCT) is indicated. Response to cold and pain on percussion are 2 common tests, yet their validity in identifying nonvital pulp in regular dental practice has not been reported. We assessed the validity of cold and percussion tests to identify nonvital pulp in teeth requiring RCT in a dental practice setting performed by 46 general dentists and 16 endodontists in the National Dental Practice-Based Research Network. The influence of patient-, tooth-, and dentist-related characteristics was investigated. Observed bleeding from the pulp chamber was the clinical reference. Sensitivity (SN), specificity (SP), overall test accuracy (TA), positive (PPV) and negative (NPV) predictive values, and likelihood and diagnostic odds ratios (LR+, LR-, dORs) were calculated for each single test and the combined cold and percussion tests. Seven hundred eight patient teeth were included. Cold test showed high validity to identify a nonvital pulp status (SN = 89%, SP = 80%, TA = 84%, PPV = 81%, NPV = 88%, LR+ = 4.35, LR- = 0.14, dOR = 31.4), whereas pain on percussion had lower validity (SN = 72%, SP = 41%, TA = 56%, PPV = 54%, NPV = 60%, LR+ = 1.22, LR- = 0.69, dOR = 1.78). Combining the 2 tests did not increase validity, whereas preoperative pain, medication intake, patient age and sex, and dentist training level affected test validity significantly. In regular dental practice, the cold test exhibits higher validity to discriminate between vital and nonvital pulp than the tooth percussion test.


Exotic magnetic states in Pauli-limited superconductors.
Magnetism and superconductivity compete or interact in complex and intricate ways. Here we review the special case where novel magnetic phenomena appear due to superconductivity, but do not exist without it. Such states have recently been identified in unconventional superconductors. They are different from the mere coexistence of magnetic order and superconductivity in conventional superconductors, or from competing magnetic and superconducting phases in many materials. We describe the recent progress in the study of such exotic magnetic phases, and articulate the many open questions in this field.


Metabolic basis of asthma. A united hypothesis.
Asthma is a heterogenous disease triggered by a large number of different stimuli. This article presents a theory of the metabolic mechanisms of asthma. The theory is based on the growing understanding of the activity of lysophosphatidylcholine (LPC). Since the effect of LPC on cell membranes, membrane bound enzymes and the various types of cells involved in the pathogenesis of asthma, this may represent a unifying link between the various types of asthma.


Comparison of Wired and Wireless Heart Rate Monitoring in the Neonatal Intensive Care Unit.
In the Neonatal Intensive Care Unit (NICU), infants' vital signs are monitored on a continuous basis via wired devices. These often interfere with patient care and pose increased risks of skin damage, infection, and tangling around the body. Recently, a wireless system for neonatal monitoring called ANNEⓇ One (Sibel Health, Chicago, USA) was developed. We designed an ongoing study to evaluate the feasibility, reliability and accuracy, of using this system in the NICU. Vital signals were simultaneously acquired by using the standard, wired clinical monitor and the ANNEⓇ device. Data from 10 NICU infants were recorded for 8 hours per day during 4 consecutive days. Initial analysis of the heart rate (HR) data revealed four problems in comparing the signals: 1) gaps in the signals - periods of time for which data were unavailable, 2) wired and wireless signals were sampled at different rates, 3) a delay between the sampled values of wired and wireless signals, and 4) this delay increased with time. To address these problems, we developed a pre-processing algorithm that interpolated samples in short gaps, resampled the signals to an equal rate, estimated the delay and drift rate between corresponding signals, and aligned the signals. Applications of the pre-processing algorithm to 40 recordings demonstrated that it was very effective. A strong agreement between wireless and wired HR signals was seen, with an average correlation of 0.95±0.04, a slope of 1.00, and a variance accounted for 89.56±7.62%. Bland-Altman analysis showed a low bias across the ensemble, with an average difference of 0.11 (95% confidence interval of -0.02 to 0.24) bpm.Clinical relevance- This algorithm provides the means for a detailed comparison of wired and wireless monitors in the NICU.


