The influence of basic ventilation strategies and anesthetic techniques on cerebral oxygenation in the beach chair position: study protocol.
Beach chair positioning during general anesthesia is associated with a high incidence of cerebral desaturation; poor neurological outcome is a growing concern. There are no published data pertaining to changes in cerebral oxygenation seen with increases in the inspired oxygen fraction or end-tidal carbon dioxide in patients anesthetized in the beach chair position. Furthermore, the effect anesthetic agents have has not been thoroughly investigated in this context. We plan to test the hypothesis that changes in inspired oxygen fraction or end-tidal carbon dioxide correlate to a significant change in regional cerebral oxygenation in anesthetized patients in beach chair position. We will also compare the effects that inhaled and intravenous anesthetics have on this process. This is a prospective within-group study of patients undergoing shoulder arthroscopy in the beach chair position which incorporates a randomized comparison between two anesthetics, approved by the Institutional Review Board of the University of Michigan, Ann Arbor. The primary outcome measure is the change in regional cerebral oxygenation due to sequential changes in oxygenation and ventilation. A sample size of 48 will have greater than 80% power to detect an absolute 4-5% difference in regional cerebral oxygenation caused by changes in ventilation strategy. The secondary outcome is the effect of anesthetic choice on cerebral desaturation in the beach chair position or response to changes in ventilation strategy. Fifty-four patients will be recruited, allowing for drop out, targeting 24 patients in each group randomized to an anesthetic. Regional cerebral oxygenation will be measured using the INVOS 5100C monitor (Covidien, Boulder, CO). Following induction of anesthesia, intubation and positioning, inspired oxygen fraction and minute ventilation will be sequentially adjusted. At each set point, regional cerebral oxygenation will be recorded and venous blood gas analysis performed. The overall statistical analysis will use a repeated measures analysis of variance with Tukey's HSD procedure for post hoc contrasts. If simple maneuvers of ventilation or anesthetic technique can prevent cerebral hypoxia, patient outcome may be improved. This is the first study to investigate the effects of ventilation strategies on cerebral oxygenation in patients anesthetized in beach chair position. NCT01535274.


Tannin containing legumes as a model for nutraceuticals against digestive parasites in livestock.
Parasitic infections with gastrointestinal nematodes (GINs) still represent a worldwide major pathological threat associated with the outdoor production of various livestock species. Because of the widespread resistance to synthetic chemical anthelmintics, there is a strong impetus to explore novel approaches for a more integrated management of these infections. The use of nutraceuticals in the control of GINs is one of the alternatives which has been widely studied for 20 years. The objectives of this review are: (i) to define and illustrate the concept of 'nutraceutical' in the context of veterinary parasitology based on data obtained on the most studied models to control GINs in small ruminants, the tannin-containing legumes (Fabaceae); (ii) to illustrate how the 'nutraceutical concept' could be expanded to other plants, other livestock production systems and other GI parasitic diseases, and (iii) to explain how this concept is opening up new research fields for better understanding the interactions between the host, the digestive parasites and the environment.


Meta-MEME: motif-based hidden Markov models of protein families.
Modeling families of related biological sequences using Hidden Markov models (HMMs), although increasingly widespread, faces at least one major problem: because of the complexity of these mathematical models, they require a relatively large training set in order to accurately recognize a given family. For families in which there are few known sequences, a standard linear HMM contains too many parameters to be trained adequately. This work attempts to solve that problem by generating smaller HMMs which precisely model only the conserved regions of the family. These HMMs are constructed from motif models generated by the EM algorithm using the MEME software. Because motif-based HMMs have relatively few parameters, they can be trained using smaller data sets. Studies of short chain alcohol dehydrogenases and 4Fe-4S ferredoxins support the claim that motif-based HMMs exhibit increased sensitivity and selectivity in database searches, especially when training sets contain few sequences.


Mometasone furoate: a review of its intranasal use in allergic rhinitis.
Mometasone furoate (Nasonex) is a high-potency intranasal corticosteroid available for the treatment and/or prophylaxis of the nasal symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). In the EU, it is approved for use in patients aged > or =6 years and, in the US, it is approved as a treatment in patients aged > or =2 years and as prophylaxis in those > or =12 years of age.Extensive experience in both clinical trials and the clinical practice setting has firmly established the efficacy and good tolerability profile of intranasal mometasone furoate in children and adults with PAR or SAR. Thus, intranasal mometasone furoate is a useful first-line option for the treatment and prophylactic management of these conditions, including in children as young as 2 years of age in some countries and 6 years of age in others.


Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2.
A prominent characteristic of the inherited intellectual impairment disease fragile X syndrome (FXS) is neuronal hyperexcitability, resulting in a variety of symptoms, such as hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. These symptoms account for a significant part of the disease pattern, but the underlying molecular mechanisms of neuronal hyperexcitability in FXS remain poorly understood. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), which regulates synaptic protein synthesis and is a key player to limit signaling pathways downstream of metabotropic glutamate receptors 1/5 (mGlu1/5). Recent findings suggest that FMRP might also directly regulate voltage-gated potassium channels. Here, we show that total and plasma membrane protein levels of Kv4.2, the major potassium channel regulating hippocampal neuronal excitability, are reduced in the brain of an FXS mouse model. Antagonizing mGlu5 activity with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) partially rescues reduced surface Kv4.2 levels in Fmr1 knock-out (KO) mice, suggesting that excess mGlu1/5 signal activity contributes to Kv4.2 dysregulation. As an additional mechanism, we show that FMRP is a positive regulator of Kv4.2 mRNA translation and protein expression and associates with Kv4.2 mRNA in vivo and in vitro. Our results suggest that absence of FMRP-mediated positive control of Kv4.2 mRNA translation, protein expression, and plasma membrane levels might contribute to excess neuronal excitability in Fmr1 KO mice, and thus imply a potential mechanism underlying FXS-associated epilepsy.


Hydrophilic coatings diminish adhesion of glue to catheter: an in vitro simulation of NBCA embolization.
To determine whether new hydrophilic microcatheter coatings exhibit characteristics that diminish the chance of permanent endovascular glue adhesion during liquid acrylic embolization. Common hydrophilic and nonhydrophilic microcatheters (both flow-directed and over-the-wire) used in neurointerventional procedures were evaluated in vitro for liquid acrylic (Histoacryl and Avacryl)-to-catheter bond strength, catheter endovascular friction, and catheter stretch (tensile strength). Sufficient test repetitions were acquired to achieve statistical significance. The bond strength between hydrophilically coated catheters and NBCA was significantly weaker than between nonhydrophilic catheters and NBCA. Hydrophilic catheter coating reduced dynamic endovascular friction by 30% to 35%. All flow-directed catheters exhibited considerably more stretch (less tensile strength) and therefore were more prone to fracture during withdrawal than over-the-wire systems. Histoacryl bonded to both hydrophilic and nonhydrophilic catheters with a significantly greater force than did Avacryl. Hydrophilically coated catheters should be less likely to exhibit permanent endovascular fixation during acrylic embolization because of a weaker catheter-NBCA bond and because of reduced catheter friction (allowing a larger portion of any applied catheter withdrawal force to be transmitted to the catheter tip with less force dissipated along the catheter resulting in stretch). A significant difference in NBCA types (Histoacryl and Avacryl) was discovered: Avacryl developed a significantly weaker bond with all catheter types.


Linear stratified approach using full geometric constraints for 3D scene reconstruction and camera calibration.
This paper presents a new linear framework to obtain 3D scene reconstruction and camera calibration simultaneously from uncalibrated images using scene geometry. Our strategy uses the constraints of parallelism, coplanarity, colinearity, and orthogonality. These constraints can be obtained in general man-made scenes frequently. This approach can give more stable results with fewer images and allow us to gain the results with only linear operations. In this paper, it is shown that all the geometric constraints used in the previous works performed independently up to now can be implemented easily in the proposed linear method. The study on the situations that cannot be dealt with by the previous approaches is also presented and it is shown that the proposed method being able to handle the cases is more flexible in use. The proposed method uses a stratified approach, in which affine reconstruction is performed first and then metric reconstruction. In this procedure, the additional constraints newly extracted in this paper have an important role for affine reconstruction in practical situations.


Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length.
Centrioles and cilia are microtubule-based structures, whose precise formation requires controlled cytoplasmic tubulin incorporation. How cytoplasmic tubulin is recognized for centriolar/ciliary-microtubule construction remains poorly understood. Centrosomal-P4.1-associated-protein (CPAP) binds tubulin via its PN2-3 domain. Here, we show that a C-terminal loop-helix in PN2-3 targets β-tubulin at the microtubule outer surface, while an N-terminal helical motif caps microtubule's α-β surface of β-tubulin. Through this, PN2-3 forms a high-affinity complex with GTP-tubulin, crucial for defining numbers and lengths of centriolar/ciliary-microtubules. Surprisingly, two distinct mutations in PN2-3 exhibit opposite effects on centriolar/ciliary-microtubule lengths. CPAP(F375A), with strongly reduced tubulin interaction, causes shorter centrioles and cilia exhibiting doublet- instead of triplet-microtubules. CPAP(EE343RR) that unmasks the β-tubulin polymerization surface displays slightly reduced tubulin-binding affinity inducing over-elongation of newly forming centriolar/ciliary-microtubules by enhanced dynamic release of its bound tubulin. Thus CPAP regulates delivery of its bound-tubulin to define the size of microtubule-based cellular structures using a 'clutch-like' mechanism.


Nonsuicidal Self-Injury and Suicide: The Role of Life Events in Clinical and Non-Clinical Populations of Adolescents.
Nonsuicidal self-injury (NSSI) is highly prevalent in clinical and non-clinical populations of adolescents. Several studies have supported both the distinction and the strong association between NSSI and suicidal behavior. Although there is a great deal of data on the role of life events in both suicidal behavior and NSSI, few studies have assessed the role of life events in the NSSI-suicidal behavior relationship. Our aims were to explore the relationship between NSSI and suicidal behavior, and the possible moderating role of stressful life events in a clinical and non-clinical adolescent population. A clinical (n = 202) and a nonclinical (n = 161) population of adolescents, aged 13-18 years were assessed. The Mini International Neuropsychiatric Interview Kid, Deliberate Self-Harm Inventory and the Life Events List were used. Group differences related to suicidal behavior, NSSI, and life events were tested with Wilcoxon tests. Two- and three-way interactions were tested with negative binomial regression models including zero-inflation parameter. The prevalence of suicidal behavior (W = 7,306, p < .001), NSSI (W = 9,652, p < .001) and life events (W = 10,410 p < .001) were significantly higher in the clinical than in the non-clinical group. Between number of life events and NSSI, a moderate effect size (.38, 95%CI [.28,.46]) was found. The main effect of NSSI (χ2 (1) = 109.65, p < .001) and group membership (χ2 (1) = 39.13, p < .001) predicted suicidal behavior; the main effect of quantity of life events did not explain suicidal behavior. The interaction between NSSI and number of life events (χ2 (1) = 10.49, p < .01) was associated with suicidal behavior. Among interpersonal, non-interpersonal events and adverse childhood circumstances, only interpersonal events were associated with both suicidal behavior (χ2 (1) = 6.08, p < .05) and had a moderating effect (χ2 (1) = 8.59, p < .01) on the NSSI-suicidal behavior relationship. Patterns of the effects of life events on the NSSI-suicidal behavior relationship did not differ in the two groups. Our results confirm the importance of prevention and intervention of NSSI, considering its high prevalence and frequent co-occurrence with suicidal behavior in both clinical and non-clinical adolescent populations. Moreover, to support NSSI and suicide prevention, we would like to highlight the importance of stressful life events, especially those associated with interpersonal conflicts, require special attention.


Outbreak of invasive group A streptococcal infections in a nursing home. Lessons on prevention and control.
Nine outbreaks of group A streptococcal (GAS) infections in nursing homes were reported to the Centers for Disease Control (Atlanta, Ga) during the past two winters. We conducted an intensive epidemiologic and laboratory investigation of one of these outbreaks to determine clinical characteristics, risk factors for transmission and infection, and methods of control and prevention. Cases were detected using cultures and serologic tests. Matched case-control and retrospective cohort studies were performed to determine risk factors for infection. Between December 13, 1989, and January 31, 1990, 16 (20%) of 80 residents, and three (7%) of 45 staff, were infected with GAS. Eleven of the residents had invasive disease and four died. Isolates were available from four persons; all were serotype M-1, T-1. There was strong spatial clustering of cases within the nursing home; having a roommate with prior infection was the most important risk factor. Residents with preexisting decubiti had a reduced risk of infection, perhaps because of stricter infection control practices in their care. No evidence was found for common-source transmission of infection. No further cases occurred after improvement of infection control practices and administration of prophylactic antimicrobials to all residents and staff. Invasive GAS disease is increasing nationwide, and is a potentially serious problem in the growing and high-risk setting of nursing homes. These data suggest that, in this outbreak, a virulent GAS strain was introduced, with subsequent person-to-person transmission. Adherence to infection control practices can prevent or control GAS outbreaks. Prophylactic antimicrobials may be an effective adjunct to control severe or ongoing outbreaks.


Neoadjuvant denosumab for the treatment of a sacral osteoblastoma.
To present a case of aggressive sacral osteoblastoma (OB) treated with neoadjuvant denosumab therapy and en bloc resection. Case report of a 14-year-old male with an aggressive OB affecting the superior articular process of the left first sacral segment. The lesion was lytic and metabolically active and involved the left-sided posterior elements of S1-S3 with extension into the spinal canal, affecting the left S1, S2, S3, S4 and S5 nerve roots. He was treated for 1 month with neoadjuvant denosumab followed by en bloc resection. Denosumab therapy caused regression of the tumour and converted the diffuse infiltrative mass into a well-defined solid (osteoma-like) structure, aiding surgical resection and preserving the S1, S4 and S5 nerve roots. Histologically, the treated lesion showed abundant sclerotic woven bone and osteoblasts with absence of osteoclasts. A short course of denosumab caused tumour regression, ossification and conversion of an aggressive OB into a sclerotic, well-defined lesion thus aiding surgical resection and preservation of neural structures. Neoadjuvant therapy reduced osteoclast numbers but PET showed that the lesion remained FDG avid post-therapy.


Carotenoids and menstrual cycle phase in young women.
An association between serum carotenoid concentrations and risk for certain cancers has been observed in epidemiological studies. Determinants of serum carotenoid concentrations are known to include dietary intake, plasma lipid concentrations, and body mass. Menstrual cycle phase, which has not been adequately addressed in previous studies, has been suggested to be a possible additional factor to consider in the interpretation of these values in women. We evaluated hormonal status, serum carotenoids, cholesterol, and triglycerides in 48 healthy women at early follicular, mid-luteal, and late luteal phases of one menstrual cycle. Eating patterns were assessed with diet records at two 3-day intervals during the cycle. Analysis was focused on the 30 subjects who were determined to have ovulated during the menstrual cycle under observation. Serum cholesterol was significantly decreased (P < 0.05) in the late luteal phase of an ovulatory cycle. Lutein concentration was increased in the early follicular phase (P < 0.05) and alpha-carotene was increased in the mid-luteal phase (P < 0.05) only if uncorrected for total cholesterol. Other carotenoids did not vary across the menstrual cycle, whether corrected or uncorrected for total cholesterol concentration. In normal healthy ovulating women, serum carotenoids do not appear to vary with menstrual cycle phase when corrected for serum cholesterol concentrations.


Perceived stress, sources and severity of stress among medical undergraduates in a Pakistani medical school.
Recently there is a growing concern about stress during undergraduate medical training. However, studies about the same are lacking from Pakistani medical schools. The objectives of our study were to assess perceived stress, sources of stress and their severity and to assess the determinants of stressed cases. A cross-sectional, questionnaire-based survey was carried out among undergraduate medical students of CMH Lahore Medical College, Pakistan during January to March 2009. Perceived stress was assessed using the perceived stress scale. A 33-item questionnaire was used to assess sources of stress and their severity. The overall response rate was 80.5% (161 out of 200 students). The overall mean perceived stress was 30.84 (SD = 7.01) and was significantly higher among female students. By logistic regression analysis, stressed cases were associated with occurrence of psychosocial (OR 5.01, 95% CI 2.44-10.29) and academic related stressors (OR 3.17 95% CI 1.52-6.68). The most common sources of stress were related to academic and psychosocial concerns. 'High parental expectations', 'frequency of examinations', 'vastness of academic curriculum', 'sleeping difficulties', 'worrying about the future', 'loneliness', 'becoming a doctor', 'performance in periodic examinations' were the most frequently and severely occurring sources of stress. There was a negative but insignificant correlation between perceived stress and academic performance (r = -0.099, p > 0.05). A higher level of perceived stress was reported by the students. The main stressors were related to academic and psychosocial domains. Further studies are required to test the association between stressed cases and gender, academic stressors and psychosocial stressors.


