Improving sun protection behaviour in children: study design and baseline results of a randomized trial in Italian elementary schools. The 'Sole Si Sole No GISED' project.
To evaluate, in the context of a randomized study, the 'Sole Si Sole No GISED' project, the effectiveness of an educational intervention to improve sun protection behaviour in schoolchildren. A large number of primary schools (classes II and III) in Italy were randomized to an educational intervention or control group: The intervention was conducted by trained teachers using ad hoc developed materials. Attitudes toward sun exposure and behaviour while in the sun were assessed at baseline and 1 year after concluding the educational intervention. In a subgroup of children, melanocytic naevi were counted on the upper limbs at the same intervals. The pilot phase of the study was started in 2001. During the pilot phase, a total of 4,233 children was recruited. Of these, 2,116 were randomized to the active intervention and 2,117 to the control group. No difference for any of the study variables was documented between the 2 groups at baseline. About 20% of the children reported intense sun exposure during the year preceding the study. About 88% of the children reported adequate modalities of sun protection. Sunscreens were commonly used. A total of 508 children (12%) reported a history of sunburns in the year preceding the start of the study. Melanocytic naevi were counted in a total of 1,503 children (852 in the experimental and 651 in the control group). No differences in terms of skin, hair and eye colours were documented between the experimental and the control groups. The mean naevus count at baseline was 9.6 (median 7) in the experimental group and 10.1 (median 8) in the control group. About 50% of the total expected number of children was recruited during the pilot phase of the study. Randomization proved to be an excellent modality to select 2 samples similar for all the important study variables examined. A history of sunburns was reported less frequently than expected. The 'Sole Si Sole No GISED programme' is one of the few examples of a controlled evaluation of the effectiveness of an educational intervention in Italy.


Pigmented lesions clinic for early detection of melanoma: preliminary results.
Early detection of malignant melanoma of the skin is the most important factor in patient survival. Naked-eye diagnostic sensitivity and specificity are low. Patients with multiple nevi are at high risk to develop melanomas and the clinical follow-up of such patients is difficult, resulting in missed melanomas on the one hand and unnecessary biopsies on the other. To describe the set-up of a special clinic aimed at early detection of melanoma and follow-up of high risk patients and preliminary results from 20 months of operation. We established a pigmented lesions clinic based on a digital photography studio enabling documentation and comparison over time of full body photography and dermoscopy. In the first 20 months of work, 895 patients were seen, 206 of them for follow-up visits. A total of 29,254 photos were taken. Altogether, 236 lesions were suspicious (either clinically or dermoscopically) and the patients were advised to excise them. Seven melanomas were found in this initial examination (which did not include long-term follow-up). With multimode photographic cutaneous surveillance, early detection of melanoma in high risk patients has been reported. Our clinic utilizes the same techniques and diagnostic algorithm as other leading clinics throughout the world, thus enabling us to deliver better follow-up for those patients.


Prediction Reweighting for Domain Adaptation.
There are plenty of classification methods that perform well when training and testing data are drawn from the same distribution. However, in real applications, this condition may be violated, which causes degradation of classification accuracy. Domain adaptation is an effective approach to address this problem. In this paper, we propose a general domain adaptation framework from the perspective of prediction reweighting, from which a novel approach is derived. Different from the major domain adaptation methods, our idea is to reweight predictions of the training classifier on testing data according to their signed distance to the domain separator, which is a classifier that distinguishes training data (from source domain) and testing data (from target domain). We then propagate the labels of target instances with larger weights to ones with smaller weights by introducing a manifold regularization method. It can be proved that our reweighting scheme effectively brings the source and target domains closer to each other in an appropriate sense, such that classification in target domain becomes easier. The proposed method can be implemented efficiently by a simple two-stage algorithm, and the target classifier has a closed-form solution. The effectiveness of our approach is verified by the experiments on artificial datasets and two standard benchmarks, a visual object recognition task and a cross-domain sentiment analysis of text. Experimental results demonstrate that our method is competitive with the state-of-the-art domain adaptation algorithms.


Nurses' Knowledge of Tuberculosis, HIV, and Integrated HIV/TB Care Policies in Rural Western Cape, South Africa.
HIV and tuberculosis (TB) co-infection remain the leading causes of mortality in many developing countries. Several policies for their prevention and management exist; however, progress to meet the World Health Organization's indicators is slow. As nurses in rural areas are the main health care professionals responsible for the implementation of policies, questions arose about nursing knowledge regarding TB and HIV policies. A concurrent mixed method research approach was used to investigate this issue in a rural area of the Western Cape in South Africa. After a two-step sampling process, data were collected through 44 questionnaires and 12 interviews. We used descriptive and inferential statistics as well as content analysis methods. We found that most of the nurses had insufficient knowledge on certain aspects of policy guidelines that included medications, intensive case findings, and management of multidrug-resistant TB. It is recommended that training be intensified to improve implementation of policies.


Developmental changes in distinguishing concurrent auditory objects.
Children have considerable difficulties in identifying speech in noise. In the present study, we examined age-related differences in central auditory functions that are crucial for parsing co-occurring auditory events using behavioral and event-related brain potential measures. Seventeen pre-adolescent children and 17 adults were presented with complex sounds containing multiple harmonics, one of which could be 'mistuned' so that it was no longer an integer multiple of the fundamental. Both children and adults were more likely to report hearing the mistuned harmonic as a separate sound with an increase in mistuning. However, children were less sensitive in detecting mistuning across all levels as revealed by lower d' scores than adults. The perception of two concurrent auditory events was accompanied by a negative wave that peaked at about 160 ms after sound onset. In both age groups, the negative wave, referred to as the 'object-related negativity' (ORN), increased in amplitude with mistuning. The ORN was larger in children than in adults despite a lower d' score. Together, the behavioral and electrophysiological results suggest that concurrent sound segregation is probably adult-like in pre-adolescent children, but that children are inefficient in processing the information following the detection of mistuning. These findings also suggest that processes involved in distinguishing concurrent auditory objects continue to mature during adolescence.


The pharmacological treatment for uremic restless legs syndrome: evidence-based review.
Restless legs syndrome (RLS) is a common and often misdiagnosed entity among the general population and it may be more common among dialysis patients, with an estimated prevalence of 6.6 to 21.5%. The treatment for uremic RLS has been controversial and therefore a systematic synthesis of the evidence is needed in order to evaluate the effectiveness and safety of treatments for uremic RLS. This was a systematic review of randomized or quasi-randomized double-blind trials on treatments for uremic RLS. The outcomes considered were relief of RLS symptoms marked on a validated scale, subjective sleep quality, sleep quality measured using night polysomnography and actigraphy, quality of life measured subjectively, and adverse events associated with these treatments. Six eligible clinical trials were included. The results from subjective analyses in these studies were divergent, although objective analyses in one trial showed that there was a statistically significant improvement in periodic leg movement while asleep in the treatment group. No combined analysis (meta-analysis) was performed. The most common adverse event seen was gastrointestinal symptoms. Only a few therapeutic trials on patients with uremia with RLS have been published, and there is insufficient scientific evidence to favor any specific therapeutic regimen for uremic-associated RLS. Therapy using levodopa, dopaminergic agonists, anticonvulsants, and clonidine tend to be effective, but further studies are needed.


Association between incidence of acute exacerbation and medication therapy in patients with COPD.
As exacerbations of chronic obstructive pulmonary disease (COPD) significantly worsen patients' health status and increase disease-related mortality, greater control of exacerbations has important implications for improving patients' health and survival. The incremental benefits of pharmacologic therapies in preventing COPD exacerbations remain unclear. The objective of this observational study was to examine the risk of COPD-related exacerbations between groups of patients receiving inhaled corticosteroids (ICS), anticholinergics (AC), long-acting beta(2)-agonists (LABA), or fixed-dose combinations of ICS and LABA. A 12-month retrospective cohort analysis of 2923 patients, who were at least 40 years old with the first time COPD in 12 months (i.e., no COPD for 12 months prior to this time) between 2000 and 2004, was conducted using the MarketScan research databases. Patients with at least two prescriptions for ICS, AC, LABA, or ICS + LABA during the observation period were followed from the index prescription date for the duration of the study. COPD-related exacerbations were defined as clinical events in which a primary diagnosis for a respiratory condition had resulted in hospitalization, an emergency room visit, or an outpatient visit followed by a prescription fill of oral corticosteroids or antibiotics within 14 days of the visit. Exacerbation rates were evaluated using a Cox proportional hazard model with adjustment for age, gender, comorbidities, hospitalizations, emergency room visits, and the number of outpatient visits. Compared with ICS alone, COPD exacerbation rates were 35% (CI:22-42%) lower with ICS + LABA, 32% (CI:13-43%) lower with LABA, and 28% (CI:15-36%) lower with AC. The hazard ratio of the first observed COPD exacerbation was 13-18% lower with the use of bronchodilators, with or without ICS, than with ICS alone. In addition, patients receiving ICS alone experienced more exacerbations during the 12-month period following initiation of therapy than those patients receiving LABA, AC, or ICS + LABA. Generalizability of the results and randomization of treatments were limited due to nature of the administrative claim databases. The present study found that use of bronchodilators, with or without ICS, in COPD patients resulted in a lower exacerbation rate when compared with ICS monotherapy. Further research is required to understand the clinical effects of specific pharmacologic therapies on COPD exacerbations, as well as their impact on long-term outcomes and costs.