Real-time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder.
Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self-control, underpinned by inferior fronto-striatal deficits. Real-time functional magnetic resonance neurofeedback (rtfMRI-NF) allows participants to gain self-control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological-NF on ADHD symptoms, no study has applied the spatially superior rtfMRI-NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI-NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region-specificity, an active control group received rtfMRI-NF of the left parahippocampal gyrus (lPHG). Thirty-one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI-NF runs over 2 weeks. Feedback was provided through a video-clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11-month follow-up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof-of-concept study demonstrates for the first time feasibility, safety, and shorter- and longer-term efficacy of rtfMRI-NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190-3209, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.


Recombination rate predicts inversion size in Diptera.
Most species of the Drosophila genus and other Diptera are polymorphic for paracentric inversions. A common observation is that successful inversions are of intermediate size. We test here the hypothesis that the selected property is the recombination length of inversions, not their physical length. If so, physical length of successful inversions should be negatively correlated with recombination rate across species. This prediction was tested by a comprehensive statistical analysis of inversion size and recombination map length in 12 Diptera species for which appropriate data are available. We found that (1) there is a wide variation in recombination map length among species; (2) physical length of successful inversions varies greatly among species and is inversely correlated with the species recombination map length; and (3) neither the among-species variation in inversion length nor the correlation are observed in unsuccessful inversions. The clear differences between successful and unsuccessful inversions point to natural selection as the most likely explanation for our results. Presumably the selective advantage of an inversion increases with its length, but so does its detrimental effect on fertility due to double crossovers. Our analysis provides the strongest and most extensive evidence in favor of the notion that the adaptive value of inversions stems from their effect on recombination.


PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival.
Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2-3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.


One-month exposure to inhaled endotoxin produces a dose-dependent increase in stored mucosubstances in rat intrapulmonary airways.
This study examined the production of stored mucosubtances in rats after repeated exposure to aerosolized endotoxin, a common contaminant of bioaerosols. Male Fischer 344 rats were exposed to aerosolized saline (sham control) or endotoxin (target concentrations of 0.05, 0.5, and 5.0 micrograms/m3) for 3 h/day, 5 days/week for 4 weeks. Following the final exposure, the left lung of each animal was lavaged and the right lung and nasal cavity were fixed with buffered formalin. Morphometric examination of Alcian blue/Periodic acid Schiffs-stained (AB/PAS) lung sections demonstrated dose-dependent increases in stored intraepithelial mucosubstances in the intrapulmonary airways of endotoxin-exposed rats. Threefold and eightfold increases in stored mucosubstances were observed in generation 5 airways of animals exposed to 0.5 or 5.0 microgram/m3 endotoxin, respectively (p < .05). This mucous cell metaplasia in the intrapulmonary airways was not accompanied by evidence of lung inflammation or increased AB/PAS-staining high molecular weight material in lavage fluid. Furthermore, despite significant deposition of endotoxin aerosols (mass median aerodynamic diameter of 1.9 microns) in the nasal cavity, no significant changes in stored mucosubstances were observed in the nasal septum. In animals repeatedly exposed to 5.0 micrograms/m3 endotoxin and allowed to recover for 1 month, stored mucosubstances in the intrapulmonary airway were still more than fivefold greater than control values. Thus, in rats, repeated exposure to inhaled endotoxin produced a persistent mucous cell metaplasia only in the intrapulmonary airways.


Static pressure-volume curves and effect of positive end-expiratory pressure on gas exchange in adult respiratory distress syndrome.
Fifteen patients with adult respiratory distress syndrome (ARDS) were studied: 11 in the early stage of ARDS (group 1); 4 in the late stage (group 2). The inspiratory and expiratory static pressure-volume (P-V) curves of the respiratory system were compared to the pulmonary shunt (Qsp/Qt) when PEEP was increased; cardiac output was kept constant. In group 1 patients, we found that a concavity on the P-V curves was associated with an abrupt decrease in Qsp/Qt when PEEP was increased; the concavity on the expiratory curve was correlated with the change in Qsp/Qt but not the concavity on the inspiratory curve. In group 2 patients, the P-V curves were found rectilinear and Qsp/Qt was not abruptly decreased when PEEP was increased. Expiratory P-V curve can be used to determine: first, whether a patient should be ventilated with PEEP; second, the PEEP level which can be set on the respirator. In group 1 patients, when PEEP was set to a value corresponding to the inflexion point, i.e., the point of departure from the exponential shape (mean value 14.6 +/- 2.8 cm H2O), Qsp/Qt compared to zero PEEP was abruptly decreased to 87.6 +/- 6%; further increase in PEEP had little advantage.


