The cigarette smoke carcinogen benzo[a]pyrene enhances human papillomavirus synthesis.
Epidemiological studies suggest that cigarette smoke carcinogens are cofactors which synergize with human papillomavirus (HPV) to increase the risk of cervical cancer progression. Benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, is detected in the cervical mucus and may interact with HPV. Exposure of cervical cells to high concentrations of BaP resulted in a 10-fold increase in HPV type 31 (HPV31) viral titers, whereas treatment with low concentrations of BaP resulted in an increased number of HPV genome copies but not an increase in virion morphogenesis. BaP exposure also increased HPV16 and HPV18 viral titers. Overall, BaP modulation of the HPV life cycle could potentially enhance viral persistence, host tissue carcinogenesis, and permissiveness for cancer progression.


Effects of anti-inflammatory agents and some other drugs on prostaglandin biotransport.
The inhibitory effects of drugs on prostaglandin biotransport were studied by measuring the concentrative accumulation of 3H by rabbit choroid plexuses, segments of anterior uvea and kidney cortex slices after incubation in tissue culture medium containing 3H-prostaglandin F2 alpha. After 10 minutes of incubation in the absence of an inhibitor, the choroid plexus showed a tissue/medium 3H accumulation ratio of 14 +/- 0.7; after 30 minutes of incubation, the anterior uvea and the kidney cortex slices showed accumulation ratios of 6.4 +/- 0.5 and 5.6 +/- 0.1, respectively. The I50 values for inhibition of 3H accumulation by indomethacin were 10, 8 and 12 muM for the three tissues, respectively. Some related drugs-oxyphenbutazone, D-naproxen, l-naproxen, ibuprofen, phenylbutazone and pirprofen-were also found to be effective inhibitors of 3H accumulation (I50 for anterior uvea, 6-28 muM) whereas aspirin, dexamethasone phosphate and penicillin had an inhibitory effect only at much higher concentrations (I50 0.1-2.0 mM). Papaverine, fursemide and probenecid were approximately as effective as the anti-inflammatory organic acids (I50 0.01-0.1 mM), whereas bromcresol green was at least 10-fold more effective. Diphenhydramine and the nonacidic prostaglandin synthesis inhibitors, phenelzine and paracetamol, showed little (I50 greater than 1 mM) or no inhibitory effect. The inhibition of this transport system by some drugs, most notably nonsteroidal anti-inflammatory organic acids, and consequent alterations in the distribution and disposition of prostaglandins must be taken into account in the development of new anti-inflammatory agents and in the interpretation of the mechansim of action and side effects of such drugs.


Transparent uniaxial anisotropic spherical particles designed using radial anisotropy.
Based on Mie scattering theory and the assumption that the particle is electrically small in size (k(t)a≪1,k(m)a≪1), an analytic relationship between radial and tangential permittivity parameters has been established for achieving minimal scattering from an arbitrary rotationally uniaxial anisotropic spherical object incident by a plane wave. Analysis of fields in both the far- and near-field zones indicates that the derived relation is not only valid for electrically small particles, but also applicable to larger ones whose sizes are comparable with the free space wavelength after slight adjustments in parameters. Furthermore, it is observed that the dielectric spherical particle of reduced tangential permittivity yields better transparency performance than the design using a plasmonic cover by Alu and Engheta [Phys. Rev. E 72, 016623 (2005)]. As such, particles with carefully engineered radial anisotropy are transparent without using any coating and are ideal for applications with space constraint and stringent transparency criteria.


Mutants of the Rous sarcoma virus envelope glycoprotein that lack the transmembrane anchor and cytoplasmic domains: analysis of intracellular transport and assembly into virions.
The envelope glycoprotein complex of Rous sarcoma virus consists of a knoblike, receptor-binding gp85 polypeptide that is linked through disulfide bonds to a membrane-spanning gp37 spike. We used oligonucleotide-directed mutagenesis to assess the role of the hydrophobic transmembrane region and hydrophilic cytoplasmic domain of gp37 in intracellular transport and assembly into virions. Early termination codons were introduced on either side of the hydrophobic transmembrane region, and the mutated env genes were expressed from the late promoter of simian virus 40. This resulted in the synthesis of glycoprotein complexes composed of a normal gp85 and a truncated gp37 molecule that lacked the cytoplasmic domain alone or both the cytoplasmic and transmembrane domains. The biosynthesis and intracellular transport of the truncated proteins were not significantly different from those of the wild-type glycoproteins, suggesting that any protein signals for biosynthesis and intracellular transport of this viral glycoprotein complex must reside in its extracellular domain. The glycoprotein complex lacking the cytoplasmic domain of gp37 is stably expressed on the cell surface in a manner similar to that of the wild type. In contrast, the complex lacking both the transmembrane and cytoplasmic domains is secreted as a soluble molecule into the media. It can be concluded, therefore, that the transmembrane domain alone is essential for anchoring the RSV env complex in the cell membrane and that the cytoplasmic domain is not required for anchor function. Insertion of the mutated genes into an infectious proviral genome allowed us to assess the ability of the truncated gene products to be assembled into virions and to determine whether such virions were infectious. Viral genomes encoding the secreted glycoprotein were noninfectious, whereas those encoding a glycoprotein complex lacking only the cytoplasmic domain of gp37 were infectious. Virions produced from these mutant-infected cells contained normal levels of glycoprotein. The cytoplasmic tail of gp37 is thus not required for the assembly of envelope glycoproteins into virions. It is unlikely, therefore, that this region of gp37 interacts with viral core proteins during the selective incorporation of viral glycoproteins into the viral envelope.


Decision-making in an era of cancer prevention via aspirin: New Zealand needs updated guidelines and risk calculators.
Based on new systematic reviews of the evidence, the US Preventive Services Task Force has drafted updated guidelines on the use of low-dose aspirin for the primary prevention of both cardiovascular disease (CVD) and cancer. The Task Force generally recommends consideration of aspirin in adults aged 50-69 years with 10-year CVD risk of at least 10%, in who absolute health gain (reduction of CVD and cancer) is estimated to exceed absolute health loss (increase in bleeds). With the ongoing decline in CVD, current risk calculators for New Zealand are probably outdated, so it is difficult to be precise about what proportion of the population is in this risk category (roughly equivalent to 5-year CVD risk ≥5%). Nevertheless, we suspect that most smokers aged 50-69 years, and some non-smokers, would probably meet the new threshold for taking low-dose aspirin. The country therefore needs updated guidelines and risk calculators that are ideally informed by estimates of absolute net health gain (in quality-adjusted life-years (QALYs) per person) and cost-effectiveness. Other improvements to risk calculators include: epidemiological rigour (eg, by addressing competing mortality); providing enhanced graphical display of risk to enhance risk communication; and possibly capturing the issues of medication disutility and comparison with lifestyle changes.


Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington's disease mouse models.
We investigated the therapeutic potential of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in Huntington's disease (HD) mouse models. Ten weeks after intrastriatal injection of quinolinic acid (QA), mice that received hBM-MSC transplantation showed a significant reduction in motor function impairment and increased survival rate. Transplanted hBM-MSCs were capable of survival, and inducing neural proliferation and differentiation in the QA-lesioned striatum. In addition, the transplanted hBM-MSCs induced microglia, neuroblasts and bone marrow-derived cells to migrate into the QA-lesioned region. Similar results were obtained in R6/2-J2, a genetically-modified animal model of HD, except for the improvement of motor function. After hBM-MSC transplantation, the transplanted hBM-MSCs may integrate with the host cells and increase the levels of laminin, Von Willebrand Factor (VWF), stromal cell-derived factor-1 (SDF-1), and the SDF-1 receptor Cxcr4. The p-Erk1/2 expression was increased while Bax and caspase-3 levels were decreased after hBM-MSC transplantation suggesting that the reduced level of apoptosis after hBM-MSC transplantation was of benefit to the QA-lesioned mice. Our data suggest that hBM-MSCs have neural differentiation improvement potential, neurotrophic support capability and an anti-apoptotic effect, and may be a feasible candidate for HD therapy.


Totally Endoscopic Atrial Septal Defect Repair on Beating Heart: Clinical Outcome and Single-Surgeon Learning Curve Experience.
To evaluate the safety and efficacy of the Hanoi ASD procedure, which is totally endoscopic surgery for atrial septal defect (ASD) repair on beating heart. In addition, the present study also aimed to analyze the learning curve for this procedure. From May 2016 to February 2023, 198 consecutive ASD patients weighing ≥20 kg were enrolled in the retrospective study. The Hanoi ASD procedure includes (1) unilateral or bilateral femoral arterial cannulation; (2) two or three 5 mm trocars and a 15 mm port; (3) ASD repair on beating heart, preventing air embolism with CO2 insufflation and keeping the left atrium full of blood; and (4) not snaring the inferior vena cava. Cumulative sum (CUSUM) analysis was used to evaluate the cardiopulmonary bypass (CPB) and operation time learning curves. Variables among the learning curve phases were compared. The CPB and operation times were 90 (72 to 115) min and 180 (150 to 220) min, respectively. Total drainage volume was 190 (120 to 290) mL. No endoscopic failure or major complications were complications were excluding factors causing bias, the CUSUMCPBtime analysis for the remaining 131 patients included 3 phases. Phase 1 was the initial learning period (cases 1 to 34), phase 2 represented the technical competence period (cases 35 to 54), and phase 3 was the challenging period (cases 55 to 131). The Hanoi ASD procedure is safe and feasible for repairing ASD in patients weighing ≥20 kg. According to the learning curve analysis, 34 cases were required to achieve technical efficiency, and 54 cases were required to address highly challenging cases.