Competition between SOCS36E and Drk modulates Sevenless receptor tyrosine kinase activity.
Modulation of signalling pathways can trigger different cellular responses, including differences in cell fate. This modulation can be achieved by controlling the pathway activity with great precision to ensure robustness and reproducibility of the specification of cell fate. The development of the photoreceptor R7 in the Drosophila melanogaster retina has become a model in which to investigate the control of cell signalling. During R7 specification, a burst of Ras small GTPase (Ras) and mitogen-activated protein kinase (MAPK) controlled by Sevenless receptor tyrosine kinase (Sev) is required. Several cells in each ommatidium express sev. However, the spatiotemporal expression of the boss ligand and the action of negative regulators of the Sev pathway will restrict the R7 fate to a single cell. The Drosophila suppressor of cytokine signalling 36E (SOCS36E) protein contains an SH2 domain and acts as a Sev signalling attenuator. By contrast, downstream of receptor kinase (Drk), the fly homolog of the mammalian Grb2 adaptor protein, which also contains an SH2 domain, acts as a positive activator of the pathway. Here, we apply the Förster resonance energy transfer (FRET) assay to transfected Drosophila S2 cells and demonstrate that Sev binds directly to either the suppressor protein SOCS36E or the adaptor protein Drk. We propose a mechanistic model in which the competition between these two proteins for binding to the same docking site results in either attenuation of the Sev transduction in cells that should not develop R7 photoreceptors or amplification of the Ras-MAPK signal only in the R7 precursor.


Experimental demonstration of broadband Lorentz non-reciprocity in an integrable photonic architecture based on Mach-Zehnder modulators.
Lorentz reciprocity is a direct consequence of Maxwell equations governing the propagation of light in passive linear media with symmetric permittivity and permeability tensors. Here, we demonstrate the first active optical isolator and circulator implemented in a linear and reciprocal material platform using commercial Mach-Zehnder modulators. In a proof-of-principle experiment based on single-mode polarization-maintaining fibers, we achieve more than 12.5 dB isolation over an unprecedented 8.7 THz bandwidth at telecommunication wavelengths, with only 9.1 dB total insertion loss. Our architecture provides a practical answer to the challenge of non-reciprocal light routing in photonic integrated circuits.


Utility of computed tomography in the detection of subclinical nodal disease in papillary thyroid carcinoma.
To characterize the ability of computed tomography (CT) to identify subclinical cervical metastatic disease in papillary thyroid carcinoma (PTC). Retrospective review. Tertiary academic center. Consecutive patients undergoing neck dissection for PTC between July 1, 2004, and July 1, 2006. Preoperative CT scans were reevaluated in a blinded fashion by a single head and neck radiologist. Positive criteria included node with size larger than 10 mm, round shape, calcification, cystic character, or abnormal enhancement. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated separately for central compartment (level VI) and lateral compartment (levels III and IV) dissections. One hundred four patients underwent selective neck dissection for PTC during the study period. Forty-three patients had disease that involved primary lymphadenectomy at the time of thyroidectomy, and 61 had persistent or recurrent disease. There were 111 lateral compartment dissections and 145 central compartment dissections. The overall sensitivity was 59% for both the central and lateral compartments, and the specificity was 76% and 71%, respectively. The PPV and NPV were 84% and 47% for the central compartment and 73% and 57% for the lateral compartment, respectively. Computed tomography has a limited capability to identify subclinical metastatic cervical disease in PTC, with a sensitivity near 60% and an NPV near 50%. Sole reliance on CT findings will miss a significant portion of disease likely because of the high incidence of microscopic foci. However, using strict criteria, a positive finding on a CT scan provides useful information because it predicts with a fairly high assurance that disease will in fact be found in a specific compartment during surgical dissection.


Probing the structure of cytoplasm.
We have used size-fractionated, fluorescent dextrans to probe the structure of the cytoplasmic ground substance of living Swiss 3T3 cells by fluorescence recovery after photobleaching and video image processing. The data indicate that the cytoplasm of living cells has a fluid phase viscosity four times greater than water and contains structural barriers that restrict free diffusion of dissolved macromolecules in a size-dependent manner. Assuming these structural barriers comprise a filamentous meshwork, the combined fluorescence recovery after photobleaching and imaging data suggest that the average pore size of the meshwork is in the range of 300 to 400 A, but may be as small as 200 A in some cytoplasmic domains.


Nerve injuries from mandibular third molar removal.
Injuries to peripheral branches (IAN, LN, LBN) of the trigeminal nerve during the removal of M3s are known and accepted risks in oral and maxillofacial surgery practice. These risks might be reduced by modifications of evaluation or surgical techniques, depending on the surgeon's judgment in individual patients. If a nerve injury does occur, prompt recognition, subjective and objective evaluation,and development of a treatment plan, if the sensory deficit fails to resolve in a reasonable period and is unacceptable to the patient, give the patient the best chance of achieving improvement or recovery of sensory function in the distribution of the injured nerve. Microneurosurgery may produce return of useful sensory function or complete sensory recovery, if done in a timely fashion by an experienced microsurgeon, in greater than 80% of patients who sustain nerve injuries during the removal of M3s.


Myocardial perfusion scintigraphy in Taiwan from 2005 to 2009.
To analyze the utilization of myocardial perfusion scintigraphy (MPS) in Taiwan within the universal healthcare system, the National Health Insurance (NHI) from 2005 to 2009, and to compare with European surveys. On the basis of Taiwan's National Health Insurance Research Database of 2005-2009, a retrospective population-based analysis was conducted. Descriptive statistics were provided on the frequencies of and distributions in the utilization of MPS during the period. In addition, correlation analysis was applied to identify correlated factors in the utility of MPS. The annual number of MPS procedures performed was estimated to be 76 448 on average in 2005-2009 and 3361 per million population (pmp) over the period. The frequency increased by 45%, from 3008 pmp in 2005 to 4371 pmp in 2009, with an annual increase rate of 11.9%. The expenditure on MPS increased by 51%, from 12.3 million USD in 2005 to 18.55 million USD in 2009, with an annual increase rate of 12.9%. The average cost of identifying a coronary artery disease (CAD) case with MPS was 248 USD, with a 2.6% annual increase rate. Most patients were more than 50 years old when they received the MPS examination, whereas inpatients were much older. In addition, most of the MPS practices were performed in medical centers and regional hospitals, although an apparent increase was seen in district hospitals on outpatients. As a consequence, the rate of CAD diagnoses by MPS decreased over time. The numbers, frequencies, and expenses of MPS practices have increased in Taiwan during the period 2005-2009, especially for outpatients. The application rate of MPS in Taiwan was higher than that in Europe, likely because of the high accessibility to MPS procedures within the NHI system. This experience in Taiwan may serve as a reference for illustrating the trends in the use of MPS procedures in countries with a universal healthcare system.