Suppression of scientific research: bahramdipity and nulltiple scientific discoveries.
The fairy tale The Three Princes of Serendip can be taken to be allegorical of not only chance discovery (serendipity) but of other aspects of scientific discovery as well. Just as Horace Walpole coined serendipity, so can the term bahramdipity be derived from the tale and defined as the cruel suppression of a serendipitous discovery. Suppressed, unpublished discoveries are designated nulltiples. Several examples are presented to make the case that bahramdipity is an existent aspect of scientific discovery. Other examples of non-ideal scientific research and discovery are provided in order to contrast and clarify the meaning and use of bahramdipity. Additional allegories of scientific discovery are taken from the tale and a hope for the strengthening of scientific integrity is expressed.


Older people's driving habits, visual abilities, and subjective assessment of daily visual functioning.
To explore the relationship between the status of daily visual functions, as measured by Mangione et al.'s (1992) ADVS, and: (a) visual functions that are related to driving; (b) the tendency of elderly people to drive in different visual conditions; and (c) the reasons older people give for limiting their driving under different conditions. The subjects were 80 elderly people, ages 64-85. Seventy three of these people still drove and seven had quit driving. Each participant was individually administered (a) a subjective questionnaire containing the ADVS and questions from the Established Populations for the Epidemiological Studies of the Elderly (EPESE); (b) objective measures of visual performance including visual acuity, contrast sensitivity, and visual search speed. Strong correlations were obtained between the responses to the subjective questionnaire and the objective measures of visual skills. Most subjects were cognizant of the changes in their quality of vision and changed their driving habits accordingly by avoiding driving at dark, on unfamiliar roads, and on long trips. There were also significant associations between the changes in driving behavior and performance on the vision tests. The ADVS can be used as a self-administered test of driving-related visual functioning, and is most relevant to self-restrictions in night driving.


The Mediterranean deep-water kelp Laminaria rodriguezii is an endangered species in the Adriatic Sea.
Deep-water kelps are little-known large brown algae occurring close to the lower limit of photosynthetic life in the sea. This study compares historical and recent records of the deep-water Mediterranean kelp Laminaria rodriguezii in the Adriatic Sea. Historical records include data from herbarium collections and trawling fishery expeditions in the mid-twentieth century, while recent data comprise records of the last 17 years from MEDITS expeditions, ROV surveys of historical kelp locations, benthic surveys and records by fishermen. Altogether, these findings demonstrate that the Adriatic population of L. rodriguezii has suffered a decline of more than 85 % of its historical range and is now present only around the small offshore island of Palagruža. Bottom trawling activities are presumably responsible for the disappearance elsewhere. We propose to classify L. rodriguezii as "Endangered" in the Adriatic Sea under IUCN criteria B1ab(i,iii,iv), ver 3.1. Oceanographic characteristics of the habitat suggest that besides high water transparency, presence of North Adriatic Dense Water with both strong currents and stable low temperatures of around 14 °C are essential oceanographic factors for the development of L. rodriguezii in the Central Adriatic. The origin of cold water thus differs from that at upwelling sites permitting populations of tropical deep-water kelps. The phylogenetic position of L. rodriguezii is so far unknown. DNA sequences from nuclear and cytoplasmic markers of two thalli from Croatia and the western Mediterranean confirmed that L. rodriguezii is a member of the Laminariaceae and most closely related to L. ochroleuca, L. pallida and the Brazilian deep-water kelp L. abyssalis.


