The dimeric ectodomain of the alkali-sensing insulin receptor-related receptor (ectoIRR) has a droplike shape.
Insulin receptor-related receptor (IRR) is a receptor tyrosine kinase of the insulin receptor family and functions as an extracellular alkali sensor that controls metabolic alkalosis in the regulation of the acid-base balance. In the present work, we sought to analyze structural features of IRR by comparing them with those of the insulin receptor, which is its closest homolog but does not respond to pH changes. Using small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM), we investigated the overall conformation of the recombinant soluble IRR ectodomain (ectoIRR) at neutral and alkaline pH. In contrast to the well-known inverted U-shaped (or λ-shaped) conformation of the insulin receptor, the structural models reconstructed at different pH values revealed that the ectoIRR organization has a "droplike" shape with a shorter distance between the fibronectin domains of the disulfide-linked dimer subunits within ectoIRR. We detected no large-scale pH-dependent conformational changes of ectoIRR in both SAXS and AFM experiments, an observation that agreed well with previous biochemical and functional analyses of IRR. Our findings indicate that ectoIRR's sensing of alkaline conditions involves additional molecular mechanisms, for example engagement of receptor juxtamembrane regions or the surrounding lipid environment.


Cancer-related fatigue: a review.
Cancer-related fatigue is the most prevalent cancer symptom, reported in 50%-90% of patients and severely impacts quality of life and functional capacity. The condition remains underreported and often goes untreated. Guidelines suggest screening for fatigue at the initial visit, when the diagnosis of advanced disease is made, and at each chemotherapy session, as well as the identification of treatable contributing factors such as anemia, hypothyroidism, depression and sleep disorders. Brief assessment tools such as the Brief Fatigue Inventory or the Visual Analog Scale may be appropriate in the initial scoring of fatigue severity, but the initial approach to treatment usually requires a more comprehensive assessment, education, and the determination of an individualized treatment plan. Patients with moderate or severe fatigue may benefit from both pharmacological and non-pharmacological interventions, whereas mild fatigue that does not interfere with quality of life can be treated with non-pharmacological measures alone. Non-pharmacological measures that have shown to be promising include cognitive-behavioral interventions such as energy conservation and activity management (ECAM), exercise and perhaps sleep therapy. Many other modalities may be beneficial and can be used on an individual basis, but there is insufficient evidence to promote any single treatment. Pharmacological therapies that have shown to be promising include the psycho-stimulants methylphenidate and dexmethylphenidate, modafinil (in severely fatigued patients only), and erythropoietin-stimulating agents in patients with chemotherapy-associated anemia and hemoglobin levels < 10 g/dL. Recently, our group reported impressive results with the use of the dry extract of Guarana (Paullinia cupana), with no significant side effects and at low cost, for the treatment of physical and mental cancer-related fatigue.


Oral Nitroglycerin Solution May Be Effective for Esophageal Food Impaction.
Esophageal food impaction is a common illness presenting to emergency departments (ED), and is frequently resistant to pharmacologic therapy. Several medications have been promoted for this indication, but so far have not proven effective. Endoscopic removal is frequently required to resolve the impaction, resulting in risks from anesthesia and the physical procedure, and in prolonged hospital stay for recovery. Oral nitroglycerin solution was recently used in two such cases and may represent a new therapeutic option. A 49-year-old man presented to an ED with dysphagia 30 min after eating steak. He was given 0.4 mg nitroglycerin dissolved in 10 mL tap water orally, and obtained complete relief of symptoms within 2 min. A 43-year-old man with eosinophilic esophagitis and two prior food impaction episodes presented to a community ED with dysphagia and epigastric discomfort 110 min after eating steak. Five hours after symptom onset and after failure of intravenous glucagon, he was given 0.4 mg nitroglycerin sublingually, which resulted in headache but no relief in dysphagia. Twenty-nine minutes later he received 0.4 mg nitroglycerin solution, as above, with symptom resolution within 2 min. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The cases presented above demonstrate close temporal relationships between administration of oral nitroglycerin solution and symptom relief. Oral nitroglycerin solution for esophageal food impaction seemed effective in these cases, but further research on this therapeutic option is warranted.


Complex Chromosomal Rearrangement Involving Chromosomes 10 and 11, Accompanied by Two Adjacent 11p14.1p13 and 11p13p12 Deletions, Identified in a Patient with WAGR Syndrome.
Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.


TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain.
DNA double-strand breaks enhance homologous recombination in cells and have been exploited for targeted genome editing through use of engineered endonucleases. Here we report the creation and initial characterization of a group of rare-cutting, site-specific DNA nucleases produced by fusion of the restriction enzyme FokI endonuclease domain (FN) with the high-specificity DNA-binding domains of AvrXa7 and PthXo1. AvrXa7 and PthXo1 are members of the transcription activator-like (TAL) effector family whose central repeat units dictate target DNA recognition and can be modularly constructed to create novel DNA specificity. The hybrid FN-AvrXa7, AvrXa7-FN and PthXo1-FN proteins retain both recognition specificity for their target DNA (a 26 bp sequence for AvrXa7 and 24 bp for PthXo1) and the double-stranded DNA cleaving activity of FokI and, thus, are called TAL nucleases (TALNs). With all three TALNs, DNA is cleaved adjacent to the TAL-binding site under optimal conditions in vitro. When expressed in yeast, the TALNs promote DNA homologous recombination of a LacZ gene containing paired AvrXa7 or asymmetric AvrXa7/PthXo1 target sequences. Our results demonstrate the feasibility of creating a tool box of novel TALNs with potential for targeted genome modification in organisms lacking facile mechanisms for targeted gene knockout and homologous recombination.


Extension of neurites on axons is impaired by antibodies against specific neural cell surface glycoproteins.
We have developed an in vitro assay which measures the ability of growth cones to extend on an axonal substrate. Neurite lengths were compared in the presence or absence of monovalent antibodies against specific neural cell surface glycoproteins. Fab fragments of antibodies against the neural cell adhesion molecule, NCAM, have an insignificant effect on the lengths of neurites elongating on either an axonal substrate or a laminin substrate. Fab fragments of polyclonal antibodies against two new neural cell surface antigens, defined by mAb G4 and mAb F11, decrease the lengths of neurites elongating on an axonal substrate, but have no effect on the lengths of neurites elongating on a laminin substrate. G4 antigen is related to mouse L1, while F11 antigen appears to be distinct from all known neural cell surface glycoproteins. Our results suggest that the G4 and F11 antigens help to promote the extension of growth cones on axons.


Photoacoustic-based oxygen saturation assessment of murine femoral bone marrow in a preclinical model of leukemia.
A variety of hematological diseases manifest in the bone marrow (BM), broadly characterized as BM failure (BMF). BMF can be caused by acute lymphoblastic leukemia (ALL), which results in an expansion of hypoxic regions in the BM. Because of this hypoxic presentation, there is potential for improved characterization of BMF through in vivo assessment of oxygenation in the BM cavity. Photoacoustic (PA) imaging can provide local assessment of intravascular oxygen saturation (SO2), which has been shown to correlate with pimonidazole-assessed hypoxia. This study introduces an optimized PA imaging technique to assess SO2 within the femoral BM cavity through disease progression in a murine model of ALL. Results show a statistically significant difference with temporal changes in SO2 (from baseline) between control and diseased cohorts, demonstrating the potential of PA imaging for noninvasive, label-free monitoring of BMF diseases.


Intracerebellar penetrating injury and abscess due to a wooden foreign body--case report.
A 4-year-old boy presented with chopstick penetration into the cerebellum via the temporal squamosa and tentorium cerebelli, which resulted in a cerebellar abscess 1.5 years after the injury. The neuroimaging appearance of the wooden chopstick were unusual, hyperdense on computed tomography, and isointense on T2-weighted and hypointense on T2-weighted magnetic resonance imaging. Abscess aspiration and continuous drainage was performed with real-time intraoperative ultrasound guidance. The chopstick fragment was surgically removed and the patient discharged with minor neurological deficits. Wooden foreign body may show changes in properties after a long period of intraparenchymal retention. Extra care is required to remove wooden foreign bodies because of the high risk of infection.


A comparative study of the type-3 fimbriae of Klebsiella species.
Type-3 fimbriae isolated from members of five different species of Klebsiella were 4-5 nm in diameter and agglutinated the tannic acid-treated erythrocytes of ox and, in some cases, the untanned erythrocytes of fowl. In sodium dodecyl sulphate-polyacrylamide gel electrophoresis, the type-3 fimbrial proteins had mol. wts in the range 19 500-21 500. Hydrophobic amino acids comprised 39.6% of all the amino acids of the type-3 fimbrial protein of K. oxytoca strain 70/1. The type-1 fimbrial protein of Klebsiella had a mol. wt of c. 18 000 and the type-1 fimbriae were serologically distinct from the type-3 fimbriae. Our results for the type-3 fimbriae of Klebsiella were compared with those of others for morphologically similar and serologically related thin fimbriae of Salmonella and Yersinia.


Radiotherapy resources for the care of head and neck patients in Italy. A survey by the head and neck group of the Italian Association for Radiation Oncology (AIRO).
In 2006 a survey was performed to define the resources available in Italy for the provision of radiotherapy services to head and neck cancer patients. This was the first initiative of the newly founded Head and Neck Group of the Italian Association for Radiation Oncology. A questionnaire was sent to all 138 radiotherapy centers active in the country. Items investigated included total numbers of head and neck cancer patients treated per year, waiting time before the start of treatment, general technical issues, and integration with surgery and chemotherapy. Sixty-nine questionnaires were returned (50% response rate). The total number of patients treated was 4,670, averaging 68 cases per center. The larynx was the primary site most frequently involved. Average waiting time was 30 days and 47 days for nonresected and postoperative cases, respectively. The combination of chemotherapy and radiotherapy was delivered to nonresected and resected patients in 96% and 54% of centers, respectively. Survey response rates, waiting time, and the use of organ preservation protocols were the issues showing more variations across the country. This survey provides important data on radiotherapy resources available for head and neck cancer patients in Italy. The evidence of significant differences across the country concerning several relevant issues and the potential for cooperative clinical efforts in this relatively rare group of diseases urge the Group to plan further initiatives.