GP awareness, practice, knowledge and confidence: evaluation of the first nation-wide dementia-focused continuing medical education program in Australia.
Dementia is under-diagnosed in primary care. Timely diagnosis and care management improve outcomes for patients and caregivers. This research evaluated the effectiveness of a nationwide Continuing Medical Education (CME) program to enhance dementia-related awareness, practice, knowledge and confidence of general practitioners (GPs) in Australia. Data were collected from self-report surveys by GPs who participated in an accredited CME program face-to-face or online; program evaluations from GPs; and process evaluations from workshop facilitators. CME participants completed surveys at one or more time-points (pre-, post-program, six to 9 months follow-up) between 2015 and 2017. Paired samples t-test was used to determine difference in mean outcome scores (self-reported change in awareness, knowledge, confidence, practice) between time-points. Multivariable regression analyses were used to investigate associations between respondent characteristics and key variables. Qualitative feedback was analysed thematically. Of 1352 GPs who completed a survey at one or more time-points (pre: 1303; post: 1017; follow-up: 138), mean scores increased between pre-CME and post-program for awareness (Mpost-pre = 0.9, p < 0.0005), practice-related items (Mpost-pre = 1.3, p < 0.0005), knowledge (Mpost-pre = 2.2, p < 0.0005), confidence (Mpost-pre = 2.1, p < 0.0005). Significant increases were seen in all four outcomes for GPs who completed these surveys at both pre- and follow-up time-points. Male participants and those who had practised for five or more years showed greater change in knowledge and confidence. Age, years in practice, and education delivery method significantly predicted post-program knowledge and confidence. Most respondents who completed additional program evaluations (> 90%) rated the training as relevant to their practice. These participants, and facilitators who completed process evaluations, suggested adding more content addressing patient capacity and legal issues, locality-specific specialist and support services, case studies and videos to illustrate concepts. The sustainability of change in key elements relating to health professionals' dementia awareness, knowledge and confidence indicated that dementia CME programs may contribute to improving capacity to provide timely dementia diagnosis and management in general practice. Low follow-up response rates warrant cautious interpretation of results. Dementia CME should be adopted in other contexts and updated as more research becomes available.


Supramolecular Double Helices from Small C3-Symmetrical Molecules Aggregated in Water.
Supramolecular fibers in water, micrometers long and several nanometers in width, are among the most studied nanostructures for biomedical applications. These supramolecular polymers are formed through a spontaneous self-assembly process of small amphiphilic molecules by specific secondary interactions. Although many compounds do not possess a stereocenter, recent studies suggest the (co)existence of helical structures, albeit in racemic form. Here, we disclose a series of supramolecular (co)polymers based on water-soluble benzene-1,3,5-tricarboxamides (BTAs) that form double helices, fibers that were long thought to be chains of single molecules stacked in one dimension (1D). Detailed cryogenic transmission electron microscopy (cryo-TEM) studies and subsequent three-dimensional-volume reconstructions unveiled helical repeats, ranging from 15 to 30 nm. Most remarkable, the pitch can be tuned through the composition of the copolymers, where two different monomers with the same core but different peripheries are mixed in various ratios. Like in lipid bilayers, the hydrophobic shielding in the aggregates of these disc-shaped molecules is proposed to be best obtained by dimer formation, promoting supramolecular double helices. It is anticipated that many of the supramolecular polymers in water will have a thermodynamic stable structure, such as a double helix, although small structural changes can yield single stacks as well. Hence, it is essential to perform detailed analyses prior to sketching a molecular picture of these 1D fibers.


Drinking Hydrogen-Rich Water Has Additive Effects on Non-Surgical Periodontal Treatment of Improving Periodontitis: A Pilot Study.
Oxidative stress is involved in the pathogenesis of periodontitis. A reduction of oxidative stress by drinking hydrogen-rich water (HW) might be beneficial to periodontal health. In this pilot study, we compared the effects of non-surgical periodontal treatment with or without drinking HW on periodontitis. Thirteen patients (3 women, 10 men) with periodontitis were divided into two groups: The control group (n = 6) or the HW group (n = 7). In the HW group, participants consumed HW 4-5 times/day for eight weeks. At two to four weeks, all participants received non-surgical periodontal treatment. Oral examinations were performed at baseline, two, four and eight weeks, and serum was obtained at these time points to evaluate oxidative stress. At baseline, there were no significant differences in periodontal status between the control and HW groups. The HW group showed greater improvements in probing pocket depth and clinical attachment level than the control group at two, four and eight weeks (p < 0.05). The HW group also exhibited an increased serum level of total antioxidant capacity at four weeks, compared to baseline (p < 0.05). Drinking HW enhanced the effects of non-surgical periodontal treatment, thus improving periodontitis.


Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.
A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the "individual level association" between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the "trial level association" between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the "surrogate threshold effect" can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta-analyses in gastric cancer.


Designing and Undertaking a Health Economics Study of Digital Health Interventions.
This paper introduces and discusses key issues in the economic evaluation of digital health interventions. The purpose is to stimulate debate so that existing economic techniques may be refined or new methods developed. The paper does not seek to provide definitive guidance on appropriate methods of economic analysis for digital health interventions. This paper describes existing guides and analytic frameworks that have been suggested for the economic evaluation of healthcare interventions. Using selected examples of digital health interventions, it assesses how well existing guides and frameworks align to digital health interventions. It shows that digital health interventions may be best characterized as complex interventions in complex systems. Key features of complexity relate to intervention complexity, outcome complexity, and causal pathway complexity, with much of this driven by iterative intervention development over time and uncertainty regarding likely reach of the interventions among the relevant population. These characteristics imply that more-complex methods of economic evaluation are likely to be better able to capture fully the impact of the intervention on costs and benefits over the appropriate time horizon. This complexity includes wider measurement of costs and benefits, and a modeling framework that is able to capture dynamic interactions among the intervention, the population of interest, and the environment. The authors recommend that future research should develop and apply more-flexible modeling techniques to allow better prediction of the interdependency between interventions and important environmental influences.


Rhesus monkeys (Macaca mulatta) do recognize themselves in the mirror: implications for the evolution of self-recognition.
Self-recognition in front of a mirror is used as an indicator of self-awareness. Along with humans, some chimpanzees and orangutans have been shown to be self-aware using the mark test. Monkeys are conspicuously absent from this list because they fail the mark test and show persistent signs of social responses to mirrors despite prolonged exposure, which has been interpreted as evidence of a cognitive divide between hominoids and other species. In stark contrast with those reports, the rhesus monkeys in this study, who had been prepared for electrophysiological recordings with a head implant, showed consistent self-directed behaviors in front of the mirror and showed social responses that subsided quickly during the first experimental session. The self-directed behaviors, which were performed in front of the mirror and did not take place in its absence, included extensive observation of the implant and genital areas that cannot be observed directly without a mirror. We hypothesize that the head implant, a most salient mark, prompted the monkeys to overcome gaze aversion inhibition or lack of interest in order to look and examine themselves in front of the mirror. The results of this study demonstrate that rhesus monkeys do recognize themselves in the mirror and, therefore, have some form of self-awareness. Accordingly, instead of a cognitive divide, they support the notion of an evolutionary continuity of mental functions.


Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses.
Formyl-peptide receptor type 2 (FPR2), also called ALX (the lipoxin A4 receptor), conveys the proresolving properties of lipoxin A4 and annexin A1 (AnxA1) and the proinflammatory signals elicited by serum amyloid protein A and cathelicidins, among others. We tested here the hypothesis that ALX might exist as homo- or heterodimer with FPR1 or FPR3 (the two other family members) and operate in a ligand-biased fashion. Coimmunoprecipitation and bioluminescence resonance energy transfer assays with transfected HEK293 cells revealed constitutive dimerization of the receptors; significantly, AnxA1, but not serum amyloid protein A, could activate ALX homodimers. A p38/MAPK-activated protein kinase/heat shock protein 27 signaling signature was unveiled after AnxA1 application, leading to generation of IL-10, as measured in vitro (in primary monocytes) and in vivo (after i.p. injection in the mouse). The latter response was absent in mice lacking the ALX ortholog. Using a similar approach, ALX/FPR1 heterodimerization evoked using the panagonist peptide Ac2-26, identified a JNK-mediated proapoptotic path that was confirmed in primary neutrophils. These findings provide a molecular mechanism that accounts for the dual nature of ALX and indicate that agonist binding and dimerization state contribute to the conformational landscape of FPRs.


Circular permutation of a synthetic eukaryotic chromosome with the telomerator.
Chromosome engineering is a major focus in the fields of systems biology, genetics, synthetic biology, and the functional analysis of genomes. Here, we describe the "telomerator," a new synthetic biology device for use in Saccharomyces cerevisiae. The telomerator is designed to inducibly convert circular DNA molecules into mitotically stable, linear chromosomes replete with functional telomeres in vivo. The telomerator cassette encodes convergent yeast telomere seed sequences flanking the I-SceI homing endonuclease recognition site in the center of an intron artificially transplanted into the URA3 selectable/counterselectable auxotrophic marker. We show that inducible expression of the homing endonuclease efficiently generates linear molecules, identified by using a simple plate-based screening method. To showcase its functionality and utility, we use the telomerator to circularly permute a synthetic yeast chromosome originally constructed as a circular molecule, synIXR, to generate 51 linear variants. Many of the derived linear chromosomes confer unexpected phenotypic properties. This finding indicates that the telomerator offers a new way to study the effects of gene placement on chromosomes (i.e., telomere proximity). However, that the majority of synIXR linear derivatives support viability highlights inherent tolerance of S. cerevisiae to changes in gene order and overall chromosome structure. The telomerator serves as an important tool to construct artificial linear chromosomes in yeast; the concept can be extended to other eukaryotes.