Incidence of cerebral vasospasm after endovascular treatment of acutely ruptured aneurysms: report on 69 cases.
Cerebral vasospasm is the most common cause of morbidity and mortality in patients admitted to the hospital after suffering aneurysmal subarachnoid hemorrhage (SAH). The early surgical removal of subarachnoid clots and irrigation of the basal cisterns have been reported to reduce the incidence of vasospasm. In contrast to surgery, the endovascular treatment of aneurysms does not allow removal of subarachnoid clots. In this study the authors measured the incidence of symptomatic vasospasm after early endovascular treatment of acutely ruptured aneurysms with Guglielmi detachable coils (GDCs). Sixty-nine patients classified as Hunt and Hess Grades I to III underwent occlusion of intracranial aneurysms via GDCs within 72 hours of rupture. The amount of blood on the initial computerized tomography (CT) scan was classified by means of Fisher's scale. Symptomatic vasospasm was defined as the onset of neurological deterioration verified with angiographic or transcranial Doppler studies. Hypertensive, hypervolemic, hemodilution therapy, with or without intracranial angioplasty, was used to treat vasospasm after GDC placement. Symptomatic vasospasm occurred in 16 (23%) of 69 patients. The clinical grade at admission and the amount of blood on the initial CT were both associated with the incidence of subsequent vasospasm. At 6-month clinical follow-up examination, 12 of these 16 patients experienced a good recovery, two were moderately disabled, and two patients had died of vasospasm. In conclusion, the 23% incidence of symptomatic vasospasm in this series compares favorably with that found in conventional surgical series of patients with acute aneurysmal SAH. These results indicate that endovascular therapy does not have an unfavorable impact on cerebral vasospasm.


GLP-1 Analog Modulates Appetite, Taste Preference, Gut Hormones, and Regional Body Fat Stores in Adults with Obesity.
Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7-36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.


Infrared band assignments and structure of even-numbered 2-alkyl-7,7, 8, 8-tetracyanoquinodimethane in cast films--two components of the CH2 scissoring vibrations not related to crystal field splitting.
Infrared (IR) spectra were measured for 2-octyl-, 2-dodecyl-, and 2-octadecyl-7, 7, 8, 8-tetracyanoquinodimethane (C8TCNQ, C12 TCNQ and C18 TCNQ) in cast films, and it was found that each spectrum shows two components for the CH2 scissoring band at 1 471 and 1 462 cm(-1). Polarized IR measurements showed that the micro-crystallites in the cast films take a random orientation in the plane of the plate. The intensity ratio of the two bands at 1 471 and 1 462 cm(-1) (I1 471/I1 462) decreases observably with the increase in the length of the alkyl chain. Moreover, the relative intensity of the 1 471 cm(-1) CH2 band to a band at 1 529 cm(-1) (C=C stretching mode of the TCNQ chromophore ring) does not change significantly for the three kinds of C(n) TCNQ while the relative intensity of the 1 462 cm(-1) CH2 band to the band at 1 529 cm(-1) increases markedly with the length of the alkyl chain. The above variations of the CH2 scissoring doublet of C(n) TCNQ are quite different from those of long-chain fatty acids (stearic acid and lignoceric acid) where the splitting of the CH2 scissoring vibration occurs due to a crystal field splitting. Considering the crystal structure of C12 TCNQ and the above spectral variations, the authors assign the two components of the CH2 scissoring bands at 1 462 and 1 471 cm(-1) of the C(n) TCNQ cast films to the interdigitated and non-interdigitated parts of the alkyl chains, respectively. Furthermore, the conclusion that the length of the non-interdigitated part of the alkyl chain is almost unchanged in the three kinds of even-numbered C(n) TCNQ could also be reached.


Valve surgery in children.
Valve surgery constitutes a small percentage of overall pediatric cardiac practice. Most of the lesions seen are congenital anomalies, often in association with other lesions. Valvotomy and valvuloplasty can usually provide good long term palliation, although reoperation is probably inevitable. The late results of valve replacement in children have been compromised by the rapid calcification of biologic valves. There is some evidence to suggest that this may not occur with homograft valves. The importance of implanting as large a valve as possible is emphasized and follow-up must include an assessment of whether the child is outgrowing the previously implanted prosthesis.