Practical use of sex-maturity rating in adolescents.
We believe that the use of sex-maturity ratings as a routine part of physical examinations for adolescents is of value to all physicians caring for adolescents. The information is useful not only in following the growth of an individual patient but in detecting early abnormal patterns of adolescent development and also as a means of comparison with other adolescents. Because anaemia or a low haemoglobin-haematocrit value is a major concern during growth, we believe norms related to the sex, race, and maturity rating of an adolescent patient are of significant value. Caloric intake as well as dietary iron intake and percentage of transferrin saturation tend to increase with increasing maturity ratings and provide an indication for further evaluation if they are below the mean and standard deviation for the rating of maturity.


Polymer Brushes via Controlled, Surface-Initiated Atom Transfer Radical Polymerization (ATRP) from Graphene Oxide.
A method for growing polymers directly from the surface of graphene oxide is demonstrated. The technique involves the covalent attachment of an initiator followed by the polymerization of styrene, methyl methacrylate, or butyl acrylate using atom transfer radical polymerization (ATRP). The resulting materials were characterized using a range of techniques and were found to significantly improve the solubility properties of graphene oxide. The surface-grown polymers were saponified from the surface and also characterized. Based on these results, the ATRP reactions were determined to proceed in a controlled manner and were found to leave the structure of the graphene oxide largely intact.


DNA ligase III is degraded by calpain during cell death induced by DNA-damaging agents.
A yeast two-hybrid screen identified the regulatory subunit of the calcium-dependent protease calpain as a putative DNA ligase III-binding protein. Calpain binds to the N-terminal region of DNA ligase III, which contains an acidic proline, aspartate, serine, and threonine (PEST) domain frequently present in proteins cleaved by calpain. Recombinant DNA ligase III was a substrate for calpain degradation in vitro. This calpain-mediated proteolysis was calcium-dependent and was blocked by the specific calpain inhibitor calpeptin. Western blot analysis revealed that DNA ligase III was degraded in human fibrosarcoma HT1080 cells following exposure to gamma-radiation. The degradation of DNA ligase III was prevented by pretreatment with calpeptin, which protected irradiated cells from death. Calpeptin treatment also blocked 9-amino camptothecin-induced DNA ligase III proteolysis and simultaneously protected the cells from death. HT1080 clones expressing a modified DNA ligase III that lacked a recognizable PEST domain were significantly more resistant to killing by gamma-radiation or 9- amino camptothecin than were cells that overexpressed the wild-type form of DNA ligase III. These data show that calpain-mediated proteolysis of DNA ligase III plays an essential role in DNA damage-induced cell death in human cells.


When prevention promotes creativity: the role of mood, regulatory focus, and regulatory closure.
Promotion-focused states generally boost creativity because they associate with enhanced activation and cognitive flexibility. With regard to prevention-focused states, research evidence is less consistent, with some findings suggesting prevention-focused states promote creativity and other findings pointing to no or even negative effects. We proposed and tested the hypothesis that whether prevention-focused states boost creativity depends on regulatory closure (whether a goal is fulfilled or not). We predicted that prevention-focused states that activate the individual (unfulfilled prevention goals, fear) would lead to similar levels of creativity as promotion-focused states but that prevention-focused states that deactivate (closed prevention goals, relief) would lead to lower levels of creativity. Moreover, we predicted that this effect would be mediated by feelings of activation. Predictions were tested in 3 studies on creative insights and 1 on original ideation. Results supported predictions. Implications for self-regulation, motivation, mood, and creativity are discussed.


The prognosis of lobar pneumonia in the Papua New Guinea Highlands.
Lobar pneumonia, usually caused by pneumococci is the commonest cause for admission to hospitals in Papua New Guinea (PNG). The mortality rate is less than 3%. In a survey of 275 adults (mean age: 36 years) admitted to Goroka hospital in the Highlands of New Guinea with this diagnosis, adverse prognostic factors observed on admission were: age over 40 years, multilobar disease, anaemia (Hb less than 11g/d1) and history of illness commencing more than 7 days before presentation. Additional adverse factors demonstrated after admission included the presence of type 3 pneumococcus and bacteraemia. It is suggested that in the Highlands of PNG initial admission of ambulant patients with lobar pneumonia should be generally restricted to those with any of the first 4 factors.


Multicenter study of genetic abnormalities associated with severe oligospermia and non-obstructive azoospermia.
Objective * Chong Xie, Xiangfeng Chen, and Yulin Liu contributed equally to this work. Genetic defects are identified in nearly 20% of infertile males. Determining the frequency and types of major genetic abnormalities in severe male infertility helps inform appropriate genetic counseling before assisted reproductive techniques. Methods Cytogenetic results of 912 patients with non-obstructive azoospermia (NOA) and severe oligozoospermia (SOS) in Eastern China were reviewed in this multicenter study from January 2011 to December 2015. Controls were 215 normozoospermic men with offspring. Results Among all patients, 22.6% (206/912) had genetic abnormalities, including 27.3% (146/534) of NOA patients and 15.9% (60/378) of SOS patients. Chromosomal abnormalities (all autosomal) were detected in only 1.9% (4 /215) of controls. In NOA patients, sex chromosomal abnormalities were identified in 25.8% (138/534), of which 8% (43/534) had a 47,XXY karyotype or its mosaic; higher than the SOS group prevalence (1.1%; 4/378). The incidence of Y chromosome microdeletions was lower in the SOS group (13.2%; 50/378) than in the NOA group (17.8%; 95/534). Conclusions The high prevalence of genetic abnormalities in our study indicates the importance of routine genetic testing in severe male infertility diagnosis. This may help determine the choice of assisted reproductive technique and allow specific pre-implantation genetic testing to minimize the risk of transmitting genetic defects.


Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors.
E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors. In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis. Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect. E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors.


Is it necessary to suture all lacerations after a vaginal delivery?
Midwives tend to leave minor perineal lacerations to heal spontaneously, and clinical experience and studies show that women can suffer from their stitched lacerations. The study purpose was to determine any differences in the healing process and experience of minor perineal lacerations when they were sutured or not sutured. Eighty term pregnant primiparas with minor perineal lacerations of grades I-II were randomized after childbirth. The experimental group was nonsutured and the control group was sutured. A follow-up examination was performed at 2 to 3 days, 8 weeks, and 6 months after the delivery. Participants were asked about the type of discomfort, and the effect of the laceration on breastfeeding and sexual intercourse. No significant differences were found in the healing process. The type of pain differed between the groups, but the amount of discomfort was the same. The sutured group had to visit the midwife more often because of discomfort from the stitches. Sixteen percent of the women in the sutured group, but none in the nonsutured group (p = 0.0385), considered that the laceration had had a negative influence on breastfeeding. Minor perineal lacerations can be left to heal spontaneously. The benefits for the woman include the possibility of having a choice, avoiding the discomfort of anesthesia and suturing, providing positive affects on breastfeeding.


Respiration audiometry with pre-school children.
Respiration audiometry with a strain gauge writeout on a dynograph was attempted with 12 children aged 3 yrs 6 mo to 4 yrs 11 mo. Test signals were at 1 kc/s of 1 sec duration presented at the beginning of a respiratory cycle, from --10 to 40 db HL in 2 ascending series (test and retest). Both series could be completed on only 5 Ss, due to interruptive behavior patterns. Of all 105 presentations, 13 were judged positive; of these, 9 were at levels lower than the play audiometry HTL (false-positive). For no S could a respiration audiometry HTL be reasonably estimated. Due to the low ratio of respiratory responses at or above behavioral HTL, the low rate of test completion for the majority of preschool Ss, and the presence of significant numbers of false-positive responses, it was recommended that further research be carried out before respiration audiometry is seriously considered or he paedoaudiologic clinic.