No evidence of association between inherited thrombophilia and increased risk of liver fibrosis.
Preliminary evidence suggests that inherited hypercoagulable disorders can lead to an increased risk of significant liver fibrosis. We aimed to investigate the prevalence of significant fibrosis in patients with inherited thrombophilia, assessed by using liver stiffness (LS), and to compare this prevalence to that found in a large population-based cohort from the same region. This was a single-center, cross-sectional study. A complete laboratory analysis for liver disease, LS by transient elastography and an abdominal ultrasound were performed in patients with inherited thrombophilia diagnosed between May 2013-February 2017. These patients were propensity score matched (ratio 1:4) with a population-based cohort from the same region (PREVHEP-ETHON study; NCT02749864; N = 5988). Of 241 patients with inherited thrombophilia, eight patients (3.3%) had significant fibrosis (LS ≥8 kPa). All of them had risk factors for liver disease and met diagnostic criteria for different liver diseases. After matching 221 patients with thrombophilia with 884 patients of the PREVHEP-ETHON cohort, the prevalence of significant fibrosis was similar between both cohorts (1.8% vs. 3.6%, p = 0.488). Multivariate analysis showed that age and liver disease risk factors, but not belonging to the thrombophilia cohort, were associated with the presence of significant fibrosis. The magnitude of the increased risk of significant fibrosis in patients with risk factors for liver disease was also similar in both cohorts. Our findings do not provide evidence supporting an association between inherited thrombophilia and an increased risk of significant liver fibrosis, independent of the presence of liver-related causes of fibrosis.


The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue.
Little is known about the alterations of metabolic organization of the human liver tissue in chronic liver diseases. We therefore compared the distribution of the following zonal metabolic markers in 10 samples of normal liver tissue, 10 samples of fibrotic tissue, and 22 samples of cirrhotic tissue: (a) the enzymatic activities of glucose-6-phosphatase (G6P), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), nicotinamide-adenine-dinucleotide-phosphate [NAPH] dehydrogenase (ND), beta-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine synthetase (GLS); and (c) albumin messenger RNA (mRNA). The normal human hepatic lobule was characterized by the periportal predominance of G6P and SDH enzymatic activities and albumin mRNAs, the perivenous predominance of ND and GDH, the restriction of GLS to a small perivenous compartment, and the predominanc of beta-HBDH at the contact of both portal tracts and centrilobular veins. In fibrosis, the overall metabolic organization of the normal liver tissue was retained. The expression of periportal markers predominated around enlarged portal tracts and that of perivenous markers around residual centrilobular veins. GLS was constantly detected at the contact of centrilobular veins. In cirrhotic nodules, no zonation was observed for most enzymatic activities or for albumin. Only G6P usually predominated at the periphery of the nodules. GLS was constantly undetectable. No difference accordingly to the etiology of the underlying disease was observed. In conclusion, the normal human hepatic lobule presents a marked metabolic zonation, preserved in fibrotic lesions, but lost in cirrhotic nodules. The alterations of the metabolic organization observed in cirrhosis might contribute to the pathogenesis of some of the metabolic disorders associated with advanced liver disease.


How does the topic of conversation affect verbal exchange and eye gaze? A comparison between typical development and high-functioning autism.
Conversation is a primary area of difficulty for individuals with high-functioning autism (HFA) although they have unimpaired formal language abilities. This likely stems from the unstructured nature of face-to-face conversation as well as the need to coordinate other modes of communication (e.g. eye gaze) with speech. We conducted a quantitative analysis of both verbal exchange and gaze data obtained from conversations between children with HFA and an adult, compared with those of typically developing children matched on language level. We examined a new question: how does speaking about a topic of interest affect reciprocity of verbal exchange and eye gaze? Conversations on generic topics were compared with those on individuals' circumscribed interests, particularly intense interests characteristic of HFA. Two opposing hypotheses were evaluated. Speaking about a topic of interest may improve reciprocity in conversation by increasing participants' motivation and engagement. Alternatively, it could engender more one-sided interaction, given the engrossing nature of circumscribed interests. In their verbal exchanges HFA participants demonstrated decreased reciprocity during the interest topic, evidenced by fewer contingent utterances and more monologue-style speech. Moreover, a measure of stereotyped behaviour and restricted interest symptoms was inversely related to reciprocal verbal exchange. However, both the HFA and comparison groups looked significantly more to their partner's face during the interest than generic topic. Our interpretation of results across modalities is that circumscribed interests led HFA participants to be less adaptive to their partner verbally, but speaking about a highly practiced topic allowed for increased gaze to the partner. The function of this increased gaze to partner may differ for the HFA and comparison groups.


Discovery of potent inhibitors of human and mouse fatty acid amide hydrolases.
Fatty acid amide hydrolase (FAAH, EC 184.108.40.206) is the main enzyme catabolizing endocannabinoid fatty acid amides. FAAH inactivation promotes beneficial effects upon pain and anxiety without the side effects accompanying agonists of type-1 cannabinoid receptors. Aiming at discovering new selective FAAH inhibitors, we developed a series of compounds (5a-u) characterized by a functionalized heteroaromatic scaffold. Particularly, 5c and 5d were identified as extremely potent, noncompetitive, and reversible FAAH inhibitors endowed with a remarkable selectivity profile and lacking interaction with the hERG channels. In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates. Aiming at improving pharmacokinetic properties and metabolic stability of 5d, we developed a subset of nanomolar dialyzable FAAH inhibitors (5v-z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings.


Common patch test allergens: general guidelines for avoidance.
Contact dermatitis is a very common diagnosis in the dermatology clinic. Simplified information offers a good starting point for patient education and instruction about avoidance measures. Using the general guidelines proposed here can be useful for the most common allergens, and will help motivate both the patient and providers to be active participants in solving the puzzle of allergic contact dermatitis.


Flow cytometry and laser scanning cytometry, a comparison of techniques.
Flow and laser scanning cytometry are used extensively in research and clinical settings. These techniques provide clinicians and scientists information about cell functioning in a variety of health and disease states. An in-depth knowledge and understanding of cytometry techniques can enhance interpretation of current research findings. Our goal with this review is to reacquaint clinicians and scientists with information concerning differences between flow and laser scanning cytometry by comparing their capabilities and applications. A Pubmed abstract search was conducted for articles on research, reviews and current texts relating to origins and use of flow and laser scanning cytometry. Attention was given to studies describing application of these techniques in the clinical setting. Both techniques exploit interactions between the physical properties of light. Data are immediately and automatically acquired; they are distinctly different. Flow cytometry provides valuable rapid information about a wide variety of cellular or particle characteristics. This technique does not provide the scanned high resolution image analysis needed for investigators to localize areas of interest within the cell for quantification. Flow cytometry requires that the sample contain a large amount disaggregated, single, suspended cells. Laser scanning cytometry is slide-based and does not require as large of a sample. The tissue sample is affixed to a slide allowing repeated sample analyses. These cytometry techniques are used in the clinical setting to understand pathophysiological derangements associated with many diseases; cardiovascular disease, diabetes, acute lung injury, hemorrhagic shock, surgery, cancer and Alzheimer's disease. Understanding the differences between FCM and LSCM can assist investigators in planning and design of their research or clinical testing. Researchers and clinicians optimize these technique capabilities with the cellular characteristics they wish to measure delineating molecular and cellular events occurring in health and disease. Discovery of mechanisms in cells using FCM and LSCM provide evidence needed to guide future treatment and interventions.