The impact of Worms and Ladders, an innovative health educational board game on Soil-Transmitted Helminthiasis control in Abeokuta, Southwest Nigeria.
In most endemic sub-Saharan African countries, repeated infections with soil-transmitted helminth (STH) occur as early as six weeks after the end of mass drug administration (MDA) with albendazole. In this study, we designed a new health educational board game Worms and Ladders and evaluated its potential to complement MDA with albendazole and reduce reinfection rates through the promotion of good hygiene practices among school-aged children. The evaluation employed a randomized control trial (RCT) design. Baseline knowledge, attitude and practices (KAP) relating to STH were obtained using a questionnaire from 372 pupils across six schools in Abeokuta, Nigeria. Schools were randomly assigned into intervention and control group, with the former and latter receiving Worms and Ladders and the common Snake and Ladder board game respectively. Fresh stool samples were also collected at baseline for STH diagnosis before administering 400mg single dose albendazole. Follow-up assessments of STH burden and KAP were conducted three and six months' post-intervention. Data generated from the study were analyzed using SPSS 20.0 software, with confidence interval set at 95%. Prevalence of STH dropped from 25.0% to 10.4% in the intervention group and 49.4% to 33.3% in the control group at three months' post-intervention. The prevalence further dropped to 5.6% in the intervention group at six months' post-intervention. However, it increased to 37.2% in the control group at six months' post-intervention. There was a significant difference (p<0.05) in prevalence after intervention among the groups. KAP on transmission, control and prevention of STH significantly improved (p<0.05) from 5.2% to 97.9% in the intervention group compared to 6.2% to 7.1% in the control group. The Worms and Ladders board game shows the potential to teach and promote good hygiene behavior among SAC. These findings posit the newly developed game as a reliable tool to complement mass drug administration campaigns for STH control.


Physical characterization of dibasic calcium phosphate dihydrate and anhydrate.
The dehydration of different commercial brands of dibasic calcium phosphate dihydrate (DCPD; CaHPO(4).2H(2)O) was examined over a range of temperatures and water vapor pressures. To determine the main factors affecting the physical stability of DCPD, the baseline characterization of DCPD and dibasic calcium phosphate anhydrate (DCPA; CaHPO(4)) was conducted by thermogravimetric analysis, differential scanning calorimetry and X-ray diffractometry. The surface area and the DCPA content (present as an impurity) depended on the commercial source of DCPD. The larger particles contained a higher concentration of DCPA and the anhydrate exhibited a concentration-dependent acceleratory effect on the dehydration of DCPD. Unlike DCPD, DCPA is physically stable and resisted hydration even when dispersed in water for over 7 months in the temperature range of 4-50 degrees C. In dosage forms containing DCPD, there is a potential for phase transformation to DCPA, while the reverse transition, that is, DCPA --> DCPD appears to be extremely unlikely. Thus, the risk of physical transformation can be minimized by using DCPA in formulations.


A radiobiological review on melatonin: a novel radioprotector.
In spite of the fact that radiotherapy is a common and effective tool for cancer treatment; the radio sensitivity of normal tissues adjacent to the tumor which are unavoidably exposed to radiation limits therapeutic gain. For the sake of improvement in radiation therapy, radiobiology- the study of the action of ionizing radiation on living things- plays a crucial role through explaining observed phenomena, and suggesting improvements to existing therapies. Due to the damaging effects of ionizing radiation, radiobiologists have long been interested in identifying novel, nontoxic, effective, and convenient compounds to protect humans against radiation induced normal tissue injuries. In hundreds of investigations, melatonin (N-acetyl-5-methoxytryptamine), the chief secretory product of the pineal gland in the brain, has been documented to ameliorate the oxidative injuries due to ionizing radiation. This article reviews different features that make melatonin a potentially useful radioprotector. Moreover, based on radiobiological models we can hypothesize that melatonin may postpone the saturation of repair enzymes which leads to repairing more induced damage by repair system and more importantly allows the use of higher doses of radiation during radiotherapy to get a better therapeutic ratio. The implications of the accumulated observations suggest by virtue of melatonin's radioprotective and anticancer effects; it is time to use it as a radioprotector both for radiation workers and patients suffering from cancer either alone for cancer inhibition or in combination with traditional radiotherapy for getting a favorable efficacy/toxicity ratio during the treatment. Although compelling evidence suggests that melatonin may be effective for a variety of disorders, the optimum dose of melatonin for human radioprotection is yet to be determined. We propose that, in the future, melatonin improve the therapeutic ratio in radiation oncology.