Implantable cardiac defibrillators for people with non-ischaemic cardiomyopathy.
There is evidence that implantable cardioverter-defibrillator (ICD) for primary prevention in people with an ischaemic cardiomyopathy improves survival rate. The evidence supporting this intervention in people with non-ischaemic cardiomyopathy is not as definitive, with the recently published DANISH trial finding no improvement in survival rate. A systematic review of all eligible studies was needed to evaluate the benefits and harms of using ICDs for primary prevention in people with non-ischaemic cardiomyopathy. To evaluate the benefits and harms of using compared to not using ICD for primary prevention in people with non-ischaemic cardiomyopathy receiving optimal medical therapy. We searched CENTRAL, MEDLINE, Embase, and the Web of Science Core Collection on 10 October 2018. For ongoing or unpublished clinical trials, we searched the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the ISRCTN registry. To identify economic evaluation studies, we conducted a separate search to 31 March 2015 of the NHS Economic Evaluation Database, and from March 2015 to October 2018 on MEDLINE and Embase. We included randomised controlled trials involving adults with chronic non-ischaemic cardiomyopathy due to a left ventricular systolic dysfunction with an ejection fraction of 35% or less (New York Heart Association (NYHA) type I-IV). Participants in the intervention arm should have received ICD in addition to optimal medical therapy, while those in the control arm received optimal medical therapy alone. We included studies with cardiac resynchronisation therapy when it was appropriately balanced in the experimental and control groups. The primary outcomes were all-cause mortality, cardiovascular mortality, sudden cardiac death, and adverse events associated with the intervention. The secondary outcomes were non-cardiovascular death, health-related quality of life, hospitalisation for heart failure, first ICD-related hospitalisation, and cost. We abstracted the log (hazard ratio) and its variance from trial reports for time-to-event survival data. We extracted the raw data necessary to calculate the risk ratio. We summarised data on quality of life and cost-effectiveness narratively. We assessed the certainty of evidence for all outcomes using GRADE. We identified six eligible randomised trials with a total of 3128 participants. The use of ICD plus optimal medical therapy versus optimal medical therapy alone decreases the risk of all-cause mortality (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.66 to 0.92; participants = 3128; studies = 6; high-certainty evidence). An average of 24 patients need to be treated with ICD to prevent one additional death from any cause (number needed to treat for an additional beneficial outcome (NNTB) = 24). Individuals younger than 65 derive more benefit than individuals older than 65 (HR 0.51, 95% CI 0.29 to 0.91; participants = 348; studies = 1) (NNTB = 10). When added to medical therapy, ICDs probably decrease cardiovascular mortality compared to not adding them (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; participants = 1781; studies = 4; moderate-certainty evidence) (possibility of both plausible benefit and no effect). Implantable cardioverter-defibrillator was also found to decrease sudden cardiac deaths (HR 0.45, 95% CI 0.29 to 0.70; participants = 1677; studies = 3; high-certainty evidence). An average of 25 patients need to be treated with an ICD to prevent one additional sudden cardiac death (NNTB = 25). We found that ICDs probably increase adverse events (possibility of both plausible harm and benefit), but likely have little or no effect on non-cardiovascular mortality (RR 1.17, 95% CI 0.81 to 1.68; participants = 1781; studies = 4; moderate-certainty evidence) (possibility of both plausible benefit and no effect). Finally, using ICD therapy probably has little or no effect on quality of life, however shocks from the device cause a deterioration in quality of life. No study reported the outcome of first ICD-related hospitalisations. The use of ICD in addition to medical therapy in people with non-ischaemic cardiomyopathy decreases all-cause mortality and sudden cardiac deaths and probably decreases mortality from cardiovascular causes compared to medical therapy alone. Their use probably increases the risk for adverse events. However, these devices come at a high cost, and shocks from ICDs cause a deterioration in quality of life.


[Herpes simplex encephalitis (author's transl)].
A 25 months old male with herpes simplex virus encephalitis is presented. After analizing the diagnostic value of several parameters, the E. E. G. findings during the first days of the illness are specially emphasized. Results obtained until now with every type of therapy are reviewed.


Opioid-prescribing Practices in a Graduate Endodontic Clinic before and after Implementation of the Federal Schedule II Prescribing Mandate.
Opioid prescriptions have the potential for misuse. In October 2014, the federal schedule II prescribing mandate reclassified hydrocodone combination products from schedule III to schedule II drugs that required a written prescription. The aim of this study was to evaluate the opioid-prescribing practices in a graduate endodontic clinic (GEC) before and after the mandate. Electronic health records from all patients treated in the GEC from 2010 to 2018 were reviewed retrospectively for opioid prescribing, the date of prescription, and the Current Dental Terminology code. Where opioid prescribing was documented in the electronic health record, additional data were extracted about pulpal and periapical diagnosis, pain level, opioid type, and prescription details. Prescribing rates were calculated and analyzed by using chi-square, analysis of variance, logistic regression, and multivariable analysis. Significance was set at P < .05. Overall, 4851 patients underwent 7841 procedures; 92.2% of patients were never prescribed opioids. The remaining 380 patients underwent 420 procedures, and 509 prescriptions were provided. Prescribing rates were 7.5% (228/3021) before versus 4.0% (192/4820) after the mandate (P < .001). Hydrocodone combinations were the most prescribed opioid (77%, 392/509). Tramadol prescribing increased after the mandate (P = .023). Multivariable analysis showed significantly higher prescribing for apicoectomy procedures (P < .001). Preoperative pulpal and periapical diagnosis and pain level were not significantly associated with opioid prescribing. An overall reduction in opioid-prescribing rates occurred coincidentally with the 2014 federal mandate. The lack of correlation between prescribing and pain level highlighted the need for evidence-based rather than habitual prescribing protocols in the GEC.


The efficacy and toxicity of belotecan (CKD-602), a camptothericin analogue topoisomerase I inhibitor, in patients with recurrent or refractory epithelial ovarian cancer.
This study evaluated the efficacy and toxicity of belotecan (CKD-602), a new camptothecin analogue topoisomerase i inhibitor, in patients with recurrent or refractory epithelial ovarian cancer. Data from 63 patients who had been treated with intravenous belotecan (0.5 mg/m(2)/day), administered for 5 days every 3 weeks at a single institute in Seoul, Korea, were collected retrospectively. The overall response rate was 30.2% including 9 patients with complete remission (CR) and the progression free survival was a median of 6.5 (0.7 - 29.7) months. The platinumsensitive group had a significantly higher response rate and longer progression-free survival more than the platinum-resistant group. The most common adverse effect of belotecan was hematologic toxicity which was tolerable. As a single chemotherapy agent, belotecan was effective in treating recurrent or refractory epithelial ovarian cancer, and had acceptable toxicity. Further studies of the efficacy of belotecan in combination with platinum or the other agents are warranted.


Enumeration of feline platelets in ethylenediamine tetra-acetic acid anticoagulated blood with the ADVIA 2120 system and two manual methods: Leucoplate and Thrombo-TIC.
A manual method (Thrombo-TIC; Bioanalytic GmbH, Umkirch/Freiburg, Germany) was advertised to disaggregate platelet clumps and to make human platelets spherical to improve platelet enumeration. The current study's hypothesis was that this method would perform better than current methods for feline blood anticoagulated with ethylenediamine tetra-acetic acid (EDTA), which often contains platelet aggregates. Platelet concentrations (PLTs) were determined in 21 feline blood samples by 3 methods. Thrombo-TIC was compared to the manual method (Leucoplate; Sobioda, Montbonnot-Saint-Martin, France) currently used in the authors' laboratory along with an ADVIA 2120 (Siemens AG, Eschborn, Germany) optical platelet concentration. Feline blood samples often contained platelet aggregates. ADVIA flagged for platelet aggregates in 11 of the 21 feline blood samples, and examination of blood smear revealed platelet aggregates in 14 of the 21 samples. The hemocytometers displayed more platelet aggregates with the Thrombo-TIC method than with Leucoplate. The method giving the greatest PLT was considered most accurate. The Leucoplate median PLT (238 × 10(9)/1) was greater than Thrombo-TIC (202 × 10(9)/1) or ADVIA (157 × 10(9)/1). Intra-assay precision was determined for the 3 methods using the 21 feline blood samples. Median Thrombo-TIC and Leucoplate precision (7.4% and 7.3% coefficient of variation [CV], respectively) were similar and not much worse than ADVIA (5.9% CV). The Thrombo-TIC method did not appear to perform better than the current manual method (Leucoplate). Leucoplate appeared least affected by platelet aggregation in feline blood. The ADVIA automated PLT appeared to be most negatively affected by platelet aggregation. The Thrombo-TIC method did not appear to prevent platelet aggregation in feline EDTA blood samples and, thus, is not recommended for such use.


Effect of using immobilization device in fluoroscopic study in pediatric patient: Focused on radiation dose reduction in voiding cystourethrogram.
To prove objective effect of using mechanical device for immobilization of pediatric patient during voiding cystourethrogram (VCUG) compare immobilization by hand-holding. This study included 77 patients, who underwent VCUG in our center from April to October 2017, who had a clinically suspicious urinary tract infection. Patients were classified into one of two groups based on whether examination was done before (Group A) or after (Group B) adaptation of immobilization device. Patient-related data, image quality related score and dose-related data were collected and compared between two groups. Group A included 36 patients and group B included 41. Patient related data including mean age, sex, body weight and height didn't show significant difference between two groups (p > 0.05 for all). Among the image quality scoring, overall image quality, motion artifact, showed significant difference between two groups with improved inadequate timing and centering after adaptation of immobilization device. Dose related data showed significantly decreased shot number, mean fluoroscopic time with decreased mean dose area product (DAP) value and effective dose after adaptation of immobilization device (p < 0.05 for all). Adaptation of immobilization device can improve overall image quality with decreased motion artifact and improved centering and timing with even shot number, mean fluoroscopic time with decreased mean DAP value and effective dose.


Facile "living" radical polymerization of methyl methacrylate in the presence of iniferter agents: homogeneous and highly efficient catalysis from copper(II) acetate.
A facile homogeneous polymerization system involving the iniferter agent 1-cyano-1-methylethyl diethyldithiocarbamate (MANDC) and copper(II) acetate (Cu(OAc)2 ) is successfully developed in bulk using methyl methacylate (MMA) as a model monomer. The detailed polymerization kinetics with different molar ratios (e.g., [MMA]0 /[MANDC]0 /[Cu(OAc)2 ]0 = 500/1/x (x = 0.1, 0.2, 0.5, 1.0)) demonstrate that this system has the typical "living"/controlled features of "living" radical polymerization, even with ppm level catalyst Cu(OAc)2 , first order polymerization kinetics, a linear increase in molecular weight with monomer conversion and narrow molecular weight distributions for the resultant PMMA. (1) H NMR spectra and chain-extension experiments further confirm the "living" characteristics of this process. A plausible mechanism is discussed.