Understanding the organisational culture of district health services: Mahalapye and Ngamiland health districts of Botswana.
Botswana has a shortage of health care workers, especially in primary healthcare. Retention and high performance of employees are closely linked to job satisfaction and motivation, which are both highest where employees' personal values and goals are realised. The aim of the study was to evaluate employees' personal values, and the current and desired organisational culture of the district health services as experienced by the primary health care workers. The study was conducted in the Ngamiland and Mahalapye health districts. This was a cross sectional survey. The participants were asked to select 10 values that best described their personal, current organisational and desired organisational values from a predetermined list. Sixty and 67 health care workers completed the survey in Mahalapye and Ngamiland districts, respectively. The top 10 prevalent organisational values experienced in both districts were: teamwork, patient satisfaction, blame, confusion, job insecurity, not sharing information and manipulation. When all the current values were assessed, 32% (Mahalapye) and 36% (Ngamiland) selected by health care workers were potentially limiting organisational effectiveness. The organisational values desired by health care workers in both districts were: transparency, professional growth, staff recognition, shared decision-making, accountability, productivity, leadership development and teamwork. The experience of the primary health care workers in the two health districts were overwhelmingly negative, which is likely to contribute to low levels of motivation, job satisfaction, productivity and high attrition rates. There is therefore urgent need for organisational transformation with a focus on staff experience and leadership development.


Development of a selective inhibitor for Kv1.1 channels prevalent in demyelinated nerves.
Members of the voltage-gated K+ channel subfamily (Kv1), involved in regulating transmission between neurons or to muscles, are associated with human diseases and, thus, putative targets for neurotherapeutics. This applies especially to those containing Kv1.1 α subunits which become prevalent in murine demyelinated axons and appear abnormally at inter-nodes, underlying the perturbed propagation of nerve signals. To overcome this dysfunction, akin to the consequential debilitation in multiple sclerosis (MS), small inhibitors were sought that are selective for the culpable hyper-polarising K+ currents. Herein, we report a new semi-podand - compound 3 - that was designed based on the modelling of its interactions with the extracellular pore region in a deduced Kv1.1 channel structure. After synthesis, purification, and structural characterisation, compound 3 was found to potently (IC50 = 8 µM) and selectively block Kv1.1 and 1.6 channels. The tested compound showed no apparent effect on native Nav and Cav channels expressed in F-11 cells. Compound 3 also extensively and selectively inhibited MS-related Kv1.1 homomer but not the brain native Kv1.1- or 1.6-containing channels. These collective findings highlight the therapeutic potential of compound 3 to block currents mediated by Kv1.1 channels enriched in demyelinated central neurons.


Dopamine-associated cached values are not sufficient as the basis for action selection.
Phasic dopamine transmission is posited to act as a critical teaching signal that updates the stored (or "cached") values assigned to reward-predictive stimuli and actions. It is widely hypothesized that these cached values determine the selection among multiple courses of action, a premise that has provided a foundation for contemporary theories of decision making. In the current work we used fast-scan cyclic voltammetry to probe dopamine-associated cached values from cue-evoked dopamine release in the nucleus accumbens of rats performing cost-benefit decision-making paradigms to evaluate critically the relationship between dopamine-associated cached values and preferences. By manipulating the amount of effort required to obtain rewards of different sizes, we were able to bias rats toward preferring an option yielding a high-value reward in some sessions and toward instead preferring an option yielding a low-value reward in others. Therefore, this approach permitted the investigation of dopamine-associated cached values in a context in which reward magnitude and subjective preference were dissociated. We observed greater cue-evoked mesolimbic dopamine release to options yielding the high-value reward even when rats preferred the option yielding the low-value reward. This result identifies a clear mismatch between the ordinal utility of the available options and the rank ordering of their cached values, thereby providing robust evidence that dopamine-associated cached values cannot be the sole determinant of choices in simple economic decision making.


SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance.
Many hormones/cytokines are secreted in response to exercise and cytokine signaling may play a pivotal role in the training adaptations. To investigate the importance of cytokine signaling during vertical ladder climbing, a resistance exercise model, we produced mice lacking SOCS3 protein exclusively in steroidogenic factor-1 (SF1) cells (SF1 Socs3 KO mice). SF1 expression is found in steroidogenic cells of the adrenal cortex and gonads, as well as in neurons of the ventromedial nucleus of the hypothalamus. Histological markers of the fetal adrenal zone (or X-zone in rodents) were still present in adult males and postpartum SF1 Socs3 KO females, suggesting a previously unrecognized effect of SOCS3 on the terminal differentiation of the adrenal gland. This change led to a distinct distribution of lipid droplets along the adrenal cortex. Under basal conditions, adult SF1 Socs3 KO mice exhibited similar adrenal weight, and plasma ACTH and corticosterone concentrations. Nonetheless, SF1 Socs3 KO mice exhibited a blunted ACTH-induced corticosterone secretion. The overall metabolic responses induced by resistance training remained unaffected in SF1 Socs3 KO mice, including changes in body adiposity, glucose tolerance and energy expenditure. However, training performance and glucose control during intense resistance exercise were impaired in SF1 Socs3 KO mice. Furthermore, a reduced counter-regulatory response to 2-deoxy-d-glucose was observed in mutant mice. These findings revealed a novel participation of SOCS3 regulating several endocrine and metabolic aspects. Therefore, cytokine signaling in SF1 cells exerts an important role to sustain training performance possibly by promoting the necessary metabolic adjustments during exercise.


Top-hat beam output of a single-mode microstructured optical fiber: impact of core index depression.
A new strategy to obtain a single-mode fiber with a flattened intensity profile distribution is presented. It is based on the use of an OVD-made high index ring deposited on a silica rod having a refractive index slightly lower than the silica used for the microstructured cladding. Using this strategy, we realized the first single-mode fiber with a quasi-perfect top-hat intensity profile around 1 µm. Numerical studies clearly demonstrate the advantage of using a core index depression to insure the single-mode operation of the fiber at the working wavelength.


Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.
Stem cells, which regenerate tissue by producing differentiating cells, also produce cells that renew the stem cell population. Signals from regulatory microenvironments (niches) are thought to cause stem cells to retain self-renewing potential. However, the molecular characterization of niches remains an important goal. In Drosophila testes, germ line and somatic stem cells attach to a cluster of support cells called the hub. The hub specifically expresses Unpaired, a ligand activating the JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling cascade. Without JAK-STAT signaling, germ line stem cells differentiate but do not self-renew. Conversely, ectopic JAK-STAT signaling greatly expands both stem cell populations. We conclude that the support cells of the hub signal to adjacent stem cells by activation of the JAK-STAT pathway, thereby defining a niche for stem cell self-renewal.


Molecular typing of pathogenic fungi.
In this Round Table, the application of several methods of molecular typing were discussed in reference to four important pathogenic fungi: Coccidioides immitis, Histoplasma capsulatum, Candida albicans and Paracoccidioides brasiliensis. Among the different methods the following were discussed: restriction fragment length polymorphisms (RFLP), single nucleotide polymorphisms, random amplified polymorphic DNA (RAPD), polymerase chain reaction (PCR)-RFLP and microsatellites. By means of these methods, several important biological questions related to speciation, mode of reproduction and population genetics could be approached. The basic information obtained from this approach has implications in the understanding of these pathogenic fungi in relation to their behavior and the development of pathogenic features, such as resistance to antimicrobials and virulence factors used for colonization of mammalian hosts. The knowledge obtained from these studies could also be used for the development of innovative diagnostic methods, as well as for novel therapeutic approaches and production of vaccines.