Carbohydrate-to-carbohydrate interaction, through glycosynapse, as a basis of cell recognition and membrane organization.
Cell adhesion mediated by carbohydrate-to-carbohydrate interaction (CCI), or cell adhesion with concurrent signal transduction, are discussed in three contexts.1. Types of cell adhesion based on interaction of several combinations of glycosphingolipids (GSLs) at the surface of interfacing cells (" trans interactio") are reviewed critically, to exclude the possible involvement of GSL-binding proteins. Special emphasis is on: (i) autoaggregation of mouse teratocarcinoma F9 cells mediated by Le( x )-to-Le( x ) interaction, in which presence of Le( x )-binding protein is ruled out; (ii) adhesion of GM3-expressing cells to Gg3-expressing cells, in which involvement of GM3- or Gg3-binding protein is ruled out.2. Characteristic features and requirements of CCI, as compared with carbohydrate-to-protein interaction (CPI) and protein-to-protein interaction (PPI), are summarized, including: (i) specificity and requirement of bivalent cation; (ii) reaction velocity of CCI as compared to PPI; (iii) negative (repulsive) interaction; (iv) synergistic or cooperative effect of CCI and PPI, particularly GM3-to-Gg3 or GM3-to-LacCer interaction in synergy with integrin-dependent adhesion, or Le( x )-to-Le( x ) interaction in cooperation with E-cadherin-dependent adhesion.3. Microdomains at the cell surface are formed based on clustering of GSLs or glycoproteins organized with signal transducers. Among such microdomains, those involved in adhesion coupled with signal transduction to alter cellular phenotype are termed "glycosynaps". In some glycosynapses, growth factor receptors or integrin receptors are also involved, and their function is modulated by GSLs only when the receptor is N -glycosylated. This modulation may occur in part via interaction of GSLs with N -linked glycans of the receptor, termed " cis interactio".


Promoting nurse practitioner practice through research: opportunities, challenges, and lessons.
To discuss the opportunities derived, challenges faced, and lessons learned in the research process, including recruiting and retaining nurse practitioner (NP) participants, obtaining institutional approval, and solving research team issues in a National Institutes of Health/National Institute of Nursing Research (NIH/NINR)-funded study of communication between NPs and their older patients in managed care and non-managed care settings. The video-taped interactions between 30 NPs and 150 patients, research team experiences in conducting the research, and a review of relevant literature. Key factors in NP study participation included recognizing the importance of research in demonstrating the effectiveness of the NP role and for advancing the profession, having participated in previous research, enjoying the research process, employer incentives, membership in NP professional organizations, relationships with the university and the school of nursing conducting the research, and knowledge of the coinvestigator's work. NP recruitment was facilitated by word of mouth, professional organization assistance, and articles in a widely distributed, free nursing journal. Data collection was significantly delayed by attrition of NP participants, logistical problems with scheduling and travel, and varied approval procedures by Institutional Review Boards (IRBs) at study sites. The pace of nursing research could be much more efficient if IRB processes involved fewer bureaucratic entanglements. Preliminary study findings, however, show positive outcomes for older patients after NP care. To demonstrate positive patient outcomes and move the NP profession forward, NPs must be willing to commit to participation in research on their effectiveness as providers in today's healthcare environment.


Directly drawn poly(3-hexylthiophene) field-effect transistors by electrohydrodynamic jet printing: improving performance with surface modification.
In this study, direct micropatterning lines of poly(3-hexylthiophene) (P3HT) without any polymer binder were prepared by electrohydrodynamic jet printing to form organic field-effect transistors (OFETs). We controlled the dielectric surface by introducing self-assembled monolayers and polymer thin films to investigate the effect of surface modifications on the characteristics of printed P3HT lines and electrical performances of the OFETs. The morphology of the printed P3HT lines depended on the surface energy and type of substrate. The resulting OFETs exhibited high performance on octadecyltrichlorosilane-modified substrates, which was comparable to that of other printed P3HT OFETs. In order to realize the commercialization of the OFETs, we also fabricated a large-area transistor array, including 100 OFETs and low-operating-voltage flexible OFETs.