An occludin-focal adhesion kinase protein complex at the blood-testis barrier: a study using the cadmium model.
Several integral membrane proteins that constitute the blood-testis barrier (BTB) in mammalian testes, in particular rodents, are known to date. These include tight junction (TJ) proteins (e.g. occludin, junctional adhesion molecule-A, claudins), basal ectoplasmic specialization proteins (e.g. N-cadherin), and gap junction proteins (e.g. connexin43). However, the regulators (e.g. protein kinases and phosphatases) that affect these proteins, such as their interaction with the cytoskeletal actin, which in turn confer cell adhesion at the TJ, remain largely unknown. We report herein that focal adhesion kinase (FAK) is a putative interacting partner of occludin, but not claudin-11 or junctional adhesion molecule-A. Immunohistochemistry and fluorescence microscopy studies illustrated that the expression of FAK in the seminiferous epithelium of adult rat testes was stage specific. FAK colocalized with occludin at the BTB in virtually all stages of the seminiferous epithelial cycle but considerably diminished in stages VIII-IX, at the time of BTB restructuring to facilitate the transit of primary leptotene spermatocytes. Using Sertoli cells cultured in vitro with established TJ-permeability barrier and ultrastructures of TJ, basal ectoplasmic specialization and desmosome-like junction that mimicked the BTB in vivo, FAK was shown to colocalize with occludin and zonula occludens-1 (ZO-1) at the Sertoli-Sertoli cell interface. When these Sertoli cell cultures were treated with CdCl(2) to perturb the TJ-barrier function, occludin underwent endocytic-mediated internalization in parallel with FAK and ZO-1. Thus, these findings demonstrate that FAK is an integrated regulatory component of the occludin-ZO-1 protein complex, suggesting that functional studies can be performed to study the role of FAK in BTB dynamics.


Co-administration of viral vector-based vaccines suppresses antigen-specific effector CD8 T cells.
In this study, we explored immune responses after intramuscular co-administration of the HIV-1 gp160 Env gene-expressing adenovirus (Ad) vector and modified vaccinia virus Ankara (MVA) vector in a mouse model. Surprisingly, the simultaneous vaccination of the two vaccines, either as a mixture or separately, suppressed responses, when compared with the administration of each vaccine separately. Ad vaccine or MVA vaccine, co-administered with a mock MVA or mock Ad vector, also resulted in suppressing HIV-specific effector T-cell responses, and a part of antigen-specific memory T-cell responses. In an in vitro experiment, the two vectors infected individual cells and MVA suppressed the transgene expression produced by the adenovirus vector. This viral interference may involve soluble factor(s), secreted by virus-infected cells. Our study may help in designing a vaccination regimen and in investigating viral interference.


Standardizing the nomenclature for clonal lineages of the sudden oak death pathogen, Phytophthora ramorum.
Phytophthora ramorum, the causal agent of sudden oak death and ramorum blight, is known to exist as three distinct clonal lineages which can only be distinguished by performing molecular marker-based analyses. However, in the recent literature there exists no consensus on naming of these lineages. Here we propose a system for naming clonal lineages of P. ramorum based on a consensus established by the P. ramorum research community. Clonal lineages are named with a two letter identifier for the continent on which they were first found (e.g., NA = North America; EU = Europe) followed by a number indicating order of appearance. Clonal lineages known to date are designated NA1 (mating type: A2; distribution: North America; environment: forest and nurseries), NA2 (A2; North America; nurseries), and EU1 (predominantly A1, rarely A2; Europe and North America; nurseries and gardens). It is expected that novel lineages or new variants within the existing three clonal lineages could in time emerge.


Uncertainties in individual doses in a case-control study of thyroid cancer after the Chernobyl accident.
Individual radiation doses to the thyroid were reconstructed for 2239 subjects of a case-control study of thyroid cancer among young people that was carried out in regions of Belarus and Russia contaminated by radioactive fallout from the Chernobyl accident. Although the process of dose reconstruction provides a point estimate of each subject's dose, it is obvious that there is uncertainty associated with these dose calculations. The following main sources of uncertainty in the estimated individual doses were identified: (1) shared and unshared errors associated with parameters of the dosimetry model; and (2) unshared errors that are associated with the variability, reliability and ability of information from the personal interviews. Besides setting up proper distributions for the parameters of the dosimetry model, inter-individual correlations were also defined to take into account shared errors. By the application of Monte Carlo simulations, a set of approximately log-normally distributed thyroid doses was obtained for each subject; the geometric standard deviations of the distributions are found to vary among individuals from 1.7 to 3.7.


Monitoring urbanization and its implications in a mega city from space: spatiotemporal patterns and its indicators.
Rapid and invasive urbanization has been associated with depletion of natural resources (vegetation and water resources), which in turn deteriorates the landscape structure and conditions in the local environment. Rapid increase in population due to the migration from rural areas is one of the critical issues of the urban growth. Urbanisation in India is drastically changing the land cover and often resulting in the sprawl. The sprawl regions often lack basic amenities such as treated water supply, sanitation, etc. This necessitates regular monitoring and understanding of the rate of urban development in order to ensure the sustenance of natural resources .Urban sprawl is the extent of urbanization which leads to the development of urban forms with the destruction of ecology and natural landforms. The rate of change of land use and extent of urban sprawl can be efficiently visualized and modelled with the help of geoinformatics. The knowledge of urban area, especially the growth magnitude, shape geometry, and spatial pattern is essential to understand the growth and characteristics of urbanization process. Urban pattern, shape and growth can be quantified using spatial metrics. This communication quantifies the urbanisation and associated growth pattern in Delhi. Spatial data of four decades were analysed to understand land over and land use dynamics. Further the region was divided into 4 zones and into circles of 1 km incrementing radius to understand and quantify the local spatial changes. Results of the landscape metrics indicate that the urban center was highly aggregated and the outskirts and the buffer regions were in the verge of aggregating urban patches. Shannon's Entropy index clearly depicted the outgrowth of sprawl areas in different zones of Delhi.


Molecular identification of zoonotic and livestock-specific Giardia-species in faecal samples of calves in Southern Germany.
Giardia-infection in cattle is often subclinical or asymptomatic, but it can also cause diarrhoea. The livestock-specific species Giardia bovis is the most frequently observed in cattle, however, the two zoonotic species Giardia duodenalis and Giardia enterica have also been found. Therefore calves are thought to be of public health significance. The aim of this study was to obtain current data about the frequency of the different Giardia-species in calves in Southern Germany. Faecal samples of calves (diarrhoeic and healthy) in Southern Germany, diagnosed Giardia-positive by microscopy, were characterised by multi-locus PCR and sequencing.Of 152 microscopically Giardia-positive samples 110 (72.4%) were positive by PCR and successfully sequenced. G. bovis (Assemblage E) was detected in 101/110 (91.8%) PCR-positive samples, whilst G. duodenalis (Assemblage A) was detected in 8/110 (7.3%) samples and a mixed infection with G. duodenalis and G. bovis (Assemblage A+E) was identified in 1/110 (0.9%) samples. The sub-genotypes A1, E2 and E3 were identified with the β-giardin and the glutamate dehydrogenase genes. In the majority of diarrhoeic faecal samples a co-infection with Cryptosporidium spp. or Eimeria spp. was present, however, there were some in which G. bovis was the only protozoan pathogen found. The results suggest that there is potentially a risk for animal handlers as calves in Southern Germany are, at a low percentage, infected with the zoonotic species G. duodenalis. In addition, it was found that G. bovis was the only pathogen identified in some samples of diarrhoeic calves, indicating that this parasite may be a contributing factor to diarrhoea in calves.


Respiratory symptoms and sensitization in bread and cake bakers.
This purpose of this study was to examine the relationship between exposure to wheat flour, soya flour and fungal amylase and the development of work-related symptoms and sensitization in bread and cake bakery employees who have regular exposure to these substances. The study populations consisted of 394 bread bakery workers and 77 cake bakery workers whose normal jobs involved the sieving, weighing and mixing of ingredients. The groups were interviewed with the aim of identifying the prevalence, nature and pattern of any work-related respiratory symptoms. They were also skin-prick tested against the common bakery sensitizing agents, i.e., wheat flour, soya flour, rice flour and fungal amylase. The results of personal sampling for sieving, weighing and mixing operations at the bakeries from which the study groups were taken were collated in order to determine typical exposures to total inhalable dust from the ingredients, expressed as 8 hour time-weighted average exposures. Data from the health surveillance and collated dust measurements were compared with the aim of establishing an exposure-response relationship for sensitization. The prevalence of work-related symptoms in bread bakery and cake bakery ingredient handlers was 20.4% and 10.4% respectively. However, in a large proportion of those reporting symptoms in connection with work, the symptoms were intermittent and of short duration. It is considered that the aetiology of such symptoms is likely to be due to a non-specific irritant effect of high total dust levels, rather than allergy. None of the cake bakers and only 3.1% of the bread bakers had symptoms which were thought to be due to allergy to baking ingredients. Using skin-prick testing as a marker of sensitization, the prevalence of positive tests to wheat flour was 6% for the bread bakers and 3% for the cake bakers. Comparable prevalences for soya flour were 7% and 1% respectively. However, the prevalence of positive skin-prick tests to fungal amylase was 16% amongst the bread baking group with only a single employee (1%) in the cake baking group having a positive test. Furthermore, this employee had previously worked in a bread bakery. The difference in rates of sensitization to wheat flour between the bread and cake bakers is not statistically significant, whereas the difference for soya flour is at the borderline of statistical significance (p = 0.045). In contrast, the difference in fungal amylase sensitization is significant at the 0.1% level. For both bread and cake bakers, the 8 hour time-weighted average exposures for each of the activities showed a wide variation with mixing having the lowest average exposure and sieving the highest. Out of the allergens studied in this investigation, fungal amylase is the principal sensitizer in large scale bread bakeries, with the main source of exposure being the handling of bread improvers. In contrast, the risk of sensitization to wheat flour is low in both bread and cake bakeries. The absence of positive skin-prick tests in the subgroup of cake bakery employees who regularly handle fungal-amylase-containing flour suggests that their levels of exposure are below the threshold for sensitization to amylase.