Comparison of Resolute zotarolimus-eluting and Xience everolimus-eluting stents in patients with de novo long coronary artery lesions: a randomized LONG-DES VI trial.
Outcomes for stent-based coronary intervention of lesions with long diseased segments remain relatively unfavorable. This study sought to compare the efficacy of Resolute zotarolimus-eluting stents (R-ZES) and Xience everolimus-eluting stents (EES) for very long coronary lesions. This randomized, multicenter, prospective trial compared the use of R-ZES with EES for very long (≥50 mm) native coronary lesions. The primary end point was in-segment late luminal loss at 12-month angiographic follow-up. A total of 400 patients were needed to assess the primary end point. However, owing to very slow enrollment of patients, this trial was early terminated (302 patients were enrolled), and thus, this report provides descriptive information on primary and secondary end points. The R-ZES and EES groups had similar baseline characteristics. Lesion length was 49.6±10.2 and 50.6±13.3 mm in the R-ZES and EES groups, respectively (P=0.47). The number of stents used at the target lesion was 2.1±0.3 and 2.2±0.5, respectively. Twelve-month angiographic follow-up was performed in 50% of eligible patients. In-segment late luminal loss did not significantly differ between the R-ZES and EES groups (0.17±0.57 vs. 0.09±0.43 mm, P=0.32). In-segment binary restenosis rates were 8.1 and 5.3% in the R-ZES and EES groups, respectively (P=0.49). There were no significant between-group differences in the rate of adverse events (death, myocardial infarction, stent thrombosis, target lesion revascularization, and composite outcomes). For patients with very long native coronary artery disease, R-ZES and EES implantation showed comparable angiographic and clinical outcomes through 1 year of follow-up.


Neurotrophic factors: important regulators of nociceptive function.
Neurotrophic factors have an established developmental role in regulating the survival and specification of sensory neurons. However, these factors continue to exert an important influence on sensory neurons throughout the postnatal period and into adult life. In adulthood, approximately one-half of nociceptors are dependent on nerve growth factor (NGF) for trophic support, whereas the other half are sensitive to glial cell line-derived neurotrophic factor (GDNF). It is now known that many chronic pain states are maintained by widespread changes in the anatomy, neurochemistry, and function of the sensory nervous system both at the level of the primary sensory neuron and the dorsal horn of the spinal cord. Trophic factors appear to orchestrate many of these dynamic changes. This review highlights some of the key roles played by these molecules and in particular the role of NGF in the peripheral sensitization of nociceptors and brain-derived neurotrophic factor (BDNF) as a central pain modulator.


Compartmentation of alpha-internexin and neurofilament triplet proteins in cultured hippocampal neurons.
Intermediate filaments comprise an integral part of the neuronal cytoskeleton. However, little is known about their function, and there remains some uncertainty about their precise subcellular localization. We examined the timing of expression and distribution of alpha-internexin, neurofilament triplet proteins and peripherin using immunocytochemistry in cultured hippocampal neurons. alpha-Internexin immunostaining was present in all neurons at all developmental stages. Immunostaining appeared as long filaments in axons and short fragments in dendrites which extended into dendritic spines. The presence of alpha-internexin in dendritic spines was confirmed in situ by electron microscopy of rat hippocampal tissue sections and suggests that this intermediate filament may serve as a link between cytoskeletal elements in dendritic shafts and spines. In culture, immunostaining using antibodies against individual triplet protein subunits indicated that light (NF-L) and middle (NF-M) subunits were first expressed in cells shortly after the initiation of axonal outgrowth. Expression of the heavy (NF-H) subunit occurred a few days later. Although timing and localization of expression did not correlate with the initiation of axonal or dendritic processes, it was coincident with periods of rapid outgrowth. Triplet proteins were more abundant in axons and appeared to be incorporated into lengthier filaments than in dendrites. Highly phosphorylated NFH/M immunoreactivity was polarized to axons after 6 days in culture. The distribution of one NF-H epitope was restricted to GABAergic neurons in mature cultures, suggesting a cell-type specific modification. Peripherin was not detectable at any time in hippocampal cultures. Our results show that intermediate filaments are integral components of the neuronal cytoskeleton of cultured hippocampal neurons throughout development. Furthermore, the localization of alpha-internexin suggests that it may be involved in the formation or maintenance of dendritic spines.


The anatomical basis for a novel classification of osteoarthritis and allied disorders.
Osteoarthritis (OA) has historically been classified as 'primary' where no discernible cause was evident and 'secondary' where a triggering factor was apparent. Irrespective of the triggering events, late-stage OA is usually characterized by articular cartilage attrition and consequently the anatomical basis for disease has been viewed in terms of cartilage. However, the widespread application of magnetic resonance imaging in early OA has confirmed several different anatomical abnormalities within diseased joints. A key observation has been that several types of primary or idiopathic OA show ligament-related pathology at the time of clinical presentation, so these categories of disease are no longer idiopathic - at least from the anatomical perspective. There is also ample evidence for OA initiation in other structures including menisci and bones in addition to articular cartilage. Therefore, a new classification for OA is proposed, which is based on the anatomical sites of earliest discernible joint structural involvement. The major proposed subgroups within this classification are ligament-, cartilage-, bone-, meniscal- and synovial-related, in addition to disease that is mixed pattern or multifocal in origin. We show how such a structural classification for OA provides a useful reference framework for staging the magnitude of disease. For late-stage or end-stage/whole organ disease, the final common pathway of these different scenarios, joint replacement strategies are likely to remain the only viable option. However, for younger subjects in particular, near the time of clinical disease onset, this scheme has implications for therapy targeted to specific anatomical locations. Thus, in the same way that tumours can be classified and staged according to their tissue of origin and extent of involvement, OA can likewise be anatomically classified and staged. This has implications for therapeutic strategies including regenerative medicine therapy development.


Psychological factors associated with recurrent vaginal candidiasis: a preliminary study.
To identify psychological factors associated with chronic recurrent vaginal candidiasis. A cross sectional exploratory study of women with chronic, recurrent vaginal candidiasis. 28 women found culture positive and treated for vaginal candidiasis by a clinic physician at least twice within the past 6 months. All women reported that they had experienced vaginal thrush six or more times within 1 year. A comparison group comprised 16 women with no history of recurrent vaginal candidiasis, of similar age range, and recruited from a women's family planning service. Both groups were compared on demographic criteria, sexual health histories, mental health, and psychological health characteristics. A purpose designed structured interview was administered alongside a battery of standardised psychometric instruments measuring mood, satisfaction with life, self esteem, and perceived stress. The two groups showed considerable similarities, with no significant differences in demographic characteristics and most sexual health issues. However, women with recurrent vaginal candidiasis were significantly more likely to suffer clinical depression, to be less satisfied with life, to have poorer self esteem, and to perceive their lives as more stressful. Additionally, women with recurrent vaginal candidiasis reported that their candidiasis seriously interfered with their sexual and emotional relationships. Overall, this study identified many areas of psychological morbidity associated with chronic vaginal candidiasis, and indicates that development of appropriate psychological treatment initiatives in this area is long overdue.


An Integrated Socio-Environmental Model of Health and Well-Being: a Conceptual Framework Exploring the Joint Contribution of Environmental and Social Exposures to Health and Disease Over the Life Span.
Environmental and social determinants of health often co-occur, particularly among socially disadvantaged populations, yet because they are usually studied separately, their joint effects on health are likely underestimated. Building on converging bodies of literature, we delineate a conceptual framework to address these issues. Previous models provided a foundation for study in this area, and generated research pointing to additional important issues. These include a stronger focus on biobehavioral pathways, both positive and adverse health outcomes, and intergenerational effects. To accommodate the expanded set of issues, we put forward the Integrated Socio-Environmental Model of Health and Well-Being (ISEM), which examines how social and environmental factors combine and potentially interact, via multi-factorial pathways, to affect health and well-being over the life span. We then provide applied examples including the study of how food environments affect dietary behavior. The ISEM provides a comprehensive, theoretically informed framework to guide future research on the joint contribution of social and environmental factors to health and well-being across the life span.