[Evaluation of a local infant formula enriched with polyunsaturated fatty acids produced in Israel].
Polyunsaturated fatty acids (PUFA) are vital for the normal development of the brain and the eye retina in infancy. Breast milk contains significant amounts of PUFA, and compensates for their low production in infancy. Only recently a few companies with worldwide product distribution have started to enrich infant formula with PUFA. We evaluated the safety and clinical efficacy of a locally made PUFA-enriched infant formula, produced for the first time in Israel. 50 normal, full term infants participated in a prospective, randomized double-blind study. Half received a regular whey-predominant infant formula (Materna Plus), and the other half a PUFA-enriched formula (Materna Premium), both produced in Israel, for 30 days. Evaluation included physical examination, growth parameters, stool analysis, daily parental questionnaires regarding infant behavior and defecation, and developmental assessment. There were no significant differences on comparing growth parameters, infant behavior, attacks of restlessness, gas severity, or stool characteristics in the 2 groups. There were no side effects or abnormal stool findings in either group, and no differences in developmental assessment at 3 months of age. We conclude that the locally-produced PUFA-enriched infant formula is safe and clinically efficient. We assume that the lack of any effect on developmental indices is due to the relatively short exposure to the PUFA-enriched diet. Nevertheless, based on the recent literature, there is no doubt that PUFA supplementation is vital in improving infant brain and eye development.


Overexpression of a tomato carotenoid ε-hydroxylase gene alleviates sensitivity to chilling stress in transgenic tobacco.
Chilling is one of the most serious environmental stresses that disrupt the metabolic balance of cells and enhance the production of reactive oxygen species (ROS). Lutein plays important roles in dissipating excess excitation energy and eliminating ROS to maintain the normal physiological function of cells. A tomato carotenoid epsilon-ring hydroxylase gene (LeLUT1) was isolated, and the LeLUT1-GFP fusion protein was localized in the chloroplast of Arabidopsis mesophyll protoplast. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that the expression of LeLUT1 was the highest in the leaves and was down-regulated by various abiotic stresses in tomato. The transgenic tobacco plants overexpressing LeLUT1 had higher lutein content, which was decreased in cold condition. Under chilling stress, the non-photochemical quenching (NPQ) values were higher in the transgenic plants than in the wild type (WT) plants. Compared with the WT plants, the transgenic plants showed lower levels of hydrogen peroxide (H2O2), superoxide radical (O2(·-)), relative electrical conductivity, and malondialdehyde content (MDA), and relatively higher values of maximal photochemical efficiency of photosystem II (Fv/Fm), oxidizable P700 of PSI, and net photosynthetic rate (Pn). Therefore, the transgenic seedlings were less suppressed in growth and lost less cotyledon chlorophyll than the WT seedlings. These results suggested that the overexpression of LeLUT1 had a key function in alleviating photoinhibition and photooxidation, and decreased the sensitivity of photosynthesis to chilling stress.


Evaluation of health care providers' use of the 'Exercise and Depression Toolkit': a case study.
Exercise is now recommended as a primary treatment for mild-moderate depression in Canada. The 'Exercise and Depression Toolkit' was developed to help health care providers (HCP) integrate these treatment guidelines into practice. The purpose of this study was to evaluate acceptability and perceived effectiveness of the toolkit in practice by HCPs working with individuals with depression. A case study design was utilized. The toolkit was given to 6 HCPs to use in practice for 4 weeks. Pre- and post-intervention phone interviews were conducted, and weekly logs were provided to track use and satisfaction of interactions with individuals with depression when using the toolkit. The study was conceptually guided by a hybrid theoretical approach using the Diffusion of Innovation Theory and the Theoretical Framework of Acceptability. All HCPs used the toolkit at least once. Participants viewed their interactions when using the toolkit to be successful (considering individuals' receptiveness, its usefulness and general satisfaction.) The average success score for all participants was 5.5/7. HCPs found the toolkit to be acceptable. All participants (n = 6) viewed the toolkit as having relative advantage in helping them to discuss exercise with individuals with depression, and as relatively simple and easy to use (not complex) and adaptable to their practice needs (having trialability). Participants liked the toolkit and had mostly positive things to say about it. Participants had mixed feelings about whether changes in the people they worked with (such as mood and activity levels) could be observed (observability) and whether the toolkit changed their belief in their ability to recommend or discuss exercise (self-efficacy). Recommended dissemination strategies were adopted in promoting the toolkit. Future work should address observability and the ability for health care providers to see other providers using it, as well as effectiveness considering outcomes for people with depression such as mood and activity changes. The results of this initial evaluation seem promising for uptake and future adoption of the toolkit by health care providers working with adults with depression in Canada.