Increased risk of coronary heart disease in patients with chronic osteomyelitis: a population-based study in a cohort of 23 million.
Chronic inflammatory disease may trigger vascular atherosclerosis. This study aimed to determine whether chronic osteomyelitis (COM) is linked to an increased risk of coronary heart disease (CHD). A national insurance claim dataset of more than 23 million enrolees was used to identify 15 054 patients with newly diagnosed COM and 60 216 randomly selected age-matched and gender-matched controls between 2001 and 2009 for comparing the risk and incidence of CHD. The study period was from the entry date to the first date of the following events: the diagnosis of CHD, death, withdrawal from the Taiwan National Health Insurance programme or the end of 2010. The analysis of the CHD risk was performed using Cox proportional hazards regression model. During a follow-up period of 67 927 person-years, the overall incidence rate of CHD in COM cohort was 1.95 times higher than non-COM cohort (16.66 vs 8.52 per 1000 person-years). After controlling age, gender and four comorbidities (hypertension, diabetes, hyperlipidaemia and stroke), the risk remained significantly higher in the COM cohort than the control group (adjusted HR=1.65, 95% CI 1.54 to 1.78, p<0.001). In age-stratified analysis, the younger population had a stronger association between COM and CHD risk than the elderly (from HR=3.42, 95% CI 1.60 to 7.32 in age <35 to HR 1.39, 95% CI 1.15 to 1.68 in age ≥80). This study demonstrates that COM is an independent risk factor for CHD, particularly in the younger population. Further studies are necessary to explore the underlying mechanisms linking COM and CHD.


"Interaction" and research utilisation in health policies and programs: does it work?
The objective of this study was to assess if interaction between users and producers of research is associated with a greater level of adoption of research findings in the design and delivery of health care programs. Responses to the dissemination of a research report on breast cancer prevention were compared between two groups of public health units in Ontario, Canada. Although all public health units received the report, only a subset of units was involved in the development of the report, while others were not. Research utilisation was conceptualized in terms of stages, including reading the report, information processing, and application of findings for public health units' policies and programs. Using a multi-case study design, three units that contributed to the report's production (the interacting units) were compared with three units were not involved in producing the report (the comparison units) on the basis of research utilisation. Data collection involved group interviews and document review. Results demonstrated that interacting units had a greater understanding of the report's analysis and attached greater value to the report. However, interaction was not associated with greater levels of utilisation in terms of application. Both interacting and comparison units used the research findings to confirm that their on-going program activities were consistent with the research findings, and to compare their program performance relative to other units. In conclusion, interaction influenced the understanding of the research, and intent to use the research findings, but applied use was independent of interaction between producers and users of research.


Spin-Polarized Radicals with Extremely Long Spin-Lattice Relaxation Time at Room Temperature in a Metal-Organic Framework.
The generation of spin polarization is key in quantum information science and dynamic nuclear polarization. Polarized electron spins with long spin-lattice relaxation times (T1) at room temperature are important for these applications but have been difficult to achieve. We report the realization of spin-polarized radicals with extremely long T1 at room temperature in a metal-organic framework (MOF) in which azaacene chromophores are densely integrated. Persistent radicals are generated in the MOF by charge separation after photoexcitation. Spin polarization of a triplet generated by photoexcitation is successfully transferred to the persistent radicals. Pulse electron spin resonance measurements reveal that the T1 of the polarized radical in the MOF is as long as 214 μs with a relatively long spin-spin relaxation time T2 of the radicals of up to 0.98 μs at room temperature. The achievement of extremely long spin polarization in MOFs with nanopores accessible to guest molecules will be an important cornerstone for future highly sensitive quantum sensing and efficient dynamic nuclear polarization.


Gender differences in isometric contractile properties and fatigability in elderly human muscle.
This study had two purposes: to compare the isometric contractile characteristics and fatigability in the elbow flexors (EF) and ankle dorsiflexors (DF) in older males and females (60-80 years), and to determine the effects of almost 2 years of twice weekly dynamic weight-lifting training on these properties One hundred nine male and female subjects completed the 22-month intervention, 54 in the exercise group and 55 in the control group. Isometric contractile properties and fatigue characteristics were assessed at baseline, 10 months, and 22 months. At baseline, males were significantly stronger (p < .05) than females in evoked twitch torque (Pt) and maximal voluntary strength (MVC) in both EF and DF. Females exhibited significantly less fatigue (expressed either absolutely or relatively) than males in both Pt and MVC during a 3-min protocol of intermittent MVCs (5 s contraction; 2 s rest). There were no significant effects of the 22 months of dynamic training on either the isometric contractile properties or the fatigue characteristics, suggesting a very strong and persistent specificity of training effect.


Evaluating a putative bottleneck in a population of bowhead whales from patterns of microsatellite diversity and genetic disequilibria.
A size-selected Balaena mysticetus genomic library was screened for clones containing simple sequence repeat, or microsatellite, loci. A total of 11 novel loci was identified. These loci were combined with a set of 9 published loci, for a total of 20 markers, and were scored across a sample of 108 bowhead whales from the Bering-Chukchi-Beaufort Seas population of bowhead whales. Genetic variability was measured in terms of polymorphism information content values and unbiased heterozygosity. From the latter, estimates of long-term effective population size were obtained. In addition, gametic phase disequilibrium among loci was investigated. Moderate to high levels of polymorphism were found overall, and the long-term effective size estimates were large relative to total population size. Tests of heterozygosity excess (Cornuet and Luikart 1996) and allele frequency distribution (Luikart et al. 1998) indicated that the possibility of a recent genetic bottleneck in the Bering-Chukchi-Beaufort Seas population of bowhead whales is highly unlikely. However, the fact that five loci displayed a statistically significant heterozygote deficiency remains to be explained.


Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity.
Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.


The dopamine D(3) receptor-preferring partial agonist BP 897 dose-dependently attenuates the expression of amphetamine-conditioned place preference in rats.
Previously we reported that systemic administration of the dopamine D3 receptor-preferring partial agonist BP 897 blocked the expression, but not the acquisition, of amphetamine-conditioned activity. This suggested the hypothesis that BP 897 would block the expression, but not the acquisition, of amphetamine-conditioned place preference (CPP). Thus, during preconditioning rats had access to two chambers connected by a tunnel for three 15-min sessions. During eight conditioning days with the tunnel blocked, one chamber was paired with drug administration for four 30-min sessions, alternating with pairing of the other chamber with saline administration. In a drug-free test session, time on the drug-paired side was compared to time spent there in preconditioning; a significant increase was defined as a place preference. Systemic amphetamine (2.0 mg/kg) or amphetamine+BP 897 (1.0, 2.0 mg/kg) during conditioning produced a significant place preference, while administration of BP 897 (1.0 or 2.0 but not 0.5 mg/kg) during the test blocked the amphetamine-CPP. There was no evidence that BP 897 produced a conditioned aversion. Results supported the hypothesis that BP 897 would block expression, but not acquisition, of amphetamine-CPP.


Prescription opioid dependence and treatment with methadone in pregnancy.
Prescription opioids are used medically to treat pain, but their diversion and abuse continues to escalate in the United States. Abuse of OxyContin (Purdue Pharma LP, Stamford, CT), a timed-release form of oxycodone, is a major focus of public health and law enforcement agencies. The rise in opioid abuse may lead to an increase in opioid dependence in pregnancy, which was a focus of this study. Our retrospective chart review examined the demographics and patterns of opioid addiction of pregnant women admitted to an inpatient psychiatric unit in an academic medical center in central Kentucky. Charts of 94 women admitted from January 2001 to May 2004 were reviewed. Information obtained included demographics and details of their opioid use, including the specific opioid(s) used, route of administration, and duration of use. Treatment information included length of hospital stay, stabilizing dose of methadone, comorbid drug use, and concomitant Axis I diagnoses. Most women were in their mid-twenties and in the second trimester of pregnancy when they sought treatment. Benzodiazepines were the most common comorbid drugs of abuse and the most frequent medical complication of their drug use was hepatitis C, newly diagnosed in 11 patients. This study demonstrates the need for further research in prescription opioid dependency in pregnancy, methadone maintenance therapy, the safety of detoxification, and neonatal outcomes.


Effects of pulsed light treatments and pectin edible coatings on the quality of fresh-cut apples: a hurdle technology approach.
Pulsed light (PL) treatments stand as an alternative for the shelf-life extension of fresh-cut products. The antimicrobial effects of PL are well known; however, its influence on quality attributes needs to be assessed. This study was aimed at evaluating the application of PL treatments in combination with pectin-based edible coatings enriched with dietary fiber for the preservation of fresh-cut apples. Dipping of fresh-cut apples in ascorbic acid/calcium chloride solution prior to pectin coating and PL treatments was effective to minimize browning and softening of apple surfaces. Incorporation of fiber in the pectin coating did not cause any change in microbial loads and sensory acceptability of apple cubes. Pectin-coated PL-treated apple pieces exhibited significantly higher antioxidant activity values than fresh and PL control samples. At the end of storage, the combination of both treatments resulted in an almost 2 log CFU g-1 reduction of microbial counts. Sensory attribute scores did not fall below the rejection limit throughout 14 days, although the presence of off-odors limited the acceptability of the pectin-coated samples. The results demonstrate that PL treatments applied to pectin-coated fresh-cut apples may be used to maintain quality attributes, thus conferring prebiotic potential and extending the shelf-life of the product. © 2016 Society of Chemical Industry.