[An analysis of the introduction of pediatric surgery in Spain].
The specialty of paediatric surgery (P.S.) has been officially recognized in Spain since 1977 as being independent of other surgical areas, and charged with carrying out pathological surgery in paediatric ages. In spite of the considerable progress made, it suffers constant threats, which is why we feel it is opportune to review various aspects of the problems it is currently facing. If we observe how the specialty is distributed, we can see that there are many paediatric services and professorships which do not send their patients to a P.S. specialist. The child's health may suffer as a result of the Administration's decision to allow twenty-two provinces (seven million inhabitants) to go without P.S. We know that many specialties carry out surgery on the paediatric population, so we may well ask: What use is the P.S. qualification? Information was collected from legal sources which indicates the need to hold the qualification of "homologated specialist", given that "the doctor who ventures into specialties which are not his/her own may add a risk factor, and thereby give rise more easily to an offence of negligence". It is time that concepts and competences of the specialty were clarified, and to fight to ensure that all Spanish children should be operated on by legally qualified specialists.


Chapter 18: Allergic bronchopulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) occurs in patients with asthma or cystic fibrosis resulting in pulmonary infiltrates, tenacious mucus plugs that harbor hyphae of Aspergillus fumigatus, elevations of total serum IgE concentration and peripheral blood, and sputum eosinophilia. Bronchiectasis is an irreversible complication of ABPA. The key to early diagnosis is considering ABPA in anyone with asthma or cystic fibrosis and a positive skin test to Aspergillus and /or recurrent infiltrates on radiographs. The differential diagnosis for ABPA in patients with asthma includes diseases in which there is an overlap of asthma, peripheral blood eosinophilia, and radiographic infiltrates. Examples include chronic eosinophilic pneumonia, Churg-Strauss syndrome, drug-induced pulmonary infiltrates, infection with a parasite, asthma with atelectasis, and lymphoma. Mucus plugging causing a "tree in bud" pattern on CT examination of the lungs may be from ABPA or other conditions such as nontuberculous (atypical) mycobacteria (Mycobacteria avium-intracellulare complex). Prednisone is indicated to clear pulmonary infiltrates, and a usual course is for 3 months. Itraconazole and voriconazole are adjunctive and drug-drug interactions must be considered as azoles decrease elimination of various medications. Although not familial in most patients, presentation of Asp f1 antigen is restricted to specific major histocompatability complex class II molecules, HLA-DR2 and HLA-DR5. There is an increased number of CD4(+) Th2 lymphocytes in bronchoalveolar lavage, and Aspergillus fumigatus can serve as a growth factor of eosinophils potentiating the effects of IL-3, IL-5, and granulocyte colony-stimulating factor.


Is antioxidant use protective of cognitive function in the community-dwelling elderly?
The role of oxidative stress in the pathogenesis of diseases such as macular degeneration, certain types of cancer, and Alzheimer's disease has received much attention. Thus, there is considerable interest in the potential contribution of antioxidants to the prevention of these diseases. The objective of this study was to determine whether use of supplemental antioxidants (vitamins A, C, or E, plus selenium or zinc) was associated with a reduced risk of development of cognitive impairment or cognitive decline in a representative sample of the community-dwelling elderly. The sample consisted of 2082 nonproxy subjects from the Duke Established Populations for Epidemiologic Studies of the Elderly who were not cognitively impaired at the 1989-1990 interview (baseline for the present analysis). Medication use was determined during in-home interviews. Cognitive function was assessed 3 and 7 years from baseline in terms of incident cognitive impairment, as measured on the Short Portable Mental Status Questionnaire (SPMSQ) using specific cut points (number of errors) based on race and education, and cognitive decline, defined as an increase of > or = 2 errors on the SPMSQ. Multivariate analyses were performed using weighted data adjusted for sampling design and controlled for sociodemographic characteristics, health-related behaviors, and health status. At baseline, 224 (10.8%) subjects were currently taking a supplement containing an antioxidant. During the follow-up period, 24.0% of subjects developed cognitive impairment and 34.5% experienced cognitive decline. Current antioxidant users had a 34.0% lower risk of developing cognitive impairment compared with non-antioxidant users (adjusted relative risk [RR], 0.66; 95% CI, 0.44-1.00) and a 29.0% lower risk of experiencing cognitive decline (adjusted RR, 0.71; 95% CI, 0.49-1.01). The results of this analysis suggest a possible beneficial effect of antioxidant use in terms of reducing cognitive decline among the community-dwelling elderly.


The nature and significance of changes in adrenal cytology, weight, and cortical/medullary ratio in experimental renal hypertension and clinical hypertension.
There is a direct proportionality between the degree of adrenal and that of cardiac enlargement in experimental renal hypertension. This is evidence for the participation of the adrenal to an extent dependent on the severity of the hypertension as reflected in the degree of cardiac hypertrophy. The greater part of the weight increase of the adrenal is due to growth of the cortex. However, the relative degree of medullary growth exceeds that of cortical growth. There is evidence of medullary hyperplasia, but the cortical growth may be due to cell hypertrophy alone. In view of the known relationship between prolonged skeletal muscle work and the size of the adrenals, in which there is likewise a relatively greater growth of the medulla, the possibility that adrenal growth in experimental renal hypertension is a consequence of the metabolic demand of increased heart muscle work must be considered. The hyperplastic, hypertrophic medulla of the renal hypertensive rat is presumed to be producing increased amounts of a hormone whose action is not known. The adrenal medulla is not necessary for the development of moderate renal hypertension though this does not exclude the possibility that it may be involved somehow in the maintainance of the hypertensive state. Large, periodic-Schiff-positive, hyaline droplets are found in the cytoplasm of adrenal cortical cells with nuclear evidence of active function. There is some evidence that these indicate hypophyseal stimulation. Similar particles are found in the medulla, suggesting an interrelationship between the two parts of the adrenal. The close resemblance of changes in adrenal weight, nuclear/cytoplasmic ratio, and nuclear and cytoplasmic structure, indicates that similar physiological and morphological controlling mechanisms are involved in the pathogenesis and maintainance of experimental renal hypertension and clinical essential hypertension.


Facial paralysis as the initial presentation of an internal carotid artery aneurysm.
Aneurysms of the intrapetrous internal carotid artery are rarely encountered and can present difficult diagnostic problems. A review of the literature revealed 34 cases, and we now add a 35th. Presenting symptoms and signs are dependent on the direction of expansion of the aneurysm, with neurologic dysfunction typical of medial expansion, whereas lateral erosion often suggests a glomus tumor.


Thrombocytopenia during the course of acute poststreptococcal glomerulonephritis.
A four-year old boy was admitted to the hospital due to acute thrombocytopenic purpura. Three days later he developed edema, hematuria and hypertension. The diagnosis of acute poststreptococcal glomerulonephritis was based upon the evidence of previous sore throat, hypocomplementemia and increased antistreptolysin O titer. Renal biopsy was contraindicated due to throbocytopenia. An extensive work-up was done to exclude mebranoproliferative glomerulonephritis and systemic diseases such as hemolytic uremic syndrome or systemic lupus erythematosus. The clinical outcome of the nephritis and thrombocytopenia was excellent in respect to both conditions. To the best of our knowledge concurrent occurrence of acute thrombocytopenic purpura and poststreptococcal glomerulonephritis is very rare; there are only four similar cases reported in the literature. A careful work-up and follow-up are mandatory to exclude systemic disease.


Tobacco use outcomes among patients with head and neck carcinoma treated for nicotine dependence: a matched-pair analysis.
The current study described tobacco use outcomes among patients with head and neck carcinoma who underwent treatment for nicotine dependence at the Mayo Clinic Nicotine Dependence Center (NDC; Rochester, MN). Using a 1:1 matched-pair design, conditional logistic regression was employed to compare the 6-month tobacco abstinence outcomes of patients with head and neck carcinoma (n = 101) with controls (n = 101) from the general patient population treated for nicotine dependence between 1988 and 2001. The two groups were matched with regard to age, gender, date of treatment, and type of NDC treatment service. Baseline demographics were similar between both groups. However, patients with head and neck carcinoma smoked significantly more cigarettes per day (cpd) than controls (P = 0.003). The self-reported tobacco abstinence rate at the 6-month follow-up was 33% for patients with head and neck carcinoma compared with 26% for matched controls (P = 0.279; after adjusting for baseline cpd and stage of change, P = 0.205). Among patients with head and neck carcinoma, the tobacco abstinence rates were 47%, 22%, and 19%, respectively, for those receiving an NDC consult within 3 months, between 3 months and 5 years, and > 5 years after their diagnosis (P = 0.021). Furthermore, the patients with head and neck carcinoma treated within 3 months of diagnosis who received surgery (with or without radiation therapy) were more likely to be tobacco abstinent than those who received primary radiation therapy (P = 0.042). These findings suggested that nicotine dependence treatments were effective among patients with head and neck carcinoma, particularly when delivered shortly after initial diagnosis and for those who received surgery as their primary treatment.


ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety.
Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.