The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5.
Innate immunity is the first-line defense against antiviral or antimicrobial infection. RIG-I and MDA5, which mediate the recognition of pathogen-derived nucleic acids, are essential for production of type I interferons (IFN). Here, we identified mitochondrion depolarization inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) inhibited the response and antiviral activity of type I IFN during viral infection. Furthermore, we found that the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin mediated mitophagy, thus negatively regulating the activation of RIG-I and MDA5. Parkin directly interacted with and catalyzed the K48-linked polyubiquitination and subsequent degradation of RIG-I and MDA5. Thus, we demonstrate that Parkin limits RLR-triggered innate immunity activation, suggesting Parkin as a potential therapeutic target for the control of viral infection.


The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.


Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985-1995).
Medical records of 104 cats with diabetes mellitus were reviewed. Information from 54 cats that had multiple blood glucose concentrations evaluated at least 5 times over a minimum of 3 months, beginning at the time insulin treatment was initiated, was used to evaluate the efficacy of insulin in treating diabetes mellitus. Fourteen of 54 cats were treated with protamine zinc insulin (PZI), 26 with ultralente insulin, and 14 with lente insulin. Six, 29, and 19 cats had good, mediocre, and poor glycemic control, respectively, based on mean blood glucose concentrations, whereas 31, 21, and 2 owners thought clinical response was good, mediocre, and poor, respectively. No significant difference was found in glycemic control among cats treated with PZI, ultralente, or lente insulin. Glycemic control was significantly (P < .05) better in 33 cats without than in 21 cats with concurrent disease. All 104 cats were used to calculate survival data. Fifty-one of 104 cats were alive at the time of the study. Mean (+/- standard deviation [SD]) and median survival times were 24 (+/- 16) and 20 months, respectively, in the 51 cats still alive at the end of the evaluation, and 25 (+/- 4) and 17 months, respectively, in the 53 cats that had died during the period of evaluation. Pancreatic abnormalities identified in 37 cats that underwent necropsy included chronic pancreatitis (n = 17), acute to subacute pancreatitis (n = 2), exocrine pancreatic adenocarcinoma (n = 7) and adenoma (n = 1), islet cell atrophy and vacuolar degeneration (n = 27), and islet amyloidosis (n = 8). No association was found between glycemic control and islet amyloidosis or exocrine pancreatic neoplasia, or between survival time and chronic pancreatitis, islet amyloidosis, or exocrine pancreatic neoplasia. In conclusion, diabetic cats evaluated in this study showed a variable response to exogenously administered insulin, ranging from excellent to poor. By maintaining mean blood glucose concentrations under 300 mg/dL, clinical signs were improved, and owners were satisfied with insulin treatment. Concurrent potentially insulin-antagonistic diseases were common and deleteriously affected glycemic control and survival time.


Seroprevalence of viral infections in captive rhesus and cynomolgus macaques.
Macaques serve as important animal models for biomedical research. Viral infection of macaques can compromise animal health as well as the results of biomedical research, and infected animals constitute an occupational health risk. Therefore, monitoring macaque colonies for viral infection is an important task. We used a commercial chip-based assay to analyze sera of 231 macaques for the presence of antibody responses against nine animal and human viruses. We report high seroprevalence of cytomegalovirus (CMV), lymphocryptovirus (LCV), rhesus rhadinovirus (RRV) and simian foamy virus (SFV) antibodies in all age groups. In contrast, antibodies against simian retrovirus type D (SRV/D) and simian T cell leukemia virus (STLV) were detected only in 5 % and 10 % of animals, respectively, and were only found in adult or aged animals. Moreover, none of the animals had antibodies against herpes B virus (BV), in keeping with the results of in-house tests previously used for screening. Finally, an increased seroprevalence of measles virus antibodies in animals with extensive exposure to multiple humans for extended periods of time was observed. However, most of these animals were obtained from external sources, and a lack of information on the measles antibody status of the animals at the time of arrival precluded drawing reliable conclusions from the data. In sum, we show, that in the colony studied, CMV, LCV, RRV and SFV infection was ubiquitous and likely acquired early in life while SRV/D and STLV infection was rare and likely acquired during adulthood.


Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight.
The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals, such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously lose body fat.