Mild head trauma and chronic headaches in returning US soldiers.
To determine the incidence and types of head or neck trauma and headache characteristics among US Army soldiers evaluated for chronic headaches at a military neurology clinic following a combat tour in Iraq. Head or neck trauma and headaches are common in US soldiers deployed to Iraq. The temporal association between mild head trauma and headaches, as well as the clinical characteristics of headaches associated with mild head trauma, has not been systematically studied in US soldiers returning from Iraq. A retrospective cohort study was conducted with 81 US Army soldiers from the same brigade who were evaluated at a single military neurology clinic for recurrent headaches after a 1-year combat tour in Iraq. All subjects underwent a standardized interview and evaluation to determine the occurrence of head or neck trauma during deployment, mechanism and type of trauma, headache type, and headache characteristics. In total, 33 of 81 (41%) soldiers evaluated for headaches reported a history of head or neck trauma while deployed to Iraq. A total of 18 (22%) subjects had concussion without loss of consciousness and 15 (19%) had concussion with loss of consciousness. Ten subjects also had an accompanying traumatic neck injury. No subjects had moderate or severe traumatic brain injury. Exposure to blasts was the most common cause of trauma, accounting for 67% of head and neck injuries. Headaches began within one week after trauma in 12 of 33 (36%) soldiers with head or neck injury. Another 12 (36%) reported worsening of pre-existing headaches after trauma. Headaches were classified as migraine type in 78% of soldiers with head or neck trauma. Headache types, frequency, severity, duration, and disability were similar for soldiers with and without a history of head or neck trauma. A history of mild head trauma, usually caused by exposure to blasts, is found in almost half of returning US combat troops who receive specialized care for headaches. In many cases, head trauma was temporally associated with either the onset of headaches or the worsening of pre-existing headaches, implicating trauma as a precipitating or exacerbating factor, respectively. Headaches in head trauma-exposed soldiers are usually migraine type and are similar to nontraumatic headaches encountered at a military specialty clinic.


Analysis of three amphibian populations with quarter-century long time-series.
Amphibians are in decline in many parts of the world. Long tme-series of amphibian populations are necessary to distinguish declines from the often strong fluctuations observed in natural populations. Time-series may also help to understand the causes of these declines. We analysed 23-28-year long time-series of the frog Rana temporaria. Only one of the three studied populations showed a negative trend which was probably caused by the introduction of fish. Two populations appeared to be density regulated. Rainfall had no obvious effect on the population fluctuations. Whereas long-term studies of amphibian populations are valuable to document population declines, most are too short to reveal those factors that govern population dynamics or cause amphibian populations to decline.


Practical approach to anticoagulation for cardiopulmonary bypass in the patient with congenital prolonged activated partial thromboplastin time.
Patients with rare, congenital deficiencies of contact proteins (e.g., factor XII, prekallikrein, high-molecular-weight kininogen) present an important challenge with regard to safe anticoagulation during cardiopulmonary bypass. Specifically, activated coagulation time values are obtained with devices that utilize contact protein activators to generate thrombin and assess the efficacy of heparin-mediated antithrombin activation, with an activated coagulation time value of 480 s considered 'safe'. Patients with contact protein deficiencies will routinely have activated coagulation time values that exceed normal baseline values to an unpredictable extent, which, when coupled with heparin administration may well exceed 480 s but still potentially not reflect adequate antithrombin activation. We present the successful management of anticoagulation of a patient with either a prekallikrein or kininogen deficiency during cardiopulmonary bypass for coronary artery bypass graft surgery with Hepcon-based heparin concentration determinations. This approach, and the other alternatives previously mentioned, can be utilized to safely care for these rare patients in the setting of cardiac surgery.


Instant room temperature synthesis of self-assembled emission-tunable gold nanoclusters: million-fold emission enhancement and fluorimetric detection of Zn2+ .
Facile synthesis of luminescent metal nanoclusters (NCs) accompanied by emission color tuning is currently an active area of research. In this work we describe a rapid (1 s) room temperature synthesis of luminescent Au NCs from completely nonluminescent NCs through the incorporation of Zn2+. The nanoclusters are initially stabilized by mercaptopropionate, and the coordination of Zn2+ with the carboxylate groups of the ligands rigidifies the Au(i) thiolates restricting the intramolecular rotation-vibrational motion. This significantly reduces the nonradiative relaxation of the excited state to produce yellow luminescent NCs (λem = 580 nm, QY: 6%, τ = 0.2 ms) with almost a million-fold emission enhancement. The enhanced luminescence is due to the self-assembly mediated aggregation induced emission (AIE) of NCs. These NCs on aging for 24 hours transform to highly ordered green emitting NCs (λem = 500 nm, QY: 20%, τ = 20 ns). The blue shift in emission is due to the dominance of inter Au(i)-Au(i) interaction and inter-NC Zn2+ interaction over the intra modes. TEM images show this distinct transition, a decrease in inter NC distance with increased self-assembly. Excited state relaxation dynamics associated with Au(i) thiolate shell dynamics in yellow and green emitting NCs is explained based on the time resolved fluorescence study. The rapid formation of luminescent NCs from nl-NCs has been used for efficient visual and fluorimetric detection of Zn2+.


Utility of CT angiography in the identification and characterization of supraclinoid internal carotid artery blister aneurysms.
Blister aneurysms of the supraclinoid ICA represent a rare but potentially catastrophic cause of SAH, often presenting both diagnostic and therapeutic dilemmas. We explore the utility of CTA in the identification and characterization of ICA blister aneurysms. We performed a retrospective review of catheter cerebral angiograms obtained at our institution over a 12-month period for evaluation of SAH, identifying 6 cases of ICA blister aneurysms. All patients underwent CTA and DSA for evaluation of SAH. The reports from the CTA and DSA studies were reviewed to identify aneurysms correctly diagnosed prospectively. Retrospective review of the CTA and DSA images was also performed. Review of the interpretations and images was performed for any follow-up studies. All 6 patients presented with SAH, diagnosed by head CT. All patients subsequently underwent CTA prior to DSA evaluation. All 6 aneurysms were identified prospectively on initial DSA imaging. Of the 6 blister aneurysms, 4 (67%) were identified prospectively; and 5 (83%), retrospectively on CTA. All 6 patients underwent endovascular treatment with stent placement. Four of the 6 aneurysms underwent follow-up CTA (range, 9-22 days), including the 2 aneurysms that had been unidentifiable preprocedurally. All 4 blister aneurysms were seen postprocedurally by DSA. Three of these 4 (75%) residual aneurysms were detected by CTA (both prospectively and retrospectively). In the presence of SAH and otherwise negative findings on CTA, a catheter cerebral angiogram should be performed to absolutely exclude an ICA blister aneurysm.


Cross-sectional survey of indicator and pathogenic bacteria on vegetables sold from Asian vendors at farmers' markets in northern California.
A cross-sectional survey was conducted during summer 2013 to determine the occurrence of Escherichia coli, fecal coliforms (FCs), E. coli O157:H7, and Salmonella on raw vegetable commodities common to Asian cuisine from 21 vendors or farmers at six farmers' markets in northern California. Based on 242 samples from six commodities (basil, yardlong beans, bitter squash, okra, squash stems and leaves, cilantro), 100% of samples had detectable FCs and 20% had detectable E. coli. The mean concentrations were 0.67 log CFU/g and 1.26 log CFU per bundle for E. coli and 4.00 log CFU/g and 6.26 log CFU per bundle for FCs. Vegetables irrigated with ground versus surface water contained lower concentrations of FCs, but this difference was not observed for E. coli. Yardlong beans, bitter squash, and okra had lower levels of FCs compared with basil, cilantro, and squash stems and leaves. Sixteen (6.6%) samples had detectable levels of Salmonella serovars (Newport, Enteritidis, Agona, and Worthington), with the majority of positives found in cilantro and squash stems and leaves. There was a twofold higher probability of Salmonella contamination in samples from growers or vendors who stated that they used organic farming practices compared with samples from those using conventional farming practices. Lastly, the concentrations of FC and E. coli bacteria were significantly associated with Salmonella contamination: for each additional 100 CFU/g or bundle, the probability of Salmonella contamination increased by ∼15 and ∼30%, respectively. None of the samples had detectable E. coli O157:H7.


Pneumococcal vaccination during pregnancy for preventing infant infection.
Each year at least one million children worldwide die of pneumococcal infections. The development of bacterial resistance to antimicrobials adds to the difficulty of treatment of diseases and emphasizes the need for a preventive approach. Newborn vaccination schedules could substantially reduce the impact of pneumococcal disease in immunized children, but does not have an effect on the morbidity and mortality of infants less than three months of age. Pneumococcal vaccination during pregnancy may be a way of preventing pneumococcal disease during the first months of life before the pneumococcal vaccine administered to the infant starts to produce protection. To assess the effect of pneumococcal vaccination during pregnancy for preventing infant infection. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2011) and reference lists of retrieved studies. Randomized controlled trials in pregnant women comparing pneumococcal vaccine with placebo or doing nothing or with another vaccine to prevent infant infections. Two review authors independently assessed trials for inclusion, methodological quality and extracted data using a data collection form. Data were checked for accuracy. We contacted study authors for additional information. Seven trials were included, but only five trials (579 participants) contributed data. There was no evidence that pneumococcal vaccination during pregnancy reduces the risk of neonatal infection (risk ratio (RR) 0.66; 95% confidence interval (CI) 0.30 to 1.46; two trials, 241 pregnancies). Although the data suggest an effect in reducing pneumococcal colonization in infants by 16 months of age (RR 0.33; 95% CI 0.11 to 0.98; one trial, 56 pregnancies), there was no evidence of this effect in infants at two to three months of age (RR 1.13; 95% CI 0.46 to 2.78; two trials, 146 pregnancies) or by six to seven months of age (RR 0.66; 95% CI 0.20 to 2.17; two trials, 144 pregnancies). No significant difference for tenderness at the injection site between women who received pneumococcal vaccine and those who received control vaccine (RR 3.20; 95% CI 0.32 to 31.54; two trials, 130 women). There is insufficient evidence to assess whether pneumococcal vaccination during pregnancy could reduce infant infections.