Ethanol consumption enhances periodontal inflammatory markers in rats.
The aim of this study was to assess the short term effect of ethanol administration on periodontal disease in rats. Rats received either ethanol 2g/kg or water by gastric gavage twice a day. On the fifth day ligatures were tied around the molars of half of the rats to induce periodontitis. After 7days gingival tissue was removed and assayed for inflammatory markers. Finally, hemi-mandibles were extracted to evaluate bone loss by histomorphometrical techniques. The experimental periodontitis increased significantly the mRNA expression (p<0.001) and activity (p<0.001) of inducible nitric oxide synthase (iNOS) in the gingival tissue, whilst short time ethanol administration increased iNOS activity (p<0.05) and produced an additive effect on iNOS mRNA expression augmented by periodontitis (p<0.01). The short time ethanol administration also potentiated the periodontitis stimulatory effect on the mRNA expression of interleukin (IL)-1β (p<0.01 and p<0.001, in semi-quantitative and real time PCR, respectively) and on the height of periodontal ligament (p<0.05). However, the ligature-induced periodontitis, but not ethanol administration, increased the prostaglandin E(2) content (p<0.05) and, diminished the alveolar bone volume (p<0.05), as compared to sham rats. The present results suggest that ethanol consumption could represent a risk indicator for periodontal disease since augments the expression of inflammatory markers, in healthy rats, and increases them, at short term, during the illness. However, scale longitudinal investigation and more case-control studies are needed to confirm this statement.


Normative Percentiles of Retinal Nerve Fiber Layer Thickness and Glaucomatous Visual Field Loss.
Circumpapillary retinal nerve fiber layer thickness (RNFLT) measurement aids in the clinical diagnosis of glaucoma. Spectral domain optical coherence tomography (SD-OCT) machines measure RNFLT and provide normative color-coded plots. In this retrospective study, we investigate whether normative percentiles of RNFLT (pRNFLT) from Spectralis SD-OCT improve prediction of glaucomatous visual field loss over raw RNFLT. A longitudinal database containing OCT scans and visual fields from Massachusetts Eye & Ear glaucoma clinic patients was generated. Reliable OCT-visual field pairs were selected. Spectralis OCT normative distributions were extracted from machine printouts. Supervised machine learning models compared predictive performance between pRNFLT and raw RNFLT inputs. Regional structure-function associations were assessed with univariate regression to predict mean deviation (MD). Multivariable classification predicted MD, pattern standard deviation, MD change per year, and glaucoma hemifield test. There were 3016 OCT-visual field pairs that met the reliability criteria. Spectralis norms were found to be independent of age, sex, and ocular magnification. Regional analysis showed significant decrease in R2 from pRNFLT models compared to raw RNFLT models in inferotemporal sectors, across multiple regressors. In multivariable classification, there were no significant improvements in area under the curve of receiver operating characteristic curve (ROC-AUC) score with pRNFLT models compared to raw RNFLT models. Our results challenge the assumption that normative percentiles from OCT machines improve prediction of glaucomatous visual field loss. Raw RNFLT alone shows strong prediction, with no models presenting improvement by the manufacturer norms. This may result from insufficient patient stratification in tested norms. Understanding correlation of normative databases to visual function may improve clinical interpretation of OCT data.


Acute Associations Between Outdoor Temperature and Premature Rupture of Membranes.
Extreme ambient temperatures have been linked to preterm birth. Preterm premature rupture of membranes is a common precursor to preterm birth but is rarely studied in relation to temperature. We linked 15,381 singleton pregnancies with premature rupture of membranes from a nationwide US obstetrics cohort (2002-2008) to local temperature. Case-crossover analyses compared daily temperature during the week preceding delivery and the day of delivery to 2 control periods, before and after the case period. Conditional logistic regression models calculated the odds ratio (OR) and 95% confidence intervals (CIs) of preterm and term premature rupture of membranes for a 1°C increase in temperature during the warm (May-September) and cold (October-April) season separately after adjusting for humidity, barometric pressure, ozone, and particulate matter. During the warm season, 1°C increase during the week before delivery was associated with a 5% (95% CI, 3%, 6%) increased preterm premature rupture of membranes risk, and a 4% (95% CI, 3%, 5%) increased term premature rupture of membranes risk. During the cold season, 1°C increase was associated with a 2% decreased risk for both preterm (95% CI, 1%, 3%) and term premature rupture of membranes (95% CI, 1%, 3%). The day-specific associations for the week before delivery were similar, but somewhat stronger for days closer to delivery. Relatively small ambient temperature changes were associated with the risk of both preterm and term premature of membranes. Given the adverse consequences of premature rupture of membranes and concerns over global climate change, these findings merit further investigation. See video abstract at, http://links.lww.com/EDE/B312.


Quantitative comparison of group-based music therapy experiences in adults with substance use disorder on a detoxification unit: a three-group cluster-randomized study.
Background: Service users' values and preferences are components of evidence-based practice and recovery. Methods: Adults (N = 113) with substance use disorder (SUD) on a detoxification unit were cluster-randomized to one of three group-based single-session conditions: Recreational music therapy (RMT), educational lyric analysis for illness management and recovery (ELA-IMR) or educational songwriting for illness management and recovery (ESW-IMR). Participants completed the Ferrara Group Experiences Scale after their session. Results: There were significant differences in the sharing of emotions and experiences subscale between the RMT and both the ELA-IMR and ESW-IMR conditions, with the educational conditions having higher scores. There was a significant difference in the total group experience between the RMT and ELA-IMR conditions, with the ELA-IMR condition having a higher score. Conclusions: Merging the results of previous literature with the current study, educational music therapy interventions can positively impact recovery-based objectives and the group-based experience in adults with SUD.


Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma.
Pilocytic astrocytomas occur predominantly in childhood. In contrast to the posterior fossa location, hypothalamo-chiasmatic pilocytic astrocytomas display a worse prognosis often leading to multiple surgical procedures and/or several lines of chemotherapy and radiotherapy to achieve long-term control. Hypothalamo-chiasmatic pilocytic astrocytomas and cerebellar pilocytic astrocytomas have a distinctive gene signature and several differential expressed genes (ICAM1, CRK, CD36, and IQGAP1) are targets for available drugs: fluvastatin and/or celecoxib. Quantification by RT-Q-PCR of the expression of these genes was performed in a series of 51 pilocytic astrocytomas and 10 glioblastomas: they were all significantly overexpressed in hypothalamo-chiasmatic pilocytic astrocytomas relative to cerebellar pilocytic astrocytomas, and CRK and ICAM1 were significantly overexpressed in pilocytic astrocytomas versus glioblastomas.We used two commercially available glioblastoma cell lines and three pilocytic astrocytoma explant cultures to investigate the effect of celecoxib/fluvastatin alone or in combination. Glioblastoma cell lines were sensitive to both drugs and a combination of 100 μM celecoxib and 240 μM fluvastatin was the most synergistic. This synergistic combination was used on the explant cultures and led to massive cell death of pilocytic astrocytoma cells.As a proof of concept, a patient with a refractory multifocal pilocytic astrocytoma was successfully treated with the fluvastatin/celecoxib combination used for 18 months. It was well tolerated and led to a partial tumor response. This study reports evidence for new targets and synergistic effect of celecoxib/fluvastatin combination in pilocytic astrocytoma. Because it is non-toxic, this new strategy offers hope for the treatment of patients with refractory pilocytic astrocytoma.


Certification for regional and international trade in livestock commodities: the need to balance credibility and enterprise.
The current system for the certification of internationally traded animal commodities can act as a barrier to developing countries accessing high-value international markets. In this Viewpoint article, Gavin Thomson and colleagues discuss the situation as it stands and identify inconsistencies with respect to the certification process. They suggest ways to address the lack of capacity for credible certification in some developing countries that will encourage market access for livestock commodities. They emphasise the role of mechanisms other than demonstrating that an area of production is free from a range of animal diseases, arguing that this could be of significant benefit to developing regions and countries, but that a reliable and independent system of certification based on international standards is essential.


Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients.
Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somatostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or monotherapy for prostate and breast cancer, and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutical industry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers.


Effect of self-adjusting file and WaveOne reciprocating file on the filling ability of oval-shaped canals with thermoplasticized gutta-percha.
The aim of the study was to compare the effect of Self-Adjusting Files (SAF) and WaveOne Primary file with syringe and needle irrigation on the filling ability of oval-shaped root canals obturated with thermoplasticized gutta-percha. Twenty-four single root teeth with single oval-shaped root canals were distributed into two experimental homogeneous groups. One group was instrumented and cleansed using the SAF system while in the other group the WaveOne system with syringe and needle irrigation was used. After instrumentation, the roots were filled by Thermafil Obturators and TopSeal sealer. Specimens were transversally sectioned at 2-, 5- and 7-mm levels from the apex and observed under light microscope. The percentage of gutta-percha filled area (PGFA), the percentage of sealer filled area (PSFA) and the percentage of voids area (PVA) were measured for each section, moreover the percentage of completely filled sections was evaluated. At all levels, no significant differences in terms of PGFA, PSFA, PVA and percentage of completely filled canals between groups were obtained (P > 0.05). On the contrary, when the data were pooled, the mean PGFA in the SAF group was 95.8%, whereas it was 93.2% in the WaveOne group (P less than 0.05). The percentage of sections completely filled was 77.8% in the SAF group, and 52.8% in the WaveOne group (P less than 0.05). Overall, the use of the SAF system in oval canals allows to obtain a significantly greater complete filling than the use of the WaveOne system.


A liquid chromatography/electrospray ionisation tandem mass spectrometry method for the simultaneous quantification of salicylic, jasmonic and abscisic acids in Coffea arabica leaves.
Plants have developed an efficient system of recognition that induces a complex network of signalling molecules such as salicylic acid (SA), jasmonic acid (JA) and abscisic acid (ABA) in case of a pathogenic infection. The use of specific and sensitive methods is mandatory for the analysis of compounds in these complex samples. In this study a liquid chromatography/electrospray ionisation tandem mass spectrometry method was developed and validated for the simultaneous quantification of SA, JA and ABA in Coffea arabica (L.) leaves in order to understand the role of these phytohormones in the signalling network involved in the coffee defence response against Hemileia vastatrix. The results showed that the method was specific, linear (r ≥ 0.99) in the range 0.125-1.00 µg mL⁻¹ for JA and ABA and 0.125-5.00 µg mL⁻¹ for SA, and precise (relative standard deviation ≤11%), and the limit of detection (0.010 µg g⁻¹ fresh weight) was adequate for quantifying these phytohormones in this type of matrix. In comparison with healthy leaves, those infected with H. vastatrix (resistance reaction) displayed an increase in SA level 24 h after inoculation, suggesting the involvement of an SA-dependent pathway in coffee resistance.