Core competencies in advanced training: what supervisors say about graduate training.
In an attempt to identify needed mental health skills, many professional organizations have or are in the process of establishing core competency standards for their professions. The AAMFT identified 128 core competencies for the independent practice of MFT. The aim of this study was to learn the opinions of AAMFT Approved Supervisors as to how well prepared postgraduate trainees are when compared to the core competencies. One hundred thirty-five AAMFT Approved Supervisors provided their perspectives on (a) which competencies are most commonly learned in MFT graduate programs, (b) how well the graduates have mastered these competencies, and (c) the level to which the supervisors need the competencies to be mastered prior to entering advanced training. Results suggest that a gap exists between the level of mastery that the postgraduate trainees exhibit and the level desired by supervisors. Implications are suggested for closing this gap.


Glycomyces terrestris sp. nov., isolated from extremely arid soil from Yuanmou Earth Forest.
A Gram-stain-positive, mycelium-forming actinobacterium, YIM 121974T was isolated from an extreme arid soil sample collected at Yuanmou Earth Forest, Yunnan Province, PR China. Classification using a polyphasic approach suggested that strain YIM 121974T belonged to the genus Glycomyces and was closely related to Glycomyces dulcitolivorans SJ-25T (98.3 %), Glycomyces scopariae YIM 56256T (98 %), Glycomyces mayteni YIM 61331T (97.9 %), Glycomyces albidus NEAU-7082T (97.9 %), Glycomyces sambucus CGMCC 4.3147T (97.7 %), Glycomyces artemisiae IXS4T (97.6 %) and Glycomyces parisis CPCC 204357T (97.5 %), but could be distinguished from its closest relatives by a combination of phenotypic and phylogenetic features. Average nucleotide identity values of YIM 121974T to its closest phylogenetic neighbours were 70.7-88.9 %, which are lower than the threshold of 95 %. The digital DNA-DNA hybridization values between YIM 121974T and these relative species were 18.0-36.3 %, which are also well below the cut-off value (>70 %) for species delineation. The DNA G+C content of strain YIM 121974T was 72.3 mol% (draft genome sequence). The predominant menaquinone was MK-11. The phospholipids were composed of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, phosphoglycolipid and glycolipid. The major fatty acid compositions were iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The draft genome of isolate YIM 121974T was found to contain 11 secondary metabolite biosynthesis gene clusters by using the antiSMASH server. Based on the above observations, strain YIM 121974T could be distinguished from closely related species belonging to the genus Glycomyces. Thus, strain YIM 121974T represents a novel species of the genus Glycomyces, for which the name Glycomyces terrestris sp. nov. is proposed. The type strain is YIM 121974T (=KCTC 39870T=DSM 106742T).


THREE STEPS OF HOMOLOGY ASSESSMENT.
- In 1991 de Pinna (Cladistics 7: 367-394) coined the term primary homology as the putative homology statements prior to tree reconstruction. However, some confusion still exists regarding the conjectural nature of homology and to the analysis of DNA sequences. By dividing de Pinna's term primary homology into topographical identity and character state identity, we emphasize the sequential refinement of putative homology statements. We discuss the problem of transformational versus taxic homology and explain the application of our terms to DNA sequence data.


Demographic, clinical, and paraclinical features of patients operated with the diagnosis of acute descending necrotizing mediastinitis: a retrospective study in Southern Iran.
Descending necrotizing mediastinitis (DNM) is a type of acute mediastinitis that is rarely reported but is regarded as a fatal disease despite improvements in technological methods and antibiotic therapies. We aimed to determine the demographic, clinical, and paraclinical features of patients diagnosed with acute DNM. In this retrospective study, patients' hospital records with a diagnosis of DNM admitted to the Namazi hospital in southern Iran during 18 years (2002-2019) were reviewed. Demographic and clinical features were recorded and subsequently analyzed via SPSS 22. Out of 67 mediastinitis patients, 25 (37.3%) were diagnosed as DNM with an average age of 37.2 ± 16.7 years, and 68% were male. Regarding etiology, 52.0% were due to neck infection. Based on the technique of surgery, 52% of the patients underwent the combined method, which was mostly among type I and IIA DNM, while thoracotomy was mostly performed on type IIB DNM (P = 0.08). Based on the incision, type IIA and IIB had the highest frequency of thoracotomy and cervicothoracic incisions (P = 0.02 and 0.002). Puss discharge was significantly lower in type I DNM (P = 0.01). Based on the presenting symptoms of our patients, the majority (72.0%) had a chief complaint of neck pain, followed by chills and fever (48%). There were no reports of mortality during our short-term follow-up. We report one of the largest retrospective studies of DNM patients in our referral center, with a high prevalence of the disease among younger populations, especially under 40 years. The method of treatment should be chosen based on the extent of infection and can be limited to neck exploration in upper mediastinal infections, though thoracic or combined approach in more broad infections.


A simple procedure for estimating the false discovery rate.
The most used criterion in microarray data analysis is nowadays the false discovery rate (FDR). In the framework of estimating procedures based on the marginal distribution of the P-values without any assumption on gene expression changes, estimators of the FDR are necessarily conservatively biased. Indeed, only an upper bound estimate can be obtained for the key quantity pi0, which is the probability for a gene to be unmodified. In this paper, we propose a novel family of estimators for pi0 that allows the calculation of FDR. The very simple method for estimating pi0 called LBE (Location Based Estimator) is presented together with results on its variability. Simulation results indicate that the proposed estimator performs well in finite sample and has the best mean square error in most of the cases as compared with the procedures QVALUE, BUM and SPLOSH. The different procedures are then applied to real datasets. The R function LBE is available at http://ifr69.vjf.inserm.fr/lbe firstname.lastname@example.com.


A two-dose-rate method for general recombination correction for liquid ionization chambers in pulsed beams.
The correction for general recombination losses in liquid ionization chambers (LICs) is more complex than that in air-filled ionization chambers. The reason for this is that the saturation charge in LICs, i.e. the charge that escapes initial recombination, depends on the applied voltage. This paper presents a method, based on measurements at two different dose rates in a pulsed beam, for general recombination correction in LICs. The Boag theory for pulsed beams is used and the collection efficiency is determined by numerical methods which are equivalent to the two-voltage method used in dosimetry with air-filled ionization chambers. The method has been tested in experiments in water in a 20 MeV electron beam using two LICs filled with isooctane and tetramethylsilane. The dose per pulse in the electron beam was varied between 0.1 mGy/pulse and 8 mGy/pulse. The relative standard deviations of the collection efficiencies determined with the two-dose-rate method ranged between 0.1% and 1.5%. The dose-rate variations of the general recombination corrected charge measured with the LICs are in excellent agreement with the corresponding values obtained with an air-filled plane parallel ionization chamber.


Increased plasminogen activator inhibitor-1 levels in patients with isolated coronary artery ectasia.
Isolated coronary artery ectasia (ICAE) is defined as the ectasia of the coronary arteries without concomitant coronary artery stenosis. The etiology and the clinical course of ICAE are still not clear. Increased levels of plasminogen activator inhibitor-1 (PAI-1) inhibit vasa vasorum, leading to diminished vessel wall supply and thus contributes to aortic aneurysm expansion. Whether the same process has role in coronary artery ectasia is not known. The aim of this study is to investigate the association between PAI-1 and coronary artery ectasia in patients without concomitant obstructive coronary artery disease. Among 2830 patients who underwent coronary angiography between March 2010 and 2011, 55 patients (40 male, 15 female, mean age 60 ± 8 years) with ICAE, formed our study group. 27 patients with similar patient characteristics, with angiographically proven normal coronary arteries, were enrolled as the control group. The basal characteristics were similar between two groups. PAI-1 levels were statistically higher in the ICAE group compared to the control group (104.13 ± 56.65 and 63.39 ± 35.01 ng/dl, respectively) (P = 0.008). A significant positive correlation between CAE and PAI-1 (r = 0.358, P = 0.007) was also demonstrated. Serum high sensitive C reactive protein (hsCRP) levels did not differ between two groups (P > 0.05). The plasma PAI-1 levels were significantly higher in ICAE patients compared to normal coronary artery group. Increased PAI-1 levels may diminish vasa vasorum by antiangiogenic activity leading to coronary ectasia.


A single amino acid difference in human APOBEC3H variants determines HIV-1 Vif sensitivity.
Several variants of APOBEC3H (A3H) have been identified in different human populations. Certain variants of this protein are particularly potent inhibitors of retrotransposons and retroviruses, including HIV-1. However, it is not clear whether HIV-1 Vif can recognize and suppress the antiviral activity of A3H variants, as it does with other APOBEC3 proteins. We now report that A3H_Haplotype II (HapII), a potent inhibitor of HIV-1 in the absence of Vif, can indeed be degraded by HIV-1 Vif. Vif-induced degradation of A3H_HapII was blocked by the proteasome inhibitor MG132 and a Cullin5 (Cul5) dominant negative mutant. In addition, Vif mutants that were incapable of assembly with the host E3 ligase complex factors Cul5, ElonginB, and ElonginC were also defective for A3H_HapII suppression. Although we found that Vif hijacks the same E3 ligase to degrade A3H_HapII as it does to inactivate APOBEC3G (A3G) and APOBEC3F (A3F), more Vif motifs were involved in A3H_HapII inactivation than in either A3G or A3F suppression. In contrast to A3H_HapII, A3H_Haplotype I (HapI), which differs in only three amino acids from A3H_HapII, was resistant to HIV-1 Vif-mediated degradation. We also found that residue 121 was critical for determining A3H sensitivity and binding to HIV-1 Vif.