Screening and verification of hemostatic effective components group of Panax Notoginseng based on spectrum-effect relationships.
Panax Notoginseng (PN) can disperse blood stasis, hemostasis, and detumescence analgesic, which can be used for hemoptysis, hematemesis and another traumatic bleeding, and it is known as "A miracle hemostatic medicine". Studies show that the chemical composition of PN is relatively comprehensive, however, its hemostatic active ingredients have not been fully clarified. This study aimed to clarify the hemostatic effective components group (HECG) of PN, provide a foundation for the assessment of PN's quality and its comprehensive development, and for further studies on the pharmacodynamic material basis of other Traditional Chinese Medicines (TCMs). UPLC-MS was used to establish the fingerprint and identify the common peaks in 44 batches of PN extracts (PNE). In addition, the plasma recalcification time and in vitro coagulation time were measured. For spectrum-effect analysis, bivariate correlation analysis (BCA) and partial least squares regression analysis (PLSR) were used to screen the hemostasis candidate active monomers of PN. The monomers were prepared by combining several preparative chromatography techniques. The efficacy was verified by plasma recalcification time, in vitro coagulation time, and a rat model of gastric hemorrhage. A total of 30 common peaks and hemostatic efficacy indexes of 44 batches of PNE were obtained. A total of 18 components were positively correlated with the comprehensive coagulation index by two statistical methods. Six and eleven monomers were obtained respectively by chromatographic preparation and procurement, and one monomer was eliminated due to preparation difficulty and other reasons. Seven active monomers with direct hemostatic effect and one active monomer with synergistic hemostatic effect were screened through plasma recalcification time, and their combinations were used as candidate HECG for hemostatic effect verification. The results of in vitro experiments showed that plasma recalcification time and in vitro coagulation time were significantly reduced (P < 0.05) in the HECG group, compared to the PNE group. The results of in vivo experiment also indicated that the hemostatic effect of HECG was comparable to that of PNE and PN powder. The composition and efficacy of the HECG of PN were screened and verified using the spectral correlation method and in vivo and in vitro efficacy verification; the HECG included Dencichine, Ginsenoside Rg1, Ginsenoside Rd, Ginsenoside Rh1, Ginsenoside F1, Notoginsenoside R1, Notoginsenoside Ft1 and Notoginsenoside Fe. These results laid a foundation for the quality evaluation of PN and provided a reference for the basic research of pharmacodynamic material basis of other TCMs.


Electrically switchable, photoaddressable cholesteric liquid crystal reflectors.
We report on the development of photoaddressable cholesteric liquid crystal (CLC) mixtures capable of large range color tuning as well as direct on-off electrical switching. The continuously photoaddressable CLC mixtures are based on a high HTP azo-containing chiral material mixed with an off-the-shelf nematic liquid crystal (QL9/E44). By polymer stabilizing the QL9/E44 mixture, it is demonstrated that the photoaddressable reflection of the notch can be switched on and off with an AC voltage. The novel combination of these effects has potential utility in lasing, dynamic notch filters, and spatial light modulators.


Enrollment in outpatient care among newly released prison inmates with HIV infection.
Although many prisoners infected with human immunodeficiency virus (HIV) initiate and adhere to treatment regimens while incarcerated, the benefits of in-prison therapy are frequently lost after community reentry. Little information is available on the percentage of released inmates who establish community-based HIV outpatient treatment in a timely fashion. We sought to determine the proportion of HIV-infected Texas prison inmates who enrolled in an HIV clinic within 90 days after release and to identify variables associated with timely linkage to clinical care. This was a retrospective cohort study of 1,750 HIV-infected inmates who were released from the Texas Department of Criminal Justice (TDCJ) and returned to Harris County between January 2004 and December 2007. We obtained demographic and clinical data from centralized databases maintained by TDCJ and the Harris County Health District, and used logistic regression analysis to identify factors associated with linkage to post-release outpatient Only 20% of released inmates enrolled in an HIV clinic within 30 days of release, and only 28% did so within 90 days. Released inmates > or = 30 years of age were more likely than their younger counterparts to have enrolled in care at the 30- and 90-day time points. Inmates diagnosed with schizophrenia were more likely to have initiated care within 30 days. Inmates who received antiretroviral therapy while incarcerated and those who received enhanced discharge planning were more likely to begin care at both time points. A large proportion of HIV-infected inmates fail to establish outpatient care after their release from the Texas prison system. Implementation of intensive discharge planning programs may be necessary to ensure continuity of HIV care among newly released inmates.


Machine learning identifies phenotypic profile alterations of human dopaminergic neurons exposed to bisphenols and perfluoroalkyls.
Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of midbrain dopaminergic neurons. Endocrine disrupting chemicals (EDCs) are active substances that interfere with hormonal signaling. Among EDCs, bisphenols (BPs) and perfluoroalkyls (PFs) are chemicals leached from plastics and other household products, and humans are unavoidably exposed to these xenobiotics. Data from animal studies suggest that EDCs exposure may play a role in PD, but data about the effect of BPs and PFs on human models of the nervous system are lacking. Previous studies demonstrated that machine learning (ML) applied to microscopy data can classify different cell phenotypes based on image features. In this study, the effect of BPs and PFs at different concentrations within the real-life exposure range (0.01, 0.1, 1, and 2 µM) on the phenotypic profile of human stem cell-derived midbrain dopaminergic neurons (mDANs) was analyzed. Cells exposed for 72 h to the xenobiotics were stained with neuronal markers and evaluated using high content microscopy yielding 126 different phenotypic features. Three different ML models (LDA, XGBoost and LightGBM) were trained to classify EDC-treated versus control mDANs. EDC treated mDANs were identified with high accuracies (0.88-0.96). Assessment of the phenotypic feature contribution to the classification showed that EDCs induced a significant increase of alpha-synuclein (αSyn) and tyrosine hydroxylase (TH) staining intensity within the neurons. Moreover, microtubule-associated protein 2 (MAP2) neurite length and branching were significantly diminished in treated neurons. Our study shows that human mDANs are adversely impacted by exposure to EDCs, causing their phenotype to shift and exhibit more characteristics of PD. Importantly, ML-supported high-content imaging can identify concrete but subtle subcellular phenotypic changes that can be easily overlooked by visual inspection alone and that define EDCs effects in mDANs, thus enabling further pathological characterization in the future.


Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion.
Acquired von Willebrand disease (aVWD) is a rare bleeding disorder that mimics congenital VWD in previously healthy individuals; it is most frequently associated with monoclonal gammopathy. Hemostatic therapy of aVWD is challenging due to the extremely shortened half-life of endogenous and exogenous VWF. High-dose intravenous immunoglobulin (ivIG) is recommended as the treatment of choice, usually rapidly normalizing coagulation; but in case of failure, alternative treatment options are not well explored. We report successful major orthopedic surgery in a 61-year-old woman with multiple myeloma IgG lambda and aVWD. IvIG alone failed to correct hemostasis. However, ivIG pretreatment improved the VWF ristocetin cofactor (VWF:RCo) half-life from only 1.5 hr to more than 4 hr, allowing desmopressin infusions twice daily to maintain sufficient VWF:RCo levels. Because of diminishing desmopressin effect, we attempted for the first time in aVWD a continuous VWF/FVIII infusion (Haemate HS), 2.1-2.7 FVIII U/kg/hr or 51-64 U/kg/day, respectively 4.6-6.0 VWF:RCo U/kg/hr or 110-145 U/kg/day) to reach constant factor levels. The steady-state clearance was 2.4 mL/kg/hr for FVIII:C and 13.5 mL/kg/hr for VWF:RCo. During surgery, VWF:RCo, FVIII:C, and PFA-100 closure time were normalized. Until day 5, VWF:RCo was kept above 50%, from day 6 to 10 at least 30% activity were attained. FVIII:C levels were always >70%. The clinical course was uneventful without bleeding. Two weeks after hip surgery the patient was discharged from the hospital without complaints. The therapy described can be recommended as safe and feasible for further evaluation in aVWD patients who are hyporesponsive to ivIG treatment alone. Continuous VWF/FVIII infusion can improve substitution therapy in aVWD.