Characterization and complete genome sequences of high- and low- virulence variants of tick-borne encephalitis virus.
The entire genomic sequences of two strains (Hypr and 263) of the flavivirus tick-borne encephalitis (TBE) virus differing in virulence from the prototypic strain Neudoerfl were determined. Strain Hypr is a human isolate of TBE virus with a high laboratory passage history which exhibits a significantly higher neuro-invasiveness in mice compared to the prototype strain. Strain 263 is a low-passage tick-isolate with a temperature-sensitive and attenuated phenotype. Except for the heterogeneous 3' non-coding regions strains Hypr and 263 share, respectively, 97.2% and 97.6% nucleotide sequence identity with strain Neudoerfl, and differ by a total of 42 and 36 amino acids from the prototypic strain. Of these, only 12 amino acids for each of the two strains represent non-conservative differences unique to an individual strain and some of these are located at positions highly conserved among flaviviruses. Based on these observations, the potential biological significance of particular sequence differences is discussed in the context of the current knowledge about molecular determinants of flavivirus virulence.


Improved success of sparse matrix protein crystallization screening with heterogeneous nucleating agents.
Crystallization is a major bottleneck in the process of macromolecular structure determination by X-ray crystallography. Successful crystallization requires the formation of nuclei and their subsequent growth to crystals of suitable size. Crystal growth generally occurs spontaneously in a supersaturated solution as a result of homogenous nucleation. However, in a typical sparse matrix screening experiment, precipitant and protein concentration are not sampled extensively, and supersaturation conditions suitable for nucleation are often missed. We tested the effect of nine potential heterogenous nucleating agents on crystallization of ten test proteins in a sparse matrix screen. Several nucleating agents induced crystal formation under conditions where no crystallization occurred in the absence of the nucleating agent. Four nucleating agents: dried seaweed; horse hair; cellulose and hydroxyapatite, had a considerable overall positive effect on crystallization success. This effect was further enhanced when these nucleating agents were used in combination with each other. Our results suggest that the addition of heterogeneous nucleating agents increases the chances of crystal formation when using sparse matrix screens.


Methods for equine preantral follicles isolation: quantitative aspects.
The aim of this study was to test the use of mechanical and mechanical-enzymatic methods, saline solution (SS), and PBS solution for the manipulation and isolation of mare ovarian preantral follicles (PAFs). The ovaries were subjected to mechanical isolation (mixer) alone or in association with enzymatic digestion (collagenase). Incubation times of 10 and 20 min were employed. In the first group, 4.1 ± 4.9 PAFs were harvested with the mechanical-enzymatic method vs 71.1 ± 19.2 with the mechanical procedure, showing a significant difference between methods; using SS and PBS, these numbers were 35.7 ± 34.3 and 39.6 ± 39.6, respectively, with no significant difference between solutions. In the second group, there was significant difference between methods, with 7.1 ± 10.6 follicles harvested with the mechanical-enzymatic method vs 63.2 ± 22.9 with the mechanical procedure; using SS and PBS, means were 35.5 ± 36.4 and 34.9 ± 31.1, respectively. The mechanical method proved more effective than the mechanical-enzymatic approach. Both SS and PBS can be used as a media for equine PAFs preparation.


Examining racial and ethnic disparities in site of usual source of care.
Little is known about why minorities have a lower propensity to use private doctors' offices for their usual source of care than non-Hispanic whites. This study used the 2001 Commonwealth Fund's Health Care Quality Survey of adults to determine if this disparity is due to racial and ethnic differences in attitudes about health and healthcare, and perceptions of racial and ethnic discrimination in healthcare. We found that race and ethnic disparities at the site of the usual source of care persisted even after controlling for individuals' attitudes about health and healthcare, and their perceptions about racial and ethnic discrimination in healthcare. We found that the impact of attitudes and perceptions did vary by subgroups. These factors were important for Asians' site of usual source of care but had little impact on African Americans' site of usual of care. However, despite their differential impact by race and ethnicity, attitudes and perceptions were not the source of observed disparities in site of care. Therefore, in addition to focusing on provider-patient relationships, perhaps future research and policymakers should focus on system-level factors to explain and increase minority use of care in private physicians' offices.


[Effect of taste deafferentation on the preference for solutions of saccharose, saccharin and salt in rats].
The preference of sucrose, saccharin and salt solutions to water was analyzed during 5 days in rats with bilateral section of the lingual nerve comprising the taste nerve--chorda tympani. In the process of the analysis of daily consumption and choice of solutions, different types of behavioural reactions were found: stable preference and change of preference. The number of rats preferring NaCl was greater among the animals with sectioned lingual nerve than among sham-operated control rats and rats with ligated ducts of submaxillary and sublingual salivary glands. The number of rats with the lingual nerve section preferring sucrose or saccharin solutions to water was equal to that among the sham-operated rats. At the same time the mean volume of sucrose solution taken in daily by rats with sectioned lingual nerve was twice as great as the volume of saccharin, drunk by the same animals. The role of taste in the process of choice and preference of NaCl to sweet solutions is discussed.


Monitoring the microbiological quality of dialysate and treated water.
During hemodialysis and related therapies, removal of waste products from the blood is made possible across a semi-permeable membrane. The microbiological quality of treated water (TW) and dialysate influences a number of dialysis-related complications. This article is a review of the microbiological features of TW and dialysate fluid over a six-year period (February 2007 to December 2012) in the Dialysis Unit, 1 st Medico-Surgical Hospital, Agadir, Morocco. Installation of a water treatment unit has been followed by a protocol to check its quality periodically. Results of microbiological monitoring (microorganisms and endotoxins) were collected over a six-year period. Fifty-four samples of TW and 12 samples of dialysate fluid were analyzed for colony forming units (CFU) and endotoxin during this period. All dialysate samples were negative, while in the TW, 9.2% of the samples yielded >100/mL CFU and 16.7% yielded >0.06 EU/mL of endotoxins. These abnormal results happened especially during the first two first years. More frequent disinfection of the distribution loop was the corrective measure. To obtain high-quality water for hemodialysis, the appropriate system must be continuously monitored in order to get high microbiological quality of TW and dialysate fluid.


Clinical features and physiological response to a test meal in purging disorder and bulimia nervosa.
Recent data suggest that purging disorder, a recently characterized form of eating disorder not otherwise specified, may be worthy of specific delineation in nosological schemes. However, more data are needed to determine how purging disorder differs from bulimia nervosa. To examine clinical features and subjective as well as objective physiological responses to a standardized test meal in purging disorder compared with bulimia nervosa and controls. Study visit 1 included psychological assessments with structured clinical interviews and questionnaires. Study visit 2 included assessment of test-meal responses. Participants recruited from the community completed test-meal studies in a General Clinical Research Center. Women with DSM-IV bulimia nervosa-purging subtype (n = 37) and purging disorder (n = 20) and non-eating disorder controls (n = 33) with a body mass index (calculated as weight in kilograms divided by height in meters squared) between 18.5 and 26.5 who were free of psychotropic medications. Assessments of eating disorder severity, postprandial cholecystokinin response, and subjective responses to test meals. Eating abnormalities were significantly elevated in participants with purging disorder and bulimia nervosa compared with controls but did not differ between eating disorder groups. Participants with purging disorder demonstrated significantly greater postprandial cholecystokinin release compared with participants with bulimia nervosa (t(76.44) = 2.51; P = .01) and did not differ significantly from controls (t(75.93) = 0.03; P = .98). Participants with purging disorder reported significantly greater postprandial fullness and gastrointestinal distress compared with participants with bulimia nervosa and controls. Purging disorder is a clinically significant disorder of eating that appears to be distinct from bulimia nervosa on subjective and physiological responses to a test meal. Findings support further consideration of purging disorder for inclusion in the classification of eating disorders. Future studies on the psychobiology of purging disorder are needed to understand the propensity to purge in the absence of binge eating.


IgG4 serology of loiasis in three villages in an endemic area of south-eastern Gabon.
Human filariasis due to Loa loa differs from other filariasis in that the majority of infected subjects are without circulating microfilariae (occult loiasis). In search for alternative diagnostic methods, which do not depend on circulating microfilariae or the (rather infrequent) eye-passage of adult worms, it was shown earlier that IgG4 antibodies directed against Loa loa adult worm antigen are apparently a good marker of occult loiasis and specific with regard to the sympatrically occurring Mansonella perstans. In this study we evaluated an IgG4 antibody-based ELISA using crude extract of Loa loa microfilariae (which is easier to obtain than adult worm) to estimate the prevalence of loiasis in 3 villages in South-East Gabon. Of 222 examined individuals (80 children < 16 years, 142 adults) 44 (20%) carried Loa loa microfilariae and 170 (77%) M. perstans. Using the mean OD-value + 1 standard deviation of 9 sera from patients solely infected with M. perstans (from the Gambia, where Loa loa is not endemic) as a cut-off, 35 of the 44 microfilaraemic Loa loa patients and 2 of the 9 Gambian controls were positive. This shows that our method had a sensitivity of 80% and a specificity of 78%. Among the remaining 178 subjects who had no microfilariae of Loa loa, as many as 97 (55%) had significant levels of specific IgG4 antibodies against Loa loa, suggesting that they carried occult loiasis. The mean IgG4 level in these putatively occult loiasis patients was slightly but significantly lower than in microfilaraemic subjects (P < 0.03). In conclusion, despite the limited sensitivity and specificity of our method, IgG4- ELISA at present is a very useful tool in estimating the real prevalence of loiasis in epidemiological surveys and at the individual level can confirm the diagnosis of L. loa amicrofilaraemic subjects with clinical signs suggesting loiasis.