High nerve growth factor receptor (p75NTR) expression is a favourable prognostic factor in paediatric B cell precursor-acute lymphoblastic leukaemia.
Nerve growth factor (NGF) plays a pivotal role in cellular survival/death decisions with the low affinity receptor p75NTR predominately transmitting anti-proliferative signals. In spite of its established role in B-cell function and identification as a prognostically favourable marker in a number of malignancies, little is known about the expression pattern and prognostic significance of p75NTR in B cell precursor-acute lymphoblastic leukaemia (BCP-ALL). p75NTR expression was prospectively studied on primary ALL-blasts in a cohort of paediatric patients with common ALL (n = 86) and preB-ALL (n = 34) treated within the Co-operative study group for childhood acute lymphoblastic leukaemia (CoALL) protocol, CoALL06-97. Flow cytometric analysis showed that almost half of the patients expressed no or negligible amounts of p75NTR (<10%). The median expression in patients expressing p75NTR beyond that threshold was 49% (range 11-100%). In patients classified as low-risk at diagnosis, p75NTR expression was significantly higher than in high-risk patients (P = 0.001). Of note, p75NTR expression was lower in the 21 patients who subsequently developed relapse compared with those remaining in remission (P = 0.038). Accordingly, relapse-free survival was significantly better in patients expressing high surface p75NTR (P = 0.041). Thus, in this prospective analysis, high p75NTR expression was a strong prognostic marker that identified a group of paediatric ALL patients with favourable outcome.


Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. The British Heart Foundation and National Institute for Health Research.


The endocrine regulation of aging by insulin-like signals.
Reduced signaling of insulin-like peptides increases the life-span of nematodes, flies, and rodents. In the nematode and the fly, secondary hormones downstream of insulin-like signaling appear to regulate aging. In mammals, the order in which the hormones act is unresolved because insulin, insulin-like growth factor-1, growth hormone, and thyroid hormones are interdependent. In all species examined to date, endocrine manipulations can slow aging without concurrent costs in reproduction, but with inevitable increases in stress resistance. Despite the similarities among mammals and invertebrates in insulin-like peptides and their signal cascade, more research is needed to determine whether these signals control aging in the same way in all the species by the same mechanism.


Effect of antenatal betamethasone administration on neonatal cardiac autonomic balance.
Beneficial effects of antenatal glucocorticoid treatment in pregnancies at risk for preterm delivery may entail long-term consequences for the establishment of sympathoadrenergic system balance. We analyzed the cardiac autonomic system activity in neonates with a single course of antenatal betamethasone (2 × 12 mg) treatment by calculating heart rate variability (HRV) time-domain parameters from 24 h ECG recordings and short-term frequency-domain parameters during infant active and resting states. In addition, resting and challenged salivary α-amylase levels were measured in 23 betamethasone-exposed neonates and compared with controls. Indicators for overall HRV (SDNN: p = 0.258; triangular index: p = 0.179) and sympathovagal balance [low- to high-frequency power (LF/HF): p = 0.82 (resting state)] were not significantly different in neonates of the betamethasone treatment group. Parameters mostly influenced by sympathetic activity [SD of the average of valid NN intervals (SDANN): p = 0.184 and SDs of all NN intervals (SDNNi): p = 0.784] and vagal tone [RMSSD: p = 1.0; NN50: p = 0.852; HF: p = 0.785 (resting state)] were unaltered. Resting α-amylase levels were not significantly different in the betamethasone treatment group (p = 0.304); however, α-amylase release after a neonatal challenge was slightly reduced (p = 0.045). Thus, cardiac autonomic balance seems to be preserved in neonates exposed to a single course of antenatal betamethasone treatment.


Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity.
Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury.


Measuring the improving quality of outpatient care in medical oncology practices in the United States.
The American Society of Clinical Oncology Quality Oncology Practice Initiative (QOPI) has provided a method for measuring process-based practice quality since 2006. We sought to determine whether QOPI scores showed improvement in measured quality over time and, if change was demonstrated, which factors in either the measures or participants were associated with improvement. The analysis included 156 practice groups from a larger group of 308 that submitted data from 2006 to 2010. One hundred fifty-two otherwise eligible practices were excluded, most commonly for insufficient data submission. A linear regression model that controlled for varied initial performance was used to estimate the effect of participation over time and evaluate participant and measure characteristics of improvement. Participants completed a mean of 5.06 (standard deviation, 1.94) rounds of data collection. Adjusted mean quality scores improved from 0.71 (95% CI, 0.42 to 0.91) to 0.85 (95% CI, 0.60 to 0.95). Overall odds ratio of improvement over time was 1.09 (P < .001). The greatest improvement was seen in measures that assessed newly introduced clinical information, in which the mean scores improved from 0.05 (95% CI, 0.01 to 0.17) to 0.69 (95% CI, 0.33 to 0.91; P < .001). Many measures showed no change over time. Many US oncologists have participated in QOPI over the past 6 years. Participation over time was highly correlated with improvement in measured performance. Greater and faster improvement was seen in measures concerning newly introduced clinical information. Some measures showed no change despite opportunity for improvement.


Reconstitution of immune cell in liver and lymph node of adult- and newborn-engrafted humanized mice.
Humanized mouse models are an increasingly popular preclinical model to study the human immune response in a biological system. There are a variety of protocols to generate these mice, each differing in the strain of the recipient, source of hematopoietic stem cells, and mode of transplantation. Though there is well-documented reconstitution information regarding the spleen, blood, and bone marrow, there is little information regarding reconstitution of the lymph node and liver. In this report, we sought to compare reconstitution levels in a variety of immunological tissues, including the lymph node and liver, between mice engrafted intravenously as adults and intrahepatically in newborns. CD34+ cells were enriched from cord blood and transplanted intravenously into irradiated adult NOD-Rag1(-/-)IL2rγ(-/-) (NRG) mice or intra-hepatically into irradiated newborn NRG mice. At 9-28 weeks post-engraftment, immunological tissues were processed and analyzed for human lymphoid and myeloid subsets. Adult and newborn engrafted humanized mice were comparable in long-term reconstitution of human CD45 cells and subsequent lymphoid and myeloid subsets in the spleen, bone marrow, thymus, lymph node, and liver. Mice engrafted as newborns had a higher level of T-cells and a lower level of B-cells compared to mice engrafted as adults. We observed significant levels of human immune cell engraftment in both the lymph node and the liver, with a predominant adaptive immune population in both compartments. Human immune cells repopulate liver and mesenteric lymph nodes of NRG mice and can be used to study the human immune system in the gastrointestinal tract.


Controlling immune rejection is a fail-safe system against potential tumorigenicity after human iPSC-derived neural stem cell transplantation.
Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.


Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis.
Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies.


Evaluation of Polymorphic Locus Sequence Typing for Candida glabrata Epidemiology.
The opportunistic yeast Candida glabratais increasingly refractory to antifungal treatment or prophylaxis and relatedly is increasingly implicated in health care-associated infections. To elucidate the epidemiology of these infections, strain typing is required. Sequence-based typing provides multiple advantages over length-based methods, such as pulsed-field gel electrophoresis (PFGE); however, conventional multilocus sequence typing (targeting 6 conserved loci) and whole-genome sequencing are impractical for routine use. A commercial sequence-based typing service for C. glabratathat targets polymorphic tandem repeat-containing loci has recently been developed. These CgMT-J and CgMT-M services were evaluated with 56 epidemiologically unrelated isolates, 4 to 7 fluconazole-susceptible or fluconazole-resistant isolates from each of 5 center A patients, 5 matched pairs of fluconazole-susceptible/resistant isolates from center B patients, and 7 isolates from a center C patient who responded to then failed caspofungin therapy. CgMT-J and CgMT-M generated congruent results, resolving isolates into 24 and 20 alleles, respectively. Isolates from all but one of the center A patients shared the same otherwise rare alleles, suggesting nosocomial transmission. Unexpectedly, Pdr1 sequencing showed that resistance arose independently in each patient. Similarly, most isolates from center B also clustered together; however, this may reflect a dominant clone since their alleles were shared by multiple unrelated isolates. Although distinguishable by their echinocandin susceptibilities, all isolates from the center C patient shared alleles, in agreement with the previously reported relatedness of these isolates based on PFGE. Finally, we show how phylogenetic clusters can be used to provide surrogate parents to analyze the mutational basis for antifungal resistance.