Thermosensitive and salt-sensitive molecularly imprinted hydrogel for bovine serum albumin.
A novel stimuli-responsive protein imprinted polymer for selective recognition of bovine serum albumin is presented. N-[3-(Dimethylamino)propyl]-methacrylamide, which is positively charged in neutral solution and is able to self-assemble onto the template protein through electrostatic interaction, was chosen as the functional monomer. Polymerization was carried out in the presence of N-isopropylacrylamide as an assistant monomer, which resulted in a stimuli-responsive protein imprinted polymer. The template proteins were easily removed by treatment with 500 mmol L(-1) NaCl solution. The influences of the external stimuli, such as temperature and ionic strength, on the polymer affinity were investigated, and a clear conformational memory was observed. The association constant ( Ka) and binding capacity ( Qmax) for the specific interaction between the protein imprinted polymer and the template protein were determined by Scatchard plots and found to be 9.6 x 10(4) L mol(-1) and 4.7 micromol g(-1), respectively. Several proteins different in molecular weight and isoelectric point were employed as reference, and it was shown that the charge effect and the shape memory effect were the major factors affecting the imprint formation and template recognition. Finally, this imprinted polymer was used to purify the bovine serum albumin from the protein mixture and real sample, which demonstrated its high selectivity.


Diagnostic laparoscopy v. combined screening laparoscopy and timed follicle aspiration for in vitro fertilisation.
Results from ovulation induction and laparoscopic oocyte retrieval for in vitro fertilisation and embryo transfer were compared in two groups of patients to determine whether oocyte retrieval subsequent to diagnostic laparoscopy had specific advantages over combined screening laparoscopy and timed follicle aspiration. There were no statistically significant differences in any of the factors investigated in the two groups. This study was useful in demonstrating firstly that there are no absolute criteria for selection of patients for either diagnostic or combination laparoscopy. Secondly, the procedure of choice is a combined screening laparoscopy and timed follicle aspiration if a patient is willing to accept a failure rate of 7.4% (2/27 in this study) due to ovarian inaccessibility.


Substitution of a single amino acid in the 2b protein of Pea early-browning virus affects nematode transmission.
The 2b protein of Pea early-browning virus (PEBV) is required for transmission of the virus by nematodes. Comparison of the 2b proteins of highly transmissible (TpA56) and poorly transmissible (SP5) isolates of PEBV identified two amino acid substitutions (G90S and G177R) that might be responsible for the poor transmission of isolate SP5. Hybrid viruses were created in which the TpA56 2b protein carried SP5-specific substitutions at residue 90 or 177, and in which the SP5 2b protein carried TpA56-specific substitutions at these positions. Transmission tests showed that the G177R substitution is sufficient to prevent nematode transmission of the virus. Examination of the 2b proteins from PEBV and other tobraviruses predicted the presence of a coiled-coil domain in the central region of the protein. This structural element is important for the association of interacting proteins and, thus, might mediate interaction of the 2b protein with the virus coat protein or with the vector nematode.


Peripheral neuritis due to isoniazid.
It is well known that in the treatment of tuberculosis with isoniazid the complication of peripheral neuritis may arise. This complication is normally rare when small dosages of the drug are used, but a high incidence of the neuropathy has recently been observed in East Africa in a group of malnourished tuberculous patients receiving isoniazid in comparatively low dosage (4-6 mg/kg body-weight daily). The present paper reports on 20 cases of peripheral neuritis encountered in Madras, India, among 338 poorly nourished tuberculous patients during a trial of four isoniazid regimens, two of low and two of high dosage (3.9-5.5 and 7.8-9.6 mg/kg body-weight daily, respectively). Nineteen of the 20 cases occurred in the two groups of patients receiving the high dosage and these 19 patients were found to have a higher mean serum level of free isoniazid than the patients in the same groups who did not develop the complication. The authors consider that dosages of 7.8-9.6 mg/kg body-weight daily should not be used for the mass therapy of poorly nourished patients unless steps are taken to prevent the development of peripheral neuritis. Pyridoxine has been reported to be an effective preventive, but is too expensive for use on a large scale. This study indicates, however, that administration of the cheaper vitamin B complex might give satisfactory results and warrants further investigation.


Synthesis and Preclinical Evaluation of a 68Ga-Labeled Pyridine-Based Benzamide Dimer for Malignant Melanoma Imaging.
Benzamide (BZA), a small molecule that can freely cross cell membranes and bind to melanin, has served as an effective targeting group for melanoma theranostics. In this study, a novel pyridine-based BZA dimer (denoted as H-2) was labeled with 68Ga ([68Ga]Ga-H-2) for positron emission tomography (PET) imaging of malignant melanomas. [68Ga]Ga-H-2 was obtained with high radiochemical yield (98.0 ± 2.0%) and satisfactory radiochemical purity (>95.0%). The specificity and affinity of [68Ga]Ga-H-2 were confirmed in melanoma B16F10 cells and in vivo PET imaging of multiple tumor models (B16F10 tumors, A375 melanoma, and lung metastases). Monomeric [68Ga]Ga-H-1 was prepared as a control radiotracer to verify the effects of the molecular structure on pharmacokinetics. The values of the lipid-water partition coefficient of [68Ga]Ga-H-2 and [68Ga]Ga-H-1 demonstrated hydrophilicity with log P = -2.37 ± 0.07 and -2.02 ± 0.09, respectively. PET imaging and biodistribution showed a higher uptake of [68Ga]Ga-H-2 in B16F10 primary and metastatic melanomas than that in A375 melanomas. However, the relatively low uptake of monomeric [68Ga]Ga-H-1 in B16F10 tumors and high accumulation in nontarget organs resulted in poor PET imaging quality. This study demonstrates the synthesis and preclinical evaluation of the novel pyridine-based BZA dimer [68Ga]Ga-H-2 and indicates that the dimer tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma.


Acute Eosinophilic Myocarditis and Hyper IgE in HIV Infection: A Case Report.
Eosinophilic myocarditis is a rare cause of myocarditis. It is manifested histopathologically by diffuse or focal myocardial inflammation with eosinophilic infiltration, often in association with peripheral blood eosinophilia. Patients infected with Human Immunodeficiency Virus (HIV), especially those with lower CD4 counts, can occasionally have hyperimmunoglobulinemia E (Hyper IgE) and eosinophilia. We report a case of a 29-year-old patient with Acquired Immunodeficiency Syndrome (AIDS) who had a persistent elevation of eosinophil counts and elevated IgE levels for a year prior to admission. He was presented to our emergency department with chest pain and laboratory tests revealed peripheral blood eosinophilia and elevated troponins. Coronary angiogram showed nonobstructive coronary artery disease. He then underwent cardiac magnetic resonance imaging which was consistent with an infiltrative myocarditis. After being put on steroid therapy, his peripheral eosinophilia resolved and his cardiac symptoms improved. Our case highlights that eosinophilia and Hyper IgE in HIV patients has the potential to contribute to end-organ damage.


Pre-natal exposure to perfluoroalkyl substances may be associated with altered vaccine antibody levels and immune-related health outcomes in early childhood.
Perfluoroalkyl substances (PFAS) are suggested to have immunosuppressive effects; exposure in utero and in the first years of life is of special concern as fetuses and small children are highly vulnerable to toxicant exposure. The objective of this study was to investigate the effect of pre-natal exposure to PFAS on responses to pediatric vaccines and immune-related health outcomes in children up to 3 years of age. In the prospective birth-cohort BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), pregnant women from Oslo and Akershus, Norway, were recruited during 2007-2008. Three annual questionnaire-based follow-ups were performed. Blood samples were collected from the mothers at the time of delivery and from the children at the age of 3 years. As a measure of pre-natal exposure to PFAS, the concentrations of perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) were determined in maternal blood from 99 BraMat participants. Main outcome measures were anti-vaccine antibody levels, common infectious diseases and allergy- and asthma-related health outcomes in the children up to the age of 3 years. There was an inverse association between the level of anti-rubella antibodies in the children's serum at age 3 years and the concentrations of the four PFAS. Furthermore, there was a positive association between the maternal concentrations of PFOA and PFNA and the number of episodes of common cold for the children, and between PFOA and PFHxS and the number of episodes of gastroenteritis. No associations were found between maternal PFAS concentrations and the allergy- and asthma-related health outcomes investigated. The results indicate that pre-natal exposure to PFAS may be associated with immunosuppression in early childhood.


Emotion and coping in the aftermath of medical error: a cross-country exploration.
Making a medical error can have serious implications for clinician well-being, affecting the quality and safety of patient care. Despite an advancing literature base, cross-country exploration of this experience is limited, and a paucity of studies has examined the coping strategies used by clinicians. A greater understanding of clinicians' responses to making an error, the factors that may influence these, and the various coping strategies used are all essential for providing effective clinician support and ensuring optimal outcomes.The objectives were therefore to investigate the following: a) the professional or personal disruption experienced after making an error, b) the emotional response and coping strategies used, c) the relationship between emotions and coping strategy selection, d) influential factors in clinicians' responses, and e) perceptions of organizational support. A cross-sectional, cross-country survey of 265 physicians and nurses was undertaken in 2 large teaching hospitals in the United Kingdom and the United States. Professional and personal disruption was reported as a result of making an error. Negative emotions were common, but positive feelings of determination, attentiveness, and alertness were also identified. Emotional response and coping strategy selection did not differ because of location or perceived harm, but responses did appear to differ by professional group; nurses in both locations reported stronger negative feelings after an error. Respondents favored problem-focused coping strategies, and associations were identified between coping strategy selection and the presence of particular emotions. Organizational support services, particularly including peers, were recognized as helpful, but fears over confidentiality may prohibit some staff from accessing these. Clinicians in the United Kingdom and the United States experience professional and personal disruption after an error. A number of factors may influence clinician recovery; these factors should be considered in the provision of comprehensive support programs so as to improve clinician recovery and ensure higher quality, safer patient care.