Implementing the Namaste Care Program for residents with advanced dementia: exploring the perceptions of families and staff in UK care homes.
Increasing numbers of older people with advanced dementia are cared for in care homes. No cure is available, so research focused on improving quality of life and quality of care for people with dementia is needed to support them to live and die well. The Namaste Care programme is a multi-dimensional care program with sensory, psycho-social and spiritual components intended to enhance quality of life and quality of care for people with advanced dementia. The aim of the study was to establish whether the Namaste Care program can be implemented in UK care homes; and what effect Namaste Care has on the quality of life of residents with advanced dementia, their families and staff. This article explores the qualitative findings of the study, reporting the effect of the programme on the families of people with advanced dementia and care home staff, and presenting their perceptions of change in care. An organisational action research methodology was used. Focus groups and interviews were undertaken pre/post implementation of the Namaste Care program. The researcher kept a reflective diary recording data on the process of change. A comments book was available to staff and relatives in each care home. Data was analysed thematically within each care home and then across all care homes. Six care homes were recruited in south London: one withdrew before the study was underway. Of the five remaining care homes, four achieved a full Namaste Care program. One care home did not achieve the full program during the study, and another discontinued Namaste Care when the study ended. Every home experienced management disruption during the study. Namaste Care challenged normal routinised care for older people with advanced dementia. The characteristics of care uncovered before Namaste was implemented were: chaos and confusion, rushing around, lack of trust, and rewarding care. After the programme was implemented these perceptions were transformed, and themes of calmness, reaching out to each other, seeing the person, and, enhanced well-being, emerged. Namaste Care can enrich the quality of life of older people with advanced dementia in care homes. The program was welcomed by care home staff and families, and was achieved with only modest expenditure and no change in staffing levels. The positive impact on residents quality of life influenced the well-being of family carers. Care staff found the changes in care enjoyable and rewarding. Namaste Care was valued for the benefits seen in residents; the improvement in relationships; and the shift towards a person-centred, relationship-based culture of care brought about by introducing the program. Namaste Care deserves further exploration and investigation including a randomised controlled trial.


A SURVEY STUDY OF RADIATION PROTECTION AWARENESS AMONG RADIOLOGY TECHNICIANS IN MOGADISHU, SOMALIA.
We investigate the ionizing radiation exposure awareness and subject matter knowledge among clinical radiology technicians working in state and private hospitals in Mogadishu, Somalia. Research data are collected via face to face interviews with a prepared questionnaire performed between April and May 2018 in Mogadishu, Somalia. A total of 61 clinical radiology technicians working in 10 state and private hospitals in Mogadishu volunteered to be part of this study. Among the participants, awareness of the harmful effects of ionizing radiation and sufficient subject matter knowledge were lacking. In addition, radiation protection equipment during radiological examinations were not adequately used by clinical radiology technicians. Our results indicate a necessity to retrain and improve the technician education curriculum before and after graduation to create a safer environment both for hospital staff and patients during radiological examinations.


Triglyceride-glucose index is associated with a higher risk of stroke in a hypertensive population.
This study aimed to evaluate the association of triglyceride-glucose (TyG) index, an insulin resistance surrogate biomarker, with first stroke in a hypertensive population and to explore potential influencing factors. This study, a cohort study among a rural Chinese hypertensive population, utilized data from the China Stroke Primary Prevention Trial (CSPPT). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multivariate analysis using Cox proportional hazards models was conducted. A total of 7569 hypertensive patients were included in this study. When TyG index was assessed as quartiles, compared with the reference group (Quartile 1), the hazard ratio of stroke was 1.04 in Quartile 2, 1.43 in Quartile 3, and 1.45 in Quartile 4, with a significant trend test (P = 0.013). When Quartiles 3 and 4 were combined (≥ 8.8), the hazard ratio was 1.41 compared with combined Quartiles 1 and 2 (< 8.8). Similar findings were observed for the association of TyG index with ischemic stroke. Further, a joint effect of baseline TyG index and age on first stroke was found. Using the group with TyG < 8.8 and age < 60 years as a reference, the highest hazard ratio of stroke was found in the group with a higher TyG index and aged 60 or greater (HR: 2.15, 95% CI 1.50, 3.07, P < 0.001). In a hypertensive population, baseline TyG index was associated with a significantly higher risk of first stroke. In addition, age was a significant effect modifier for this association.


Exoenzymes as a Signature of Microbial Response to Marine Environmental Conditions.
Microbial heterotopic metabolism in the ocean is fueled by a supply of essential nutrients acquired via exoenzymes catalyzing depolymerization of high-molecular-weight compounds. Although the rates of activity for a variety of exoenzymes across various marine environments are well established, the factors regulating the production of these exoenzymes, and to some extent their correlation with microbial community composition, are less known. This study focuses on addressing these challenges using a mesocosm experiment that compared a natural seawater microbial community (control) and exposed (to oil) treatment. Exoenzyme activities for β-glucosidase, leucine aminopeptidase (LAP), and lipase were significantly correlated with dissolved nutrient concentrations. We measured correlations between carbon- and nitrogen-acquiring enzymes (β-glucosidase/lipase versus LAP) and found that the correlation of carbon-acquiring enzymes varies with the chemical nature of the available primary carbon source. Notably, a strong correlation between particulate organic carbon and β-glucosidase activity demonstrates their polysaccharide depolymerization in providing the carbon for microbial growth. Last, we show that exoenzyme activity patterns are not necessarily correlated with prokaryotic community composition, suggesting a redundancy of exoenzyme functions among the marine microbial community and substrate availability. This study provides foundational work for linking exoenzyme function with dissolved organic substrate and downstream processes in marine systems.IMPORTANCE Microbes release exoenzymes into the environment to break down complex organic matter and nutrients into simpler forms that can be assimilated and utilized, thereby addressing their cellular carbon, nitrogen, and phosphorus requirements. Despite its importance, the factors associated with the synthesis of exoenzymes are not clearly defined, especially for the marine environment. Here, we found that exoenzymes associated with nitrogen and phosphorus acquisition were strongly correlated with inorganic nutrient levels, while those associated with carbon acquisition depended on the type of organic carbon available. We also show a linear relationship between carbon- and nitrogen-acquiring exoenzymes and a strong correlation between microbial biomass and exoenzymes, highlighting their significance to microbial productivity. Last, we show that changes in microbial community composition are not strongly associated with changes in exoenzyme activity profiles, a finding which reveals a redundancy of exoenzyme activity functions among microbial community. These findings advance our understanding of previously unknown factors associated with exoenzyme production in the marine environment.


Electrical creation of spin polarization in silicon at room temperature.
The control and manipulation of the electron spin in semiconductors is central to spintronics, which aims to represent digital information using spin orientation rather than electron charge. Such spin-based technologies may have a profound impact on nanoelectronics, data storage, and logic and computer architectures. Recently it has become possible to induce and detect spin polarization in otherwise non-magnetic semiconductors (gallium arsenide and silicon) using all-electrical structures, but so far only at temperatures below 150 K and in n-type materials, which limits further development. Here we demonstrate room-temperature electrical injection of spin polarization into n-type and p-type silicon from a ferromagnetic tunnel contact, spin manipulation using the Hanle effect and the electrical detection of the induced spin accumulation. A spin splitting as large as 2.9 meV is created in n-type silicon, corresponding to an electron spin polarization of 4.6%. The extracted spin lifetime is greater than 140 ps for conduction electrons in heavily doped n-type silicon at 300 K and greater than 270 ps for holes in heavily doped p-type silicon at the same temperature. The spin diffusion length is greater than 230 nm for electrons and 310 nm for holes in the corresponding materials. These results open the way to the implementation of spin functionality in complementary silicon devices and electronic circuits operating at ambient temperature, and to the exploration of their prospects and the fundamental rules that govern their behaviour.


A membrane filter technique for testing disinfectants.
A membrane filter was used for assessing the surface disinfecting activity of phenolic disinfectants and a chloroxylenol disinfectant. The influence of the type of organism, inoculum size, and hardness of water was investigated. Pseudomonas aeruginosa was chosen for the standardized test. Disinfectant solutions were prepared in water of 300 ppm hardness and applied for two and a half minutes and eight minutes to the bacteria deposited from filtration of 1 ml of a suspension containing 10-6 bacteria. The membrane filter test has certain advantages over many tests, eg, all organisms surviving after treatment can be counted and residual disinfectant is easily removed.


Applying the precautionary principle to nutrition and cancer.
Research has identified certain foods and dietary patterns that are associated with reduced cancer risk and improved survival after cancer diagnosis. This research has formed the basis for dietary guidance issued by cancer organizations. Unfortunately, gaps within nutrition research have made it difficult to make recommendations in some areas. This review specifies suggested dietary guidance in which evidence of a dietary influence on cancer risk is substantial, even if not conclusive. Evidence summaries within the review are based on the 2007 report of the World Cancer Research Fund/American Institute for Cancer Research. This review also describes advantages and disadvantages of following the suggested dietary guidance and includes putative mechanisms involved in cancer progression. Suggested dietary guidance where evidence is sufficiently compelling include (1) limiting or avoiding dairy products to reduce the risk of prostate cancer; (2) limiting or avoiding alcohol to reduce the risk of cancers of the mouth, pharynx, larynx, esophagus, colon, rectum, and breast; (3) avoiding red and processed meat to reduce the risk of cancers of the colon and rectum; (4) avoiding grilled, fried, and broiled meats to reduce the risk of cancers of the colon, rectum, breast, prostate, kidney, and pancreas; (5) consumption of soy products during adolescence to reduce the risk of breast cancer in adulthood and to reduce the risk of recurrence and mortality for women previously treated for breast cancer; and (6) emphasizing fruits and vegetables to reduce risk of several common forms of cancer. By adopting the precautionary principle for nutrition research, this review aims to serve as a useful tool for practitioners and patients.