An Overview of the Research on Mindfulness-Based Interventions for Treating Symptoms of Posttraumatic Stress Disorder: A Systematic Review.
This systematic review aimed to collate and evaluate the existing research for the use of mindfulness-based approaches to treat posttraumatic stress disorder (PTSD). Our primary objectives were to explore the effects of mindfulness-based approaches on PTSD symptoms and associated psychological distress, with secondary objectives to explore the attrition rate, adverse effects, resource implications, and long-term effects of such interventions. We systematically searched research databases, EMBASE, OVID MedLine, Psycinfo, CINAHL, and PILOTS, contacted relevant authors in the field, and conducted a hand search of relevant papers. The search resulted in 12 studies that met eligibility criteria, many of which studies lacked methodological rigor. The majority of the studies indicated positive outcomes with improvements in PTSD symptoms, particularly in reducing avoidance. The preliminary evidence for the use of mindfulness-based approaches to treat PTSD symptoms is encouraging, although further studies with a more robust research design are required.


Mesenchymal stem cells in the aging and osteoporotic population.
Because of their ability to self-renew and differentiate, mesenchymal stem cells (MSCs) are the in vivo source for replacing lost cells in high-turnover tissues during the life of an organism. MSCs have osteogenic potential and can be eligible for the repair and maintenance of the skeleton, thus they are very attractive for tissue engineering and regenerative medicine approaches. However, many changes in their behavior, caused by aging and bone disease, have been reported in the literature. These changes, which affect MSC self-renewal ability and differentiation potentiality, are related to cell proliferation, differentiation, cell cycle phases (depending on gene modification), and cytokine and growth factor production. This review summarizes the literature related to intrinsic and extrinsic characteristics of human bone marrow or adipose tissue MSCs during aging and osteoporosis. Although some studies reveal contrasting results, the results of this review suggest that the cellular modifications due to aging and osteoporosis should be carefully considered in relation to the use of MSCs for therapeutic application.


[Evaluation of the work time used in outpatient ophthalmology techniques].
To determine the work time used for out-patients seen in the ophthalmology out-patient clinic according to treatment for each diagnosis and examination guidelines. Another objective was to discover the diagnostic related outpatient demand as well as the time spent on each technique. We have designed a computer database system that includes examinations, treatments and medical services. Their duration was measured in a random sample of 127 ophthalmology outpatients in the General Hospital of Castellon. Sixty five of the patients had come to their first visit and 62 to the follow-up visits. A new patient spends a mean of 42 minutes and a follow-up patient spends a mean of 27 minutes. The most frequent diagnoses are retinal diseases (30%), cataract (18.6%), glaucoma (11.8%) and ocular motility disorders (11.8%). We present the mean times used by the physician in the ophthalmic techniques used in outpatients. We have modified the standard times of 30 minutes for the first visit and 15 minutes for the follow-up visit. Data on the work time used for all the ophthalmics techniques in our outpatient clinic are presented. This ophthalmology survey can be used for health care managers to establish the <<Outpatient Visit Groups>> and health care plan administration to adapt the resources to the demand.


Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?
Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs) is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i) what constitutes an iN cell, ii) which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii) whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.


Multimodal Endovascular approach in a Case of Multiple Dural Arteriovenous Fistulae.
Dural arteriovenous fistulae (DAVF) are vascular abnormalities in which arteriovenous shunts are contained in between the periosteal and meningeal lamellae of the dura matter. Rarely, multiple DAVF are diagnosed in a single patient; occurring in only about 8% of the diagnosed cases. We describe a rare presentation of DAVF in a patient with multiple DAVF, at 3 separate sites within the cranial cavity; associated with a medical history of two traumatic motor-vehicle accidents, total anomalous pulmonary venous return (TAPVR), and acquired aplastic anemia. We describe our approach in the treatment of this complex condition.


Protecting Abortion with State Health Care Freedom of Choice.
This essay examines the right of health care freedom of choice contained in some state constitutions. It explores how courts have, and could, use this constitutional health care right as a basis for recognizing or reinforcing a fundamental right to choose an abortion.


SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.
Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+ -Cl- cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH. These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.


A randomized double-blind study of epicardial left atrial cryoablation for permanent atrial fibrillation in patients undergoing mitral valve surgery: the SWEDish Multicentre Atrial Fibrillation study (SWEDMAF).
The efficacy of epicardial left atrial (LA) cryoablation in eliminating atrial fibrillation (AF) in patients undergoing mitral valve surgery (MVS) is unknown. We hypothesized that MVS combined with LA cryoablation is superior to MVS alone. Sixty-nine patients with permanent AF, included at four centres, underwent MVS with or without epicardial LA cryoablation. The primary endpoint was regained sinus rhythm. Risk factors for failed AF cryoablation were elucidated. Sixty-five out of 69 patients reached the primary endpoint. At 6 and 12 months follow-up, 73.3% of patients who underwent cryoablation had regained sinus rhythm at both follow-ups, compared with 45.7 and 42.9% of patients, respectively, who underwent MVS alone (group differences, at 6 months P = 0.024, after 12 months P = 0.013). The in-hospital complication rate was 11.4% in the MVS group and 26.5% in the cryoablation group (P = 0.110). Risk factors for failed elimination of AF by cryoablation were duration of permanent AF (P = 0.012) and presence of coronary artery disease (P = 0.047), according to multiple logistic regression analysis. This first prospective randomized study showed that combining MVS with epicardial LA cryoablation is significantly better in eliminating pre-operative permanent AF than MVS alone.


Prediction of clinical response after 1 year of infliximab therapy in rheumatoid arthritis based on disease activity at 3 months: posthoc analysis of the RISING study.
To investigate the probability of clinical remission (REM) or low disease activity (LDA) after 1 year of infliximab (IFX) therapy based on disease activity at 3 months in patients with rheumatoid arthritis (RA). Methotrexate-refractory patients with RA received 3 mg/kg of IFX at weeks 0, 2, and 6, followed by 3 mg/kg, 6 mg/kg, or 10 mg/kg every 8 weeks from Week 14 (W14) to Week 46. Correlation of disease activity at W14 with disease activity at W54 and probability of REM/LDA at W54 were analyzed in each dosing group. Disease activities at W14 were significantly correlated with both disease activity at W54 and probability of REM/LDA at W54 in patients continuing 3 mg/kg as well as in those receiving 6 mg/kg or 10 mg/kg therapy from W14. Results showed that, if approximate REM or LDA had not been achieved by W14, > 50% of patients continuing 3 mg/kg therapy would not be able to achieve REM or LDA at W54. However, even in patients with high or moderate disease activity at W14, dose escalation to 6 mg/kg or 10 mg/kg enabled many to achieve REM/LDA. Disease activity at W14 in standard-dose IFX therapy enabled the prediction of longterm clinical response at continued standard dose, as well as subsequent escalated-dose regimens. Disease activity at W14 was hypothesized to be an important index for IFX treatment strategy.


In vivo monitoring of Ca(2+) uptake into mitochondria of mouse skeletal muscle during contraction.
Although the importance of mitochondria in patho-physiology has become increasingly evident, it remains unclear whether these organelles play a role in Ca(2+) handling by skeletal muscle. This undefined situation is mainly due to technical limitations in measuring Ca(2+) transients reliably during the contraction-relaxation cycle. Using two-photon microscopy and genetically expressed "cameleon" Ca(2+) sensors, we developed a robust system that enables the measurement of both cytoplasmic and mitochondrial Ca(2+) transients in vivo. We show here for the first time that, in vivo and under highly physiological conditions, mitochondria in mammalian skeletal muscle take up Ca(2+) during contraction induced by motor nerve stimulation and rapidly release it during relaxation. The mitochondrial Ca(2+) increase is delayed by a few milliseconds compared with the cytosolic Ca(2+) rise and occurs both during a single twitch and upon tetanic contraction.


Learning to collaborate: a case study of performance improvement CME.
Performance Improvement Continuing Medical Education (PI CME) is a mechanism for joining quality improvement (QI) in health care to continuing medical education (CME) systems together. Although QI practices and CME approaches have been recognized for years, what emerges from their integration is largely unfamiliar, because it requires the collaboration of CME providers and stakeholders within the health care systems who traditionally have not worked together and may not have the same understanding of QI issues to close performance gaps. This study describes how an academic institution and a community-based primary care practice collaborated to enhance patient care in the area of hypertension. It offers lessons learned from a PI CME activity in the area of hypertension. This was an observational case study. Data were collected through interviews, observations of educational events, and review of documents such as learning logs, which were designed to: (1) help physicians learn and change, (2) satisfy requirements for CME credit, (3) serve as the basis for reimbursement, and (4) provide data for the case study. Nine clinicians from one clinic completed the PI CME activity, achieved measurable improvements in their practice, and contributed to systems change. The study highlighted (1) the value of shared goals and agreement on the process among the participants, planners, and others involved; (2) the advantage of a multidisciplinary approach; (3) the importance of supporting clinicians' continuing motivation to participate; and (4) the need to allow sufficient time to enable the initiative to evolve. PI CME required unprecedented collaboration between CME planners and QI stakeholders to enable change in clinical practice.