Invited commentary: Positive youth development and human complexity.
The process of positive development for adolescents includes struggling to address a wide variety of complex, often unstated bio-psycho-social-cultural challenges. These include formulating workable values, learning self-regulation, preparation for adult work roles-and innumerable other un-tidy puzzles. Variable-based research can only scratch the surface of how youth go about these processes; nonetheless, systematic longitudinal research like this can provide valuable information about developmental pathways and directions of change. Highlights from these papers include the finding that older youth report more goals aimed at meaningful connection with others and contributing to society; yet also that moral character did not differ by age. The papers suggest that relationships adults, hope, school engagement, participation in out-of-school programs, and intentional self-regulation can serve as mediators of positive development. Yet, a striking finding was that comparatively few youth in the study manifest a pattern of change marked by the coupling of increases in positive youth development and decreases in risk/problem behavior. We believe there is much beneath the surface to be uncovered.


Synthesis, characterization, and linkage isomerism in mononuclear ruthenium complexes containing the new pyrazolate-based ligand Hpbl.
A new tetradentate dinucleating ligand [1,1'-(4-methyl-1H-pyrazole-3,5-diyl)bis(1-(pyridin-2-yl)ethanol)] (Hpbl) containing an O/N mixed donor set of atoms has been synthesized and characterized by analytical and spectroscopic techniques. The Ru-Cl and Ru-aqua complexes containing this ligand of general formula [Ru(II)X(Hpbl)(trpy)](y+) (trpy = 2,2':6',2″-terpyridine; X = Cl, y = 1; X = H2O, y = 2) have been prepared and thoroughly characterized by spectroscopic and electrochemical techniques. The Ru-aqua complex 2 undergoes N → O linkage isomerization as observed electrochemically, and the related thermodynamic and kinetic parameters are extracted from cyclic voltammetry experiments together with DIGISIM, a CV simulation package. Under basic conditions an additional isomer is observed where the pyrazolyl group in the Hpbl ligand is replaced by the geminal pyridyl group. Further structural and electronic characterization of all the isomers has been carried out by means of DFT calculations.


European Society of Hypertension recommendations for the validation of cuffless blood pressure measuring devices: European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability.
There is intense effort to develop cuffless blood pressure (BP) measuring devices, and several are already on the market claiming that they provide accurate measurements. These devices are heterogeneous in measurement principle, intended use, functions, and calibration, and have special accuracy issues requiring different validation than classic cuff BP monitors. To date, there are no generally accepted protocols for their validation to ensure adequate accuracy for clinical use. This statement by the European Society of Hypertension (ESH) Working Group on BP Monitoring and Cardiovascular Variability recommends procedures for validating intermittent cuffless BP devices (providing measurements every >30 sec and usually 30-60 min, or upon user initiation), which are most common. Six validation tests are defined for evaluating different aspects of intermittent cuffless devices: static test (absolute BP accuracy); device position test (hydrostatic pressure effect robustness); treatment test (BP decrease accuracy); awake/asleep test (BP change accuracy); exercise test (BP increase accuracy); and recalibration test (cuff calibration stability over time). Not all these tests are required for a given device. The necessary tests depend on whether the device requires individual user calibration, measures automatically or manually, and takes measurements in more than one position. The validation of cuffless BP devices is complex and needs to be tailored according to their functions and calibration. These ESH recommendations present specific, clinically meaningful, and pragmatic validation procedures for different types of intermittent cuffless devices to ensure that only accurate devices will be used in the evaluation and management of hypertension.


Dietary marine fatty acids (fish oil) for asthma.
Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. The Cochrane Airways Review Group register was search using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of 4 weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. Eight randomised controlled trials conducted between 1986 and 1998 satisfied the inclusion criteria. Six were of parallel design and two were cross-over studies. Seven compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analyzable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. The single study performed in children also combined dietary manipulation with fish oil supplementation and showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. Updated Search conducted August 2000. No new trials were found. There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so.


Constitutive Phosphorylation as a Key Regulator of TRPM8 Channel Function.
In mammals, environmental cold sensing conducted by peripheral cold thermoreceptor neurons mostly depends on TRPM8, an ion channel that has evolved to become the main molecular cold transducer. This TRP channel is activated by cold, cooling compounds, such as menthol, voltage, and rises in osmolality. TRPM8 function is regulated by kinase activity that phosphorylates the channel under resting conditions. However, which specific residues, how this post-translational modification modulates TRPM8 activity, and its influence on cold sensing are still poorly understood. By mass spectrometry, we identified four serine residues within the N-terminus (S26, S29, S541, and S542) constitutively phosphorylated in the mouse ortholog. TRPM8 function was examined by Ca2+ imaging and patch-clamp recordings, revealing that treatment with staurosporine, a kinase inhibitor, augmented its cold- and menthol-evoked responses. S29A mutation is sufficient to increase TRPM8 activity, suggesting that phosphorylation of this residue is a central molecular determinant of this negative regulation. Biophysical and total internal reflection fluorescence-based analysis revealed a dual mechanism in the potentiated responses of unphosphorylated TRPM8: a shift in the voltage activation curve toward more negative potentials and an increase in the number of active channels at the plasma membrane. Importantly, basal kinase activity negatively modulates TRPM8 function at cold thermoreceptors from male and female mice, an observation accounted for by mathematical modeling. Overall, our findings suggest that cold temperature detection could be rapidly and reversibly fine-tuned by controlling the TRPM8 basal phosphorylation state, a mechanism that acts as a dynamic molecular brake of this thermo-TRP channel function in primary sensory neurons.SIGNIFICANCE STATEMENT Post-translational modifications are one of the main molecular mechanisms involved in adjusting the sensitivity of sensory ion channels to changing environmental conditions. Here we show, for the first time, that constitutive phosphorylation of the well-conserved serine 29 within the N-terminal domain negatively modulates TRPM8 channel activity, reducing its activation by agonists and decreasing the number of active channels at the plasma membrane. Basal phosphorylation of TRPM8 acts as a key regulator of its function as the main cold-transduction channel, significantly contributing to the net response of primary sensory neurons to temperature reductions. This reversible and dynamic modulatory mechanism opens new opportunities to regulate TRPM8 function in pathologic conditions where this thermo-TRP channel plays a critical role.


Genetic signals of demographic expansion in Downy Woodpecker (Picoides pubescens) after the last North American glacial maximum.
The glacial cycles of the Pleistocene have been recognized as important, large-scale historical processes that strongly influenced the demographic patterns and genetic structure of many species. Here we present evidence of a postglacial expansion for the Downy Woodpecker (Picoides pubescens), a common member of the forest bird communities in North America with a continental distribution. DNA sequences from the mitochondrial tRNA-Lys, and ATPase 6 and 8 genes, and microsatellite data from seven variable loci were combined with a species distribution model (SDM) to infer possible historical scenarios for this species after the last glacial maximum. Analyses of Downy Woodpeckers from 23 geographic areas suggested little differentiation, shallow genealogical relationships, and limited population structure across the species' range. Microsatellites, which have higher resolution and are able to detect recent differences, revealed two geographic groups where populations along the eastern edge of the Rocky Mountains (Montana, Utah, Colorado, and southern Alberta) were genetically isolated from the rest of the sampled populations. Mitochondrial DNA, an important marker to detect historical patterns, recovered only one group. However, populations in Idaho and southeast BC contained high haplotype diversity and, in general were characterized by the absence of the most common mtDNA haplotype. The SDM suggested several areas in the southern US as containing suitable Downy Woodpecker habitat during the LGM. The lack of considerable geographic structure and the starburst haplotype network, combined with several population genetic tests, suggest a scenario of demographic expansion during the last part of Pleistocene and early Holocene.


[Therapy with perindopril: organoprotection, not just the antihypertensive effect].
Perindopril is one of the most prescribed inhibitors of angiotensin converting enzyme, has a large evidence base, which allows to use it in patients with hypertension, diabetes mellitus type 2, coronary heart disease and chronic heart failure. In this review, the author focused on the evidence of organoprotecting properties of perindopril that lie outside lowering blood pressure.


Food intolerances and eosinophilic esophagitis in childhood.
Food intolerance is an adverse reaction to a particular food or ingredient that may or may not be related to the immune system. A deficiency in digestive enzymes can also cause some types of food intolerances like lactose and gluten intolerance. Food intolerances may cause unpleasant symptoms, including nausea, bloating, abdominal pain, and diarrhea, which usually begin about half an hour after eating or drinking the food in question, but sometimes symptoms may delayed up to 48 h. There is also a strong genetic pattern to food intolerances. Intolerance reactions to food chemicals are mostly dose-related, but also some people are more sensitive than others. Diagnosis can include elimination and challenge testing. Food intolerance can be managed simply by avoiding the particular food from entering the diet. Babies or younger children with lactose intolerance can be given soy milk or hypoallergenic milk formula instead of cow's milk. Adults may be able to tolerate small amounts of troublesome foods, so may need to experiment. Eosinophilic esophagitis (EE) is defined as isolated eosinophilic infiltration in patients with reflux-like symptoms and normal pH studies and whose symptoms are refractory to acid-inhibition therapy. Food allergy, abnormal immunologic response, and autoimmune mechanisms are suggested as possible etiological factors for EE. This article is intended to review the current literature and to present a practical approach for managing food intolerances and EE in childhood.