The scholar as craftsman: Derek de Solla Price and the reconstruction of a medieval instrument.
The Royal Society Conversaziones were biannual social evenings at which distinguished guests could learn about the latest scientific developments. The Conversazione in May 1952 featured an object that came to be called King Arthur's Table. It was a planetary equatorium, made in Cambridge's Cavendish Laboratory at the behest of Sir Lawrence Bragg. Conceived by the historian of science Derek de Solla Price as a huge, tangible realization of Chaucerian astronomy, it was displayed at the new Whipple Museum of the History of Science, discarded, stored incognito, catalogued with that whimsical name, and finally re-identified in 2012. This article examines the biography of that object and, through it, the early, inchoate years of the discipline of history of science in Cambridge. The process of disciplinary establishment involved a range of actors beyond well-known figures such as Herbert Butterfield and Joseph Needham; the roles of Price and Bragg are highlighted here. Study of these individuals, and of the collaboration that brought about the reconstruction, reveals much about the establishment of a discipline, as well as changing scholarly and curatorial attitudes towards replicas.


Regulation of alternative splicing of NMDAR1 in the kindling model.
Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. Several lines of investigation suggest that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor participates in the expression of the increased neuronal excitability of the kindled brain. Many studies demonstrate that kindling results in altered NMDA receptor functional and pharmacological properties, indicating that kindling may cause changes intrinsic to the NMDA receptor itself. It is possible that altered expression of NMDA receptor subunit genes and splice isoforms of genes leads to subunit combinations resulting in the novel NMDA receptor properties identified in the hippocampus of kindled animals. To begin to address this possibility, we previously examined the hippocampal expression of known NMDA receptor genes and found no differences in expression between control and kindled animals either 24 h or 28 days after the last kindled seizure. Here, we extend that earlier study by examining the expression of NMDAR1 splice isoforms in the hippocampus of control and kindled animals. We report that kindling induces the transient reduction of specific splice isoforms of NMDAR1 containing the first of the carboxy-terminal splice cassettes (exon 21). We discuss the potential significance of this regulation in terms of its relevance to previous findings in the kindling model and possible effects on NMDA receptor function.


Rescue of W-associated mast cell defects in W/Wv bone marrow cells by ectopic expression of normal and mutant epidermal growth factor receptors.
The normal human epidermal growth factor receptor (EGF-R) (HERc), a chimeric EGF-R/v-erbB (HERerbB) receptor, and the ligand-independent oncogenic EGF-R variant (v-erbB) were used to correct the mast cell defects in W/Wv bone marrow (BM) cells. In culture, all three receptor molecules transduced functional mitogenic signals in infected interleukin-3 (IL-3)-dependent bone marrow-derived mast cells (BMMCs) and enabled their differentiation into safranin-positive mast cells resembling connective tissue-type mast cells (CTMCs). Furthermore, expression of these receptors restored the capacity of W/Wv BMMCs to colonize the peritoneal cavity of mast cell-deficient W/Wv mice where they differentiated to safranin-positive cells with similar frequencies as wild-type BMMCs. These experiments show that expression of normal and mutant EGF-Rs in W/Wv BM cells is able to complement the function of the c-kit-encoded Steel factor receptor (SLF-R) in mast cell development. We conclude that signal transduction by normal and mutant EGF-Rs in murine hematopoietic cells apparently involves components also used by the SLF-R, which suggests that these receptors use overlapping pathways for signal transduction.


A Cross-sectional Study Examining the (In)congruency of Sexual Identity, Sexual Behavior, and Romantic Attraction among Adolescents in the US.
To examine how sexual identity, romantic attraction, and sexual behavior co-relate for cisgender adolescents. The Teen Health and Technology survey was a cross-sectional, self-report online survey. More than 5000 youth between 13 and 18 years of age were randomly recruited through Harris Panel OnLine's panel as well as outreach by GLSEN to over-recruit lesbian, gay, bisexual, and other sexual minority youth. Data were collected between 2010 and 2011. Analyses were conducted in 2018 and restricted to cisgender youth. Overall, romantic attraction and sexual behavior most closely mapped each other. The greatest discordance was noted between sexual identity and romantic attraction. For example, 59% of girls and 16% of boys who identified with a nonheterosexual identity reported that at least 1 of their 2 most recent sexual partners was a different gender. Nine percent of heterosexually-identified girls and 3% of heterosexually-identified boys reported romantic attraction to the same sex, and 6% and 7% of heterosexually-identified girls and boys, respectively, reported that at least 1 of their 2 most recent sexual partners was the same gender. Treating romantic attraction, sexual identity, and sexual behavior as synonymous assumes a unidimensionality that is unsupported by the data. Pediatricians and others working with youth, including researchers, should be mindful not to assume identity on the basis of behavior. Researchers should be clear and purposeful about how they are operationalizing "sexual minority" and how it may affect the composition of their study population. Healthy sexuality and risk reduction programs need to acknowledge that adolescents with a particular sexual identity may have romantic attractions, and even sexual encounters, with people who fall outside of that identity.


Palpebral Anthrax.
A 13-year-old male patient presented with a complaint of swelling of the left eye starting 3 days ago. Bullous lesion and purulent discharge were present on his left eyelids. Bacillus anthracis was shown in culture and diagnosis was confirmed. Oculocutaneous anthrax is a rare condition, but the diagnosis should be considered in patients with a painless necrotizing ulcer.


Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance.
This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the n-3 family, play essential roles in the maintenance of energy balance and glucose metabolism. The data discussed indicate that dietary PUFA function as fuel partitioners in that they direct glucose toward glycogen storage, and direct fatty acids away from triglyceride synthesis and assimilation and toward fatty acid oxidation. In addition, the n-3 family of PUFA appear to have the unique ability to enhance thermogenesis and thereby reduce the efficiency of body fat deposition. PUFA exert their effects on lipid metabolism and thermogenesis by upregulating the transcription of the mitochondrial uncoupling protein-3, and inducing genes encoding proteins involved in fatty acid oxidation (e.g. carnitine palmitoyltransferase and acyl-CoA oxidase) while simultaneously down-regulating the transcription of genes encoding proteins involved in lipid synthesis (e.g. fatty acid synthase). The potential transcriptional mechanism and the transcription factors affected by PUFA are discussed. Moreover, the data are interpreted in the context of the role that PUFA may play as dietary factors in the development of obesity and insulin resistance. Collectively the results of these studies suggest that the metabolic functions governed by PUFA should be considered as part of the criteria utilized in defining the dietary needs for n-6 and n-3 PUFA, and in establishing the optimum dietary ratio for n-6:n-3 fatty acids.


Human papillomavirus vaccine coverage among females aged 11 to 17 in Texas counties: an application of multilevel, small area estimation.
Local data are often used to plan and evaluate public health interventions and policy. With increasingly fewer public resources to collect sufficient data to support direct estimation of local outcomes, methods for deriving small area estimates are vital. The purpose of this study is to describe the county-level geographic distribution of human papillomavirus (HPV) vaccine coverage among adolescent females in Texas using multilevel small area estimation. Multilevel (individual, county, public health region) random-intercept logit models were fit to HPV vaccination data (≥1 dose Gardasil) from the 2008 Behavioral Risk Factor Surveillance System. Using the parameter estimates from the final model, we simulated 10,000 data sets for each regression coefficient from the normal distribution and applied them to the logit model to estimate HPV vaccine coverage in each county. County-level coverage estimates ranged from 7% to 29%, compared with the state average of 18% (95% confidence interval [CI], 13.59-21.88). Many Southwestern border and metropolitan counties exhibited high coverage estimates. Low coverage estimates were noted in the Panhandle, Southeastern border region, and Northeast. Significant correlations were observed between HPV vaccination and Hispanic ethnicity, county poverty, and public health region poverty. Harnessing the flexibility of multilevel small area models to estimate HPV vaccine coverage at the county level, we have provided data that may inform the development of health education programs/policies, the provision of health services, and the planning of new research studies. Additionally, we have provided a framework for modeling other health outcomes at the county level using national survey data.


Common isolation of New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae in a large surgical hospital in Vietnam.
This study sought to monitor the presence of carbapenem-resistant Enterobacteriaceae (CRE) and the proportion New Delhi metallo-beta-lactamase 1 (NDM-1)-producing bacteria between August 2010 and December 2012 in a surgical hospital in Vietnam. We identified 47 CRE strains from a total of 4,096 Enterobacteriaceae isolates (1.1 %) that were NDM-1-positive from 45 patients admitted to 11 different departments, with the majority being from the urology department. The NDM-1 gene was found in seven different species. Genotyping revealed limited clonality of NDM-1-positive isolates. Most of the isolates carried the NDM-1 gene on a plasmid and 17.8 % (8/45) of those were readily transferable. We found five patients at admission and one patient at discharge with NDM-1-positive bacteria in their stool. From 200 screening environmental hospital samples, five were confirmed to be NDM-1-positive and included Acinetobacter species (n = 3) and Enterobacter aerogenes (n = 2). The results reveal that NDM-1-producing Enterobacteriaceae are commonly isolated in patients admitted to a Vietnamese surgical hospital and are also detected in the hospital environment.