A quantitative trait locus on chromosome 5p influences d-dimer levels in the san antonio family heart study.
Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.


Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine.
(-)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (-)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.


Resource allocation in public health practice: a national survey of local public health officials.
The purpose of this study was to gain an empirical understanding of the types of allocation decisions local health officials (LHOs) make and the factors that influence those allocation decisions. We conducted a national survey of LHOs in the United States in 2008 to 2009. The sample was stratified by the size of the population served by the department. We merged our data with data from the 2008 National Association of County and City Health Officials Profile survey. Descriptive statistics were generated using weighted data. Our final sample size was 608 respondents, with an average of 10 years experience. The LHOs reported little shifting of resources among population groups but greater capacity to redirect staffing time. Less than half of LHOs reported using economic analyses or conducting needs assessments when setting priorities. Having sole provider status in a community strongly influenced LHOs' allocation decisions. In addition, the effectiveness of activities, previous budget allocations, and input from boards of health were influential factors in allocation decisions. Public expectations were moderately to very influential, but direct public input had a low impact on allocation decisions. Survey findings provide a clearer understanding of how LHOs fulfill their obligations as stewards of public health resources and ensure effective activities and access to needed services. It may be useful to assess the value of more structured allocation methods (eg, decision frameworks) in the allocation process. Expanding opportunities for public engagement in priority setting may also be valuable for difficult allocation decisions.


Continuity across inpatient and outpatient mental health care or specialisation of teams? A systematic review.
A central question for the organisation of mental health care is whether the same clinicians should be responsible for a patient's care across inpatient and outpatient settings (continuity of care) or if there should be separate teams (specialisation). Current reforms in Europe are inconsistent on which to favour, and are based on little research evidence. This review is the first systematic appraisal of the existing evidence comparing continuity of care and specialisation across inpatient and outpatient mental health care. A systematic search for studies of any design comparing mental health care systems based on continuity or specialisation of care was performed. Differences in clinical, social and cost-effective outcomes, and the views and experiences of patients and staff were assessed using narrative synthesis. Seventeen studies met the inclusion criteria. All studies had methodological shortcomings, but findings point towards reduced length and number of hospitalisations, and faster or more flexible transitions between services in continuity systems. Survey and qualitative findings suggest advantages of both systems, whilst patients and staff appear to prefer a continuity system. The evidence base suggests better outcomes and stakeholder preferences for continuity of care systems, but the quality of existing studies is insufficient to draw definitive conclusions. Higher quality comparative studies across various settings and population groups are urgently needed.


An antithrombin-heparin complex increases the anticoagulant activity of fibrin clots.
Clotting blood contains fibrin-bound thrombin, which is a major source of procoagulant activity leading to clot extension and further activation of coagulation. When bound to fibrin, thrombin is protected from inhibition by antithrombin (AT) + heparin but is neutralized when AT and heparin are covalently linked (ATH). Here, we report the surprising observation that, rather than yielding an inert complex, thrombin-ATH formation converts clots into anticoagulant surfaces that effectively catalyze inhibition of thrombin in the surrounding environment.


Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis.
Repetitive transcranial magnetic stimulation (TMS) is an FDA-approved antidepressant treatment but little is known of its mechanism of action. Specifically, downstream effects of TMS remain to be elucidated. This study aims to identify brain structural changes from TMS treatment of a treatment resistant depressive episode through an exploratory analysis. Twenty-seven subjects in a DSM-IV current major depressive episode and on a stable medication regimen had a 3T magnetic resonance T1 structural scan before and after five weeks of standard TMS treatment to the left dorsolateral prefrontal cortex. Twenty-seven healthy volunteer (HVs) subjects had the same brain MRI acquisition. Voxel-based morphometry was performed using high dimensional non-linear diffusomorphic anatomical registration (DARTEL). Six clusters of gray matter volume (GMV) that were lower in pre-treatment MRIs of depressed subjects than in HVs. GMV in four of these regions increased in MDD after TMS treatment by 3.5-11.2%. The four brain regions that changed with treatment were centered in the left anterior cingulate cortex, the left insula, the left superior temporal gyrus and the right angular gyrus. Increases in the anterior cingulate GMV with TMS correlated with improvement in depression severity. To our knowledge, this is the first study of brain structural changes during TMS treatment of depression. The affected brain areas are involved in cognitive appraisal, decision-making and subjective experience of emotion. These effects may have potential relevance for the antidepressant action of TMS.


Information science. Going, going, gone: lost Internet references.
The use of Internet references in academic literature is common, and Internet references are frequently inaccessible. The extent of Internet referencing and Internet reference activity in medical or scientific publications was systematically examined in more than 1000 articles published between 2000 and 2003 in the New England Journal of Medicine, The Journal of the American Medical Association, and Science. Internet references accounted for 2.6% of all references (672/25548) and in articles 27 months old, 13% of Internet references were inactive. Publishers, librarians, and readers need to reassess policies, archiving systems, and other resources for addressing Internet reference attrition to prevent further information loss.


Novel combined insulin-like 3 variations of a single nucleotide in cryptorchidism.
Background Insulin-like 3 hormone (INSL3) is involved in the process of testicular descent, and has been thoroughly studied in cryptorchidism. However, INSL3 allelic variations found in the human genome were heterozygous and only a few of them were found exclusively in patients with cryptorchidism. Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences. Methods Blood samples were collected from 46 male patients with non-syndromic cryptorchidism and from 43 age-matched controls. DNA extraction and polymerase chain reaction (PCR) were performed for exons 1 and 2 of the INSL3 gene in all subjects. Sequencing analysis was carried out on the PCR products. All data were grouped according to testicular location. Results Seven variations of a single nucleotide (SNVs) were identified both in patients with cryptorchidism and in controls: rs2286663 (c.27G > A), rs1047233 (c.126A > G) and rs6523 (c.178A > G) at exon 1, rs74531687 (c.191-30C > T) at the intron, rs121912556 (c.305G > A) at exon 2 and rs17750642 (c.*101C > A) and rs1003887 (c.*263G > A) at the untranslated region (UTR). The allelic variants rs74531687 and rs121912556 were found for the first time in the Greek population. The novel homozygotic combination of the three allelic variants rs1047233-rs6523-rs1003887 seemed to present a stronger correlation with more severe forms of cryptorchidism. Conclusions The combination of specific INSL3 SNVs rather than the existence of each one of them alone may offer a new insight into the involvement of allelic variants in phenotypic variability and severity.


Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions.
Detection of causal mutations is required for genetic counseling. Molecular modeling combined with patients' phenotype provides significant insight into structure-function relationship of factor (F)VIII molecule. Our objective was to identify defects in the gene of FVIII by a sensitive and simple scanning technique with high throughput in order to study molecular mechanisms by which novel amino acid substitutions may lead to hemophilia A. A cohort of 81 families with mild, moderate and severe hemophilia A negative in intron 22 inversion was studied. For detection of mutations in the FVIII gene a conformation sensitive gel electrophoresis (CSGE) was modified by multiplexing. Thirteen novel amino acid substitutions were studied by molecular modeling and a correlation with the cross-reactive material (CRM) phenotype was performed. In 74 families, 59 different mutations were detected. Six different mutations were recurrent in 21 unrelated families. Thirty-four novel mutations included 19 point mutations, four small insertions, nine small deletions and two complex mutations. Thirteen novel amino acid substitutions occurred at residues conserved in FVIII orthologs. Five of them were associated with a discrepancy between FVIII activity and antigen; another five with CRM reduced phenotype and one with undetectable FVIII antigen. Multiplexing of the CSGE significantly increased its throughput without substantial loss of sensitivity. Molecular modeling suggested mechanisms by which substitutions at residues 382 and 569, located outside the proposed FIXa-binding region, may influence FVIII/FIXa interaction. His2155 was predicted to participate in FVIII/VFW binding.


Analysis of p53 tumour suppressor gene somatic mutations in rheumatoid arthritis synovium.
In order to study the role of the p53 tumour suppressor gene in the proliferation of rheumatoid arthritis (RA) synovium, we analysed the mutation of p53 in the synovial fibroblast-like type B synoviocyte from RA patients. Synovial fibroblast-like type B synoviocytes were prepared from the synovial tissues from nine Japanese patients with RA. The p53 cDNA region from exons 4-11 was screened for mutations by the streamlined mutation detection method in which polymerase chain reaction (PCR) products are post-labelled and are analysed by automated capillary electrophoresis using single-strand conformation polymorphism conditions, followed by direct sequencing of the subclones of the PCR products. p53 mutation with possible functional alteration was detected in four of the nine RA patients (44.4%). Of a total of 262 p53 cDNA subclones, 10 subclones were carrying 10 p53 mutations, eight of which were associated with amino acid alterations or protein truncation. Of the p53 functional mutations, a substitution of Gly at amino acid residue 245 to Asp (G245D) was identified in two patients in three subclones. G245D was the first mutation that was recurrently identified in different RA individuals. G245D is also one of the relatively common mutations in human cancers. In some patients with RA, dysfunction of p53 might play a role in the proliferation of the synovial tissue. G245D mutation might especially need further study as it is the first recurrently identified p53 mutation in RA and is also one of the frequently identified mutations in human cancers.