Spatial Effects and GWA Mapping of Root Colonization Assessed in the Interaction Between the Rice Diversity Panel 1 and an Arbuscular Mycorrhizal Fungus.
If water saving methods of rice management are to be adopted, the interaction between rice plants and arbuscular mycorrhizal (AM) fungi will grow in agronomic significance. As yet there are very few studies on the interaction between rice and AM fungi and none on host genetics. A subset 334 cultivars from the Rice Diversity Panel 1 were grown in 250 L boxes filled with phosphorus (P) deficient aerobic soil without addition, with added rock phosphate and with rock phosphate and the AM fungus Rhizophagus irregularis. Statistical analysis of position of plants revealed a positive effect of their neighbors on their dry weight which was stronger in the presence of rock phosphate and even stronger with rock phosphate and AM fungi. A weak but significant difference in the response of cultivars to AM fungus treatment in terms of shoot dry weight (SDW) was revealed. Neighbor hyphal colonization was positively related to a plant's hyphal colonization, providing insights into the way a network of AM fungi interact with multiple hosts. Hyphal colonization ranged from 21 to 89%, and 42% of the variation was explained by rice genotype. Colonization was slightly lower in aus cultivars than other rice subgroups and high in cultivars from the Philippines. Genome wide association (GWA) mapping for hyphal colonization revealed 23 putative quantitative trait loci (QTLs) indicating there is an opportunity to investigate the impact of allelic variation in rice on AM fungal colonization. Using published transcriptomics data for AM response in rice, some promising candidate genes are revealed under these QTLs being a calcium/calmodulin serine/threonine protein kinase at 4.9 Mbp on chromosome 1, two ammonium transporters genes at 24.6 Mbp on chromosome 2 and a cluster of subtilisin genes at 1.2 Mbp on chromosome 4. Future studies should concentrate on the biological significance of genetic variation in rice for AM colonization.


Automatic referral to standardize palliative care access: an international Delphi survey.
Palliative care referral is primarily based on clinician judgment, contributing to highly variable access. Standardized criteria to trigger automatic referral have been proposed, but it remains unclear how best to apply them in practice. We conducted a Delphi study of international experts to identify a consensus for the use of standardized criteria to trigger automatic referral. Sixty international experts stated their level of agreement for 14 statements regarding the use of clinician-based referral and automatic referral over two Delphi rounds. A consensus was defined as an agreement of ≥70% a priori. The response rate was 59/60 (98%) for the first round and 56/60 (93%) for the second round. Twenty-six (43%), 19 (32%), and 11 (18%) respondents were from North America, Asia/Australia, and Europe, respectively. The panel reached consensus that outpatient palliative care referral should be based on both automatic referral and clinician-based referral (agreement = 86%). Only 18% felt that referral should be clinician-based alone, and only 7% agreed that referral should be based on automatic referral only. There was consensus that automatic referral criteria may increase the number of referrals (agreement = 98%), facilitate earlier palliative care access, and help administrators to set benchmarks for quality improvement (agreement = 86%). Our panelists favored the combination of automatic referral to augment clinician-based referral. This integrated referral framework may inform policy and program development.


Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers.
A diagnosis of pancreatic cancer is devastating owing to its poor prognosis, with a 5-year survival rate of only 9%. Currently, most individuals are diagnosed at a late stage when treatment options are limited. Early detection of pancreatic cancer provides the greatest hope for making substantial improvements in survival. The Kenner Family Research Fund in partnership with the American Pancreatic Association has sponsored a series of fora to stimulate discussion and collaboration on early detection of pancreatic cancer. At the first forum in 2014, "Early Detection of Sporadic Pancreatic Cancer Summit Conference," a strategic plan was set forth by an international group of interdisciplinary scientific representatives and subsequently The Strategic Map for Innovation was generated. The current conference report is the third forum in the series, "Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers," which was held in Boston, Massachusetts, on October 27, 2016. This report provides an overview of examples of innovative initiatives by industry and confirms the critical need for collaboration among industry, government, research institutions, and advocacy groups in order to make pancreatic cancer more easily detectable in its earlier stages, when it is more treatable.


Influence of treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta9-THC) on neuropsychological performance.
Previous studies have suggested that marijuana (cannabis sativa) and delta-9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient of marijuana, are effective in the therapy of tics and associated behavioral disorders in Tourette Syndrome (TS). Because there is also evidence that cannabis sativa may cause cognitive impairment in healthy users, we performed a randomized double-blind placebo-controlled crossover trial for delta9-THC in 12 adult TS patients to investigate whether treatment of TS with a single dose of delta9-THC at 5.0 to 10.0 mg causes significant side effects on neuropsychological performance. Using a variety of neuropsychological tests, we found no significant differences after treatment with delta9-THC compared to placebo treatment in verbal and visual memory, reaction time, intelligence, sustained attention, divided attention, vigilance, or mood. Only when using the Symptom Checklist 90-R (SCL-90-R) did our data provide evidence for a deterioration of obsessive-compulsive behavior (OCB) and a trend towards an increase in phobic anxiety. However, these results should be interpreted with caution as SCL-90-R has known limitations on measuring OCB. We suggest that the increase in phobic anxiety is mainly due to the fact that a single-dose treatment rules out the possibility of administering the dosage slowly. In contrast to results obtained from healthy marijuana users, a single-dose treatment with delta9-THC in patients suffering from TS does not cause cognitive impairment. We therefore suggest that further investigations should concentrate on the effects of a longer-term therapy of TS with delta9-THC.


Reactive angioendotheliomatosis associated with cyroglobulinemia in a marathon runner.
We report a case of a 65-year-old marathon runner who presented with painful plaques, which were worse in cold weather and progressed to ulceration. A punch biopsy revealed vascular endothelial hyperplasia and an appearance consistent with reactive angioendotheliomatosis (RAE), a rare, but benign disorder of the skin. Subsequent investigations resulted in the diagnosis of type I cryoglobulinemia; the lesions resolved completely following treatment of the underlying disorder with lenalidomide.


Effects of internal stress concentrations in plantar soft-tissue--A preliminary three-dimensional finite element analysis.
It has been hypothesized that diabetic foot ulceration might be internally initiated. This study established a three-dimensional and nonlinear finite element model of a human foot complex with comprehensive skeletal and soft-tissue components. The model was validated by experimental data of subject-specific barefoot plantar pressure measurements. The feasibility of the model to predict the 3D, internal, plantar soft-tissue deformation and stress was evaluated. The preliminary results indicate that large von Mises stress occurs where plantar soft-tissue contacts with geometrically irregular bony structures, thus internal stress distribution within the plantar soft-tissue was dramatically influenced by bony prominences due to stress concentration. At the forefoot part, an average stress magnification factor of 3.01 was quantified. The lateral sesamoid bone associated to the 1st MTH showed the largest effect of stress concentration. The modeling approach presented provides a possible way to explore the complexity of the mechanical environment inside the plantar soft-tissue.


Timing of Primary Surgery for Cleft Palate.
Among infants with isolated cleft palate, whether primary surgery at 6 months of age is more beneficial than surgery at 12 months of age with respect to speech outcomes, hearing outcomes, dentofacial development, and safety is unknown. We randomly assigned infants with nonsyndromic isolated cleft palate, in a 1:1 ratio, to undergo standardized primary surgery at 6 months of age (6-month group) or at 12 months of age (12-month group) for closure of the cleft. Standardized assessments of quality-checked video and audio recordings at 1, 3, and 5 years of age were performed independently by speech and language therapists who were unaware of the trial-group assignments. The primary outcome was velopharyngeal insufficiency at 5 years of age, defined as a velopharyngeal composite summary score of at least 4 (scores range from 0 to 6, with higher scores indicating greater severity). Secondary outcomes included speech development, postoperative complications, hearing sensitivity, dentofacial development, and growth. We randomly assigned 558 infants at 23 centers across Europe and South America to undergo surgery at 6 months of age (281 infants) or at 12 months of age (277 infants). Speech recordings from 235 infants (83.6%) in the 6-month group and 226 (81.6%) in the 12-month group were analyzable. Insufficient velopharyngeal function at 5 years of age was observed in 21 of 235 infants (8.9%) in the 6-month group as compared with 34 of 226 (15.0%) in the 12-month group (risk ratio, 0.59; 95% confidence interval, 0.36 to 0.99; P = 0.04). Postoperative complications were infrequent and similar in the 6-month and 12-month groups. Four serious adverse events were reported (three in the 6-month group and one in the 12-month group) and had resolved at follow-up. Medically fit infants who underwent primary surgery for isolated cleft palate in adequately resourced settings at 6 months of age were less likely to have velopharyngeal insufficiency at the age of 5 years than those who had surgery at 12 months of age. (Funded by the National Institute of Dental and Craniofacial Research; TOPS ClinicalTrials.gov number, NCT00993551.).


A Method for Performing Islet Transplantation Using Tissue-Engineered Sheets of Islets and Mesenchymal Stem Cells.
Mesenchymal stem cells (MSCs) are known to have a protective effect on islet cells. Cell sheets developed using tissue engineering help maintain the function of the cells themselves. This study describes a tissue engineering approach using islets with MSC sheets to improve the therapeutic effect of islet transplantation. MSCs were obtained from Fischer 344 rats and engineered into cell sheets using temperature-responsive culture dishes. The islets obtained from Fischer 344 rats were seeded onto MSC sheets, and the islets with MSC sheets were harvested by low-temperature treatment after coculture. The functional activity of the islets with MSC sheets was confirmed by a histological examination, insulin secretion assay, and quantification of the levels of cytokines. The therapeutic effects of the islets with MSC sheets were investigated by transplanting the sheets at subcutaneous sites in severe combined immunodeficiency (SCID) mice with streptozotocin-induced diabetes. Improvement of islet function and viability was shown in situ on the MSC sheet, and the histological examination showed that the MSC sheet maintained adhesion factor on the surface. In the recipient mice, normoglycemia was maintained for at least 84 days after transplantation, and neovascularization was observed. These results demonstrated that islet transplantation in a subcutaneous site would be possible by using the MSC sheet as a scaffold for islets.