Cross specificity in some vertebrate and insect glutathione-transferases with methyl parathion (dimethyl p-nitrophenyl phosphorothionate), 1-chloro-2,4-dinitro-benzene and s-crotonyl-N-acetylcysteamine as substrates.
1. Enzymes catalysing the reaction between GSH and methylparathion (dimethyl p-nitrophenyl phosphorothionate), 1-chloro-2,4-dinitrobenzene and S-crotonyl-N-acetylcysteamine were separated by (NH(4))(2)SO(4) precipitation from homogenates of sheep, rat and mouse livers and from homogenates of cockroaches, houseflies and grass grubs. 2. Electrofocusing of the preparations from each of these species separated a number of zones, each of which catalysed the reaction of GSH with all three substrates. 3. Ion-exchange chromatography on CM-cellulose also separated a number of fractions in which activity towards the three substrates coincided. 4. In both separation methods patterns of the activities were consistent with the presence in all species of several GSH transferases each having a degree of cross specificity towards the three substrates.


Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming.
Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg-/- (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon+insulin+ cells and insulin+ ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.


Simultaneous expression of Fas and nonfunctional Fas ligand in Ewing's sarcoma.
Fas-Fas ligand interactions play a central role in the regulation of the immune response. Fas ligand expression by tumors has been implicated in the abrogation of the host antitumor response by killing of Fas-positive effector lymphocytes. We have studied the presence and functional status of Fas and Fas ligand in Ewing's sarcoma. All Ewing's sarcoma cell lines tested expressed Fas on their surface. Three of the cell lines were readily killed after ligation of the Fas receptor. Four additional cell lines exhibited Fas-mediated apoptosis after preincubation with IFN-gamma and/or cycloheximide, whereas two cell lines were resistant to Fas-mediated killing. With regard to Fas ligand, all cell lines examined were positive for protein by immunoblot, and specificity was confirmed by reverse transcription-PCR. However, using flow cytometric analysis, Fas ligand could only be detected in Ewing's sarcoma cells after permeabilization. Furthermore, the cell lines were not capable of inducing apoptosis of Fas-sensitive Jurkat cells. In addition, Ewing's sarcoma cell lines were able to serve as stimulators for the generation of cytotoxic effector lymphocytes and were susceptible to lysis by them. Therefore, Fas ligand is expressed in Ewing's sarcoma but is not functional, suggesting that Ewing's sarcoma is a potential target for immunotherapy.


The enigma of ultraviolet radiation stress granules: Research challenges and new perspectives.
Stress granules (SGs) are non-membrane bound cytoplasmic condensates that form in response to a variety of different stressors. Canonical SGs are thought to have a cytoprotective role, reallocating cellular resources during stress by activation of the integrated stress response (ISR) to inhibit translation and avoid apoptosis. However, different stresses result in compositionally distinct, non-canonical SG formation that is likely pro-apoptotic, though the exact function(s) of both SGs subtypes remain unclear. A unique non-canonical SG subtype is triggered upon exposure to ultraviolet (UV) radiation. While it is generally agreed that UV SGs are bona fide SGs due to their dependence upon the core SG nucleating protein Ras GTPase-activating protein-binding protein 1 (G3BP1), the localization of other key components of UV SGs are unknown or under debate. Further, the dynamics of UV SGs are not known, though unique properties such as cell cycle dependence have been observed. This Perspective compiles the available information on SG subtypes and on UV SGs in particular in an attempt to understand the formation, dynamics, and function of these mysterious stress-specific complexes. We identify key gaps in knowledge related to UV SGs, and examine the unique aspects of their formation. We propose that more thorough knowledge of the distinct properties of UV SGs will lead to new avenues of understanding of the function of SGs, as well as their roles in disease.


Improvements in the diagnosis of acute kidney injury.
Acute kidney injury (AKI) represents a wide range of heterogeneous clinical conditions with a high mortality rate. Despite improvements in our understanding of the disease processes, mortality has only marginally improved and remains unacceptably high. An additional consequence of AKI is the marked acceleration of pre-existing chronic kidney disease to end-stage renal disease. A major limitation in improving outcomes of AKI has been the lack of common standards for diagnosis and severity stratification. Serum creatinine is a late marker of kidney dysfunction and injury. Presently, no available commercial test offers diagnosis, nor the ability to stratify patients by severity of injury, early in the course of disease when therapy may be beneficial. The Acute Dialysis Quality Initiative (ADQI) group proposed a standard definition and classification system for the syndrome of acute renal failure. Based on data that even small changes of serum creatinine result in increased mortality, the Acute Kidney Injury Network (AKIN) has recently proposed modified criteria. Both staging systems emphasize changes in serum creatinine and urine output. There is also potential that a number of serum and urine bio-markers developed in preclinical studies and currently being investigated and validated, will enable the early diagnosis of AKI.


Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries.
Cells of multicellular organisms have diverse characteristics despite having the same genetic identity. The distinctive phenotype of each cell is determined by molecular mechanisms such as epigenetic changes that occur throughout the lifetime of an individual. Recently, technologies that enable modification of the fate of somatic cells have been developed, and the number of studies using these technologies has increased drastically in the last decade. Various cell types, including neuronal cells, cardiomyocytes, and hepatocytes, have been generated using these technologies. Although most direct reprogramming methods employ forced transduction of a defined sets of transcription factors to reprogram cells in a manner similar to induced pluripotent cell technology, many other strategies, such as methods utilizing chemical compounds and microRNAs to change the fate of somatic cells, have also been developed. In this review, we summarize transcription factor-based reprogramming and various other reprogramming methods. Additionally, we describe the various industrial applications of direct reprogramming technologies.


Size and shape of soft-tissue facial profile: effects of age, gender, and skeletal class.
A method for the quantitative and qualitative analysis of the facial soft-tissue profile has been developed, and applied to analyze the pretreatment lateral head films of 240 orthodontic patients aged 8 to 14 years. Patients were subdivided for sex, age, and skeletal class. To standardize for different facial sizes, soft-tissue profiles from nasion to pogonion were traced in polar coordinates without modifications of facial shape, and standardized for an equal skeletal vertical dimension. The method allowed a simple and rapid quantitative evaluation of soft-tissue profiles during facial growth. An approximate evaluation of the soft-tissue thickness at nose, lips, and chin was also possible. No particular mathematical knowledge was required at any step of the analysis. Facial soft-tissue size and shape were influenced by age and sex, and to a minor extent by skeletal class.


The effect of visuospatial resolution on discharge variability among motor units and force-discharge relation.
Although force steadiness varies with visuospatial information, accountable motor unit (MU) behaviors are not fully understood. This study investigated the modulation of MU discharges and force-discharge relation due to variations in the spatial resolution of visual feedback, with a particular focus on discharge variability among MUs. Fourteen young adults produced isometric force at 10% of maximal voluntary contraction (MVC) through index abduction, under the conditions of force trajectory displayed with low visual gain (LVG) and high visual gain (HVG). Together with smaller and more complex force fluctuations, HVG resulted in greater variabilities of the mean interspike interval and discharge irregularity among MUs than LVG did. Estimated via smoothening of a cumulative spike train of all MUs, global discharge rate was tuned to visual gain, with a more complex global discharge rate and a lower force-discharge relation in the HVG condition. These higher discharge variabilities were linked to larger variance of the common drive received by MUs for regulation of muscle force with higher visuospatial information. In summary, higher visuospatial information improves force steadiness with more complex force fluctuations, underlying joint effects of low-pass filter property of the musculotendon complex and central modulation of discharge variability among MUs.