The effect of sterols on structures formed in the gel/subgel phase state of dipalmitoylphosphatidylcholine bilayers.
The effect of cholesterol and lanosterol on the formation of structures in the gel/subgel phase of 1,2-dipalmitoylphosphatidylcholine was investigated using freeze-fracture electron microscopy and X-ray diffraction. Mixtures with up to 25 mol% sterol were analysed after annealing for between several days and some months at 4 degrees C. Bilayers of DPPC with 5 or 10 mol% sterol showed a domain structure in the gel state. There are rounded or lens-like and often inclined plates within less smooth either plane or striped bilayer areas. The stripes are formed by parallel lines separated by a distance of 30-60 nm. Parallel lines can be induced also in the less smooth but plane areas by warming up to 25 degrees C. X-ray diffraction showed two lamellar repeat spacings at 6.45 and 8.3 nm in both 5 and 10 mol% samples. The plates are interpreted as domains of (nearly) pure DPPC within the sterol containing bilayer. Stripes are present if the concentration of cholesterol is below a critical value (approx. 15 mol%). With time of incubation at 4 degrees C curved deformations appear in parts of the bilayers. Two main types are formed. The small type has a repeat distance of about 100 nm and the large type of about 400 nm. The curved deformations were progressively flattened by warming up to 25-32 degrees C with an accompanying reappearance of stripes but no plates. After prolonged annealing at 4 degrees C there is also the formation of regular ripples. It is concluded that in presence of 5 and 10 mol% sterol in bilayers of 1,2-dipalmitoy-phosphatidylcholine the immiscibility of gel phase and subgel phase changes during prolonged annealing at 4 degrees C. We assume a rearrangement of the molecules into a homogeneous phase state with liquid-ordered properties.


Association of nascent polypeptide with 30S ribosomal subunits.
1. Crude extracts of Escherichia coli were used to synthesize nascent peptides under the direction of endogenous mRNA and in the presence of radioactive amino acids. Analysis of such extracts by sucrose-gradient centrifugation in low Mg(2+) concentration has shown that after 2min of incubation approximately 14% of the total labelled protein recovered on the gradient, in association with whole ribosomes, sediments with 30S ribosomal subunits; this value rises to approximately 24% after 30min of incubation. The labelled protein associated with 30S ribosomal subunits is insoluble in hot trichloroacetic acid. 2. Similar results were also obtained in extracts that synthesized polypeptides under the direction of either of the synthetic polyribonucleotides poly(A) or poly(A,G,C,U). In contrast, however, analysis of crude extracts programmed in protein synthesis by poly(U) has indicated that under these conditions 30S ribosomal subunits have no associated polyphenylalanine; similarly there is little associated peptide after programming of extracts by poly(U,C).


Combined Effects of HLA-B*57/5801 Elite Suppressor CD8+ T Cells and NK Cells on HIV-1 Replication.
Elite controllers or suppressors (ES) are HIV-1 infected individuals who maintain undetectable viral loads without anti-retroviral therapy. The HLA-B*57 allele is overrepresented in ES suggesting a role for HIV-specific CD8+ T cells in immune control. Natural killer (NK) cells also play a role in controlling viral replication, and genetic studies demonstrate that specific combinations of killer cell immunoglobulin-like receptor (KIR) alleles and HLA subtypes including HLA-B*57 correlate with delayed progression to AIDS. While prior studies have shown that both HIV-specific CD8+ T cells and NK cells can inhibit viral replication in vitro, the interaction between these two effector cells has not been studied. We performed in vitro suppression assays using CD8+ T cells and NK cells from HLA-B*57 ES either alone or in combination with each other. We found no evidence of antagonism or synergy between the CD8+ T cells and NK cells, suggesting that they have independent mechanisms of inhibition in vitro. Our data has implications for combined immunotherapy with CD8+ T cells and NK cells in HIV cure strategies.


NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.
Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-κB-dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.


Carbon-fiber reinforced intramedullary nailing in musculoskeletal tumor surgery: a national multicentric experience of the Italian Orthopaedic Society (SIOT) Bone Metastasis Study Group.
Carbon fiber reinforced (CFR) implants have been proposed for the treatment of fractures or impending fractures of the long bones in the oncology patient. Aim of this study is to present the largest cohort of oncology patients operated by CFR nailing by the Italian Orthopaedic Society (SIOT) Bone Metastasis Study Group. 53 adult oncology patients were operated on with a CFR-PEEK nail. All the data from adjuvants therapies were collected. Bone callus formation, response to radiotherapy, relapse or progression of the osteolysis were recorded. Hardware survival and failure, breakage and need for implant revision were also analysed. Anatomical implantation of nails include humerus (n = 35), femur (n =11) and tibia (n = 7). The most frequent tumors affecting the bone were myeloma (n = 13), breast (n = 11), lung (n = 8), and renal cell cancer (n = 7). Acrylic cement reinforcement was used in 2 patients. One patient was subjected to electrochemotherapy after nail insertion. Intraoperative and early postoperative complications occurred in 13.2% and 7.54% of patients respectively. Eight patients had local progression and one developed a stress fracture proximally to the distal static screw. Radiographic union occurred in 14 patients; one screw loosening was recorded. There is currently a lack of solid evidence on the clinical use of CFR nails in oncologic patients. This is the first and largest study of CFR nailing, with the longest available follow up. Implant related complications and surgery-related morbidity should be taken into account in the decision-making process for the surgical management of these patients. These data can improve the surgeon-patient communication and guide further studies on patients' survival and complications with respect to surgery.


Effect of the environment on alpha-Al2O3 (0001) surface structures
We report that calculating the Gibbs free energy of the alpha-Al2O3 (0001) surfaces in equilibrium with a realistic environment containing both oxygen and hydrogen species is essential for obtaining theoretical predictions consistent with experimental observations. Using density-functional theory we find that even under conditions of high oxygen partial pressure the metal-terminated surface is surprisingly stable. An oxygen-terminated alpha-Al2O3 (0001) surface becomes stable only if hydrogen is present on the surface. In addition, including hydrogen on the surface resolves discrepancies between previous theoretical work and experimental results with respect to the magnitude and direction of surface relaxations.


Improved Overall Survival of Patients with Pancreatic Cancer through Multiagent Chemotherapy and Increased Rates of Surgical Resection.
Seminal trials have demonstrated improved survival in pancreatic adenocarcinoma with novel multiagent chemotherapy regimens. To understand the clinical ramifications of this paradigm shift, we reviewed our institutional experience. This retrospective cohort study utilized a prospective database at a single institution to study all patients diagnosed with and treated for pancreatic adenocarcinoma between 2000 and 2020. 1,572 patients were included of which 36% were diagnosed before (Era 1) and 64% after (Era 2) 2011. Survival improved in Era 2 (Median survival 10 vs 8 months, HR .79; P < .001). The survival advantage for Era 2 was primarily seen in patients with high-risk disease (12 vs10 months, HR .71; P < .001). A similar trend was noted for patients undergoing surgical resection (26 vs 21 months, HR .80; P = .081) and with imminently resectable tumors (19 vs 15 months, HR .88; P = .4); however, this was not statistically significant. There was no survival advantage for patients with stage IV disease (4 vs 4 months). Patients in Era 2 were more likely to undergo surgery (OR 2.78; CI 2.00-3.92, P < .001). This increase was driven primarily by increased surgical resection for those with high-risk disease (42 vs 20%, OR 3.74; P < .001). This single institutional study showed improved survival after the shift to novel chemotherapy regimens. This was driven by improved survival for patients with high-risk disease and may be due to more effective eradication of microscopic metastatic disease with adjuvant chemotherapy and increased resection rates.


Paediatric serum sickness-like reaction: A 10-year retrospective cohort study.
Serum sickness-like reaction (SSLR) is an acute inflammatory condition affecting predominantly children. The pathophysiology remains unclear, but drugs are considered the main trigger. The aim of this study was to describe the clinical and laboratory features, triggers, and treatment modalities in children diagnosed with SSLR. We conducted a 10-year retrospective cohort study including all paediatric patients (0 to 18 years old) with query SSLR referred to the Adverse Drug Reactions Clinic at the Children's Hospital of Western Ontario. Diagnostic criteria included acute skin rash plus joint inflammation with or without fever. We included 83 patients (47 females). Age ranged from 11 months to 12 years (mean 3.2 years). Amoxicillin was the trigger in 82.7% of patients. The mean time between the exposure to the triggering drug and the development of the symptoms was 8.5 days. Urticaria-like and Erythema multiforme-like lesions were present in 35% and 38.5% of the cases, respectively. Joint inflammation affecting hands/feet was present in 60%. Pruritus, lip/eye swelling, and fever were reported in 33, 31, and 45% of patients, respectively. The lymphocyte toxicity assay (LTA) showed incremental T-cell toxicity in 32 of 34 patients. Children that received treatment with antihistamines/nonsteroidal anti-inflammatory drugs (NSAIDs) plus oral steroids had a mean recovery time shorter than those treated only with antihistamines/NSAIDs (6 versus 8 days; P=0.09). In our study, SSLR was mostly triggered by amoxicillin and had a mean time presentation of 8.5 days. Further prospective and well-conducted studies are needed.