Exposure to paternal alcoholism does not predict development of alcohol-use disorders in offspring: evidence from an offspring-of-twins study.
Using an offspring-of-twins design, we tested the hypothesis that exposure to paternal alcoholism during the child's first 12 years will increase offspring risk for subsequent alcohol-use disorders (AUD). Structured psychiatric interviews assessed history of psychiatric and substance-use disorders in Vietnam Era Twin Registry fathers (n = 512), their offspring (n = 877), and mothers of the offspring (n = 507). Exposure was defined as the fathers' endorsement of any Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, AUD symptom, according to the Lifetime Drinking History assessment (administered in 1999), at any time between off- spring ages 0-12 years; all fathers had satisfied DSM, Third Edition, Revised (DSM-III-R), criteria for alcohol dependence in a 1992 diagnostic interview. Cox proportional hazards models were fit to predict time to first symptom of abuse/dependence in offspring. Off- spring exposed to paternal alcoholism were significantly more likely to develop an AUD when compared with offspring of nonalcoholic fathers (hazard ratio [HR] = 1.51; 95% confidence interval [CI]: 1.10-2.07). Although offspring unexposed to paternal alcoholism did not significantly differ from control offspring (HR = 1.50, 95% CI: 0.93-2.41), the magnitude of association was similar to that in the exposed offspring. There were no significant differences in AUD between offspring of alcoholics who were exposed and those who were not exposed to paternal alcoholism, as long as fathers had satisfied DSM-III-R criteria for alcohol dependence at some point in their lives. There does not appear to be a relationship between exposure to paternal alcoholism during childhood and development of an AUD in offspring. Genetic and high-risk environmental factors that are correlated with lifetime paternal alcoholism may be stronger predictors of offspring AUD than fathers' problem drinking. Future research should be encouraged, using more comprehensive analyses, to examine the role of family genetic influences and other family environmental influences on offspring alcohol outcomes.


Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.


Establishing an investigational drugs and research residency at an academic medical center.
The development, structure, and implementation of an innovative residency program designed to help meet a growing need for pharmacists with specialized expertise in investigational drug use and clinical research are described. Clinical research has become an increasingly complex field, but prior to 2017 there were no U.S. specialty residency training programs focused on pharmacists' role in drug development and the care of patients enrolled in clinical trials. In 2016 Johns Hopkins Hospital (JHH) launched an initiative to develop residency training standards specific to the areas of investigational drug use and clinical research. The residency development process consisted of creation of a residency development committee; a needs assessment, including formation of a diverse panel of internal and external experts to guide identification of key competency areas and development of residency goals and objectives; design of the program's structure, including a framework for required and elective rotations; submission of an application for pre-candidate status to the ASHP Commission on Credentialing; and recruitment efforts. The JHH investigational drugs and research residency, a combined PGY1 and PGY2 program with 5 competency areas, 14 goals, and 49 objectives, was granted pre-candidate status by ASHP in November 2016. The first resident began the program in June 2017.


Enterococcus plantarum sp. nov., isolated from plants.
Eight Gram-positive, catalase-negative bacterial strains were isolated during screening of enterococcal populations on plants. rep-PCR fingerprinting using the (GTG)(5) primer showed that the isolates constituted a single cluster that was separate from all known enterococcal species. 16S rRNA gene sequence phylogenetic analysis of three representative strains showed that the isolates belonged to the genus Enterococcus and that they clustered with the Enterococcus faecalis species group. Sequencing of the genes for the phenylalanyl-tRNA synthase alpha subunit (pheS) and the RNA polymerase alpha subunit (rpoA) also revealed the isolates' separate taxonomic position. Application of whole-cell protein fingerprinting, automated ribotyping and extensive phenotyping demonstrated the genetic and phenotypic homogeneity of the isolates and confirmed their separate position within the E. faecalis species group. The isolates represent a novel species of the genus Enterococcus, for which the name Enterococcus plantarum sp. nov. is proposed; the type strain is CCM 7889(T) (=LMG 26214(T)=C27(T)).


Body mass index, neighborhood fast food and restaurant concentration, and car ownership.
Eating away from home and particularly fast food consumption have been shown to contribute to weight gain. Increased geographic access to fast food outlets and other restaurants may contribute to higher levels of obesity, especially in individuals who rely largely on the local environment for their food purchases. We examined whether fast food and restaurant concentrations are associated with body mass index and whether car ownership might moderate this association. We linked the 2000 US Census data and information on locations of fast food and other restaurants with the Los Angeles Family and Neighborhood Study database, which consists of 2,156 adults sampled from 63 neighborhoods in Los Angeles County. Multilevel modeling was used to estimate associations between body mass index (BMI), fast food and restaurant concentration, and car ownership after adjustment for individual-level factors and socioeconomic characteristics of residential neighborhoods. A high concentration of local restaurants is associated with BMI. Car owners have higher BMIs than non-car owners; however, individuals who do not own cars and reside in areas with a high concentration of fast food outlets have higher BMIs than non-car owners who live in areas with no fast food outlets, approximately 12 lb more (p = 0.02) for an individual with a height of 5 ft. 5 in. Higher restaurant density is associated with higher BMI among local residents. The local fast food environment has a stronger association with BMI for local residents who do not have access to cars.


[Immunobiologic characteristics of carbohydrate-containing preparations of Haemophilus influenzae].
Comparative assessment of immunobiological characteristics of 3 antigenic preparations containing capsular polysaccharide of Haemophilus influenzae type b (CPS Hib). The following preparations were assessed: CPS Hib obtained by using cetavlon; hydroxylamine preparation of Hib (HAP Hib); mixture of CPS Hib and lipooligosaccharide of non-typeable H. influenzae (LOS NTHi) detoxified by hydroxylamine hydrochloride. Effects of these preparations on immunophenotype of mononuclear leukocytes of mice spleen as well as on spectrum and level of cytokines in serum were studied. It was shown that mixture of CPS Hib and detoxified LOS NTHi has low toxicity and most protective activity during Hib challenge leading to activation of innate immunity effectors and initiation of adaptive immune response. Obtained data provide perspective for development of preparation able to protect from infections caused by both capsular and acapsular strains of H. influenzae.


Glucose-6-phosphate dehydrogenase mRNA sequence abundance in primary cultures of rat hepatocytes. Effect of insulin and dexamethasone.
Hepatic glucose-6-phosphate dehydrogenase (G6PDH; EC 22.214.171.124) is subject to nutritional regulation. To assess the possible role of hormones in this regulation, the amounts of G6PDH mRNA were studied in primary cultures of rat hepatocytes treated with insulin and dexamethasone, alone or in combination. Relative concentrations of G6PDH mRNA were directly assessed by a dot-blot hybridization procedure with nick-translated cDNA probes. G6PDH sequence abundance increased when the cultures were treated with insulin or dexamethasone, but the G6PDH mRNA induced by dexamethasone was not expressed at the protein level as active enzyme. In cultures treated with insulin and dexamethasone in combination, enzyme activity and G6PDH sequence abundance were greater than those induced by insulin alone. Our results directly demonstrate that G6PDH mRNA amounts are modulated in liver by these two classes of hormones and can partially account for the dietary induction of the enzyme observed in vivo.


Outpatient Total Thyroidectomy Is Safe for Moderate-Volume Surgeons.
Traditionally, total thyroidectomy (TT) was an inpatient procedure, but recent trends indicate that patients are often discharged on the day of surgery. This has been proven safe for high-volume surgeons but has not been studied for low (<10 TT per year) and moderate volume surgeons (<24 TT per year). Retrospective review was performed for 414 total thyroidectomies between 2005 and 2013. Emergency department visits and readmissions within 30 days of surgery were captured, but were considered the same for the purpose of this analysis. Patients were identified as outpatient if the day of discharge matched the day of surgery. The groups were compared based on demographic variables, comorbidities, postop calcium supplementation, and serum calcium. We found that moderate-volume surgeons were more likely to perform outpatient TT than low-volume surgeons (31.6% vs 6.0%, P < 0.001), but there was no correlation between length of stay and readmission (P = 0.688). Readmitted patients had lower postop serum calcium (8.3 mg/dL) than patients who were not readmitted (8.8 mg/dL, P = 0.006). Our data show that moderate-volume surgeons performing outpatient TT have an acceptable safety profile with respect to emergency department visits and hospital readmissions, and that same day discharge had no bearing on readmission.


Use of fusion proteins and procaryotic display systems for delivery of HIV-1 antigens: development of novel vaccines for HIV-1 infection.
Two non-pathogenic scaffolds (represented by the filamentous bacteriophage fd and the dihydrolipoyl acetyltransferase E2 protein of the Bacillus stearothermophilus pyruvate dehydrogenase (PDH) complex) able to deliver human immunodeficiency virus (HIV)-1 antigenic determinants, were designed in our laboratories and investigated in controlled assay conditions. Based on a modification of the phage display technology, we developed an innovative concept for a safe and inexpensive vaccine in which conserved antigenic determinants of HIV-1 reverse transcriptase (RTase) were inserted into the N-terminal region of the major pVIII coat protein of bacteriophagefd virions. Analogously, we developed another antigen delivery system based on the E2 component from the PDH complex and capable of displaying large intact proteins on the surface of an icosahedral lattice. Our data show that both of these systems can deliver B and T epitopes to their respective presentation compartments in target cells and trigger a humoral response as well as a potent helper and cytolytic response in vitro and in vivo.


Pharmacology of bisphosphonates.
The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from "bench to bedside and back again". Several of the leading BPs achieved "blockbuster" status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.