A possible role of cIAP2 in Helicobacter pylori-associated gastric cancer.
Cellular inhibitor of apoptosis protein 2 (cIAP2) is a member of the IAP family and is over-expressed in most cancer tissues. In this study, we investigated the role cIAP2 in Helicobacter pylori (HP) related gastric carcinogenesis. We measured the expression of cIAP2 at mRNA and protein levels in a panel of gastric cancer cell lines and human gastric cancer tissues by semi-quantitative reverse transcriptase PCR (RT-PCR), quantitative real time PCR (qPCR), immunoblotting, and immunohistochemistry. The effects of cIAP2 down-regulation on gastric cell proliferation and apoptosis were detected by standard WST-1 assay and flow cytometry, respectively. Infection of gastric mucosa by HP enhances the expression of cIAP2 in mouse gastric tissues. Over 70% of human gastric cancer tissues express higher amount of cIAP2. Well-differentiated gastric cancer cells express more cIAP2 than moderately- and poorly-differentiated gastric cancer cells. Knocking down of cIAP2 in SGC-7901 cells results in a 30% decrease in cell proliferation, a 20% increase in apoptosis and delayed migration. Thus, cIAP2 may play an important role in HP-induced gastric carcinogenesis, and it may serve as a potential target for gastric cancer therapy.


Clinical analysis and follow-up study of chronic active Epstein-Barr virus infection in 53 pediatric cases.
Chronic active Epstein-Barr virus infection (CAEBV) has been previously reported to be sometimes associated with an aggressive clinical course. The characteristics of CAEBV in Mainland Chinese pediatric patients are largely unreported. The main aims of this survey were to recognize the clinical features of CAEBV in children and to explore its diagnostic criteria and risk factors. A retrospective study was performed on 53 pediatric patients (36 boys and 17 girls) with CAEBV who were admitted to Beijing Children's Hospital between 2003 and 2007. All their medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory data and outcome were collected. Independent-samples t test was used for statistical analysis. The age at onset of CAEBV was from 2 months to 14.6 years (mean (5.3+/-3.3) years). At the time of onset, 43.4% patients had an infectious mononucleosis-like symptom. Most patients exhibited intermittent fever (92.5%, 49/53), hepatomegaly (81.1%, 43/53) and splenomegaly (77.4%, 41/53). Life-threatening complications including hemophagocytic syndrome (24.5%, 13/53), interstitial pneumonia (24.5%, 13/53), hepatic failure (15.1%, 8/53) and malignant lymphoma (11.3%, 6/53) were also observed. The serum EBV DNA level in 23 patients with CAEBV was in the range of 5.05 x 10(2)-4.60 x 10(6) copies/ml with a mean value of 10(3.7) copies/ml. Many patients with CAEBV generally had continuous symptoms during the observational period. Eleven out of 42 patients (26.2%) died 7 months to 3 years after onset. Deceased patients were more likely to have had lower platelet counts and albumin levels than the living patients (P<0.05 for all comparisons). The study reveals that CAEBV in Chinese pediatric patients has a severe clinical course and prognosis is poor. Thrombocytopenia and decreases in albumin might potentially be risk factors for a poor prognosis. EBV loads should be measured and tissue should be stained on hybridization probes for EBV-encoded small RNA (EBER) if a patient presents with the known symptoms of CAEBV.


Comprehensive review of the prognostic value of galectin-3 in heart failure.
Heart failure (HF) is a major cause of morbidity and mortality in the United States; however, reliable biomarkers predicting outcomes of patients suffering from HF are still not available. Finding a prognostic indicator in patients with HF could ultimately help improve the quality of goal-directed care for these patients. A number of recent studies suggest that galectin-3, a peptide that has been repeatedly shown to be elevated in the setting of inflammatory processes, may provide information regarding the pathophysiologic process underlying HF. If this is the case, galectin-3 may independently be able to provide more information regarding prognosis in patients with HF than some of the more conventional indicators currently in use today (ie, natriuretic peptide, C-reactive protein). We analyzed the most recent and comprehensive studies that have looked at the utility of galectin-3 as a prognostic marker in patients with HF. After a thorough review, we found that the evidence against the use of galectin-3 as a prognostic biomarker in HF was too strong to support its routine use in current clinical settings. However, many of the studies, both in support of and in opposition to the prognostic potential of galectin-3, were uniformly limited by undersized cohorts, and thus the need for further exploration is clearly warranted.


A Web Based Tool to Enhance Monitoring and Retention in Care for Tuberculosis Affected Patients.
Tuberculosis (TB) is responsible for a global epidemic. TB treatment requires long-term therapy usually with multiple drugs, which have potential side effects and interactions that may influence patients' adherence to treatment. The TB Ge network is a multi-centric web based platform that collects clinical information of TB affected patients to increase their support and retention in care. The system stores the list of all tuberculosis episodes for each patient with the related data, starting from the first visit including follow-ups clinical evaluations, laboratory tests, imaging and therapies. Data can be manually input through the web interface or can be automatically imported from hospitals Laboratory Information Systems without human intervention. Automatic data import enhances data reuse and prevents errors introduction and time wasting. The network is an implementation of the Healthcare Services Specification Project (HSSP), as the Retrieve, Locate, and Update Service (RLUS) is used to manage patients' data. Clinical data are shared through standard HL7 Clinical Document Architecture (CDA) documents. Semantic interoperability is granted by the adoption of LOINC and ATC codes.


Age-related impairment of endothelial progenitor cell migration correlates with structural alterations of heparan sulfate proteoglycans.
Aging poses one of the largest risk factors for the development of cardiovascular disease. The increased propensity toward vascular pathology with advancing age maybe explained, in part, by a reduction in the ability of circulating endothelial progenitor cells to contribute to vascular repair and regeneration. Although there is evidence to suggest that colony forming unit-Hill cells and circulating angiogenic cells are subject to age-associated changes that impair their function, the impact of aging on human outgrowth endothelial cell (OEC) function has been less studied. We demonstrate that OECs isolated from cord blood or peripheral blood samples from young and old individuals exhibit different characteristics in terms of their migratory capacity. In addition, age-related structural changes were discovered in OEC heparan sulfate (HS), a glycocalyx component that is essential in many signalling pathways. An age-associated decline in the migratory response of OECs toward a gradient of VEGF significantly correlated with a reduction in the relative percentage of the trisulfated disaccharide, 2-O-sulfated-uronic acid, N, 6-O-sulfated-glucosamine (UA[2S]-GlcNS[6S]), within OEC cell surface HS polysaccharide chains. Furthermore, disruption of cell surface HS reduced the migratory response of peripheral blood-derived OECs isolated from young subjects to levels similar to that observed for OECs from older individuals. Together these findings suggest that aging is associated with alterations in the fine structure of HS on the cell surface of OECs. Such changes may modulate the migration, homing, and engraftment capacity of these repair cells, thereby contributing to the progression of endothelial dysfunction and age-related vascular pathologies.


Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study.
Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959-90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed, of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22-5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40-1.91). Mortality in these patients was significantly raised from diabetes and diseases of the cardiovascular, respiratory and digestive systems. There was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43-3.02)) and Y polysomy (RR = 1.90 (1.20-2.85)), the former with significantly increased mortality from cardiovascular disease and the latter from respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non-Hodgkin's lymphoma in men with more than three sex chromosomes.


Association of Incident, Clinically Undiagnosed Radiographic Vertebral Fractures With Follow-Up Back Pain Symptoms in Older Men: the Osteoporotic Fractures in Men (MrOS) Study.
Prior data in women suggest that incident clinically undiagnosed radiographic vertebral fractures (VFs) often are symptomatic, but misclassification of incident clinical VF may have biased these estimates. There are no comparable data in men. To evaluate the association of incident clinically undiagnosed radiographic VF with back pain symptoms and associated activity limitations, we used data from the Osteoporotic Fractures in Men (MrOS) Study, a prospective cohort study of community-dwelling men aged ≥65 years. A total of 4396 men completed spine X-rays and symptom questionnaires at baseline and visit 2, about 4.6 years later. Incident clinical VFs during this interval were defined by self-reported clinical diagnosis plus community imaging showing a centrally adjudicated ≥1 increase in semiquantitative (SQ) grade in any thoracic or lumbar vertebra versus baseline study X-rays. Incident radiographic VFs (≥1 increase in SQ grade between baseline and visit 2 study X-rays) were categorized as radiographic-only (not clinically diagnosed) or radiographic plus clinical (also clinically diagnosed). Multivariable-adjusted log binomial regression was used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs). Men with incident radiographic plus clinical VF were most likely to have back pain symptoms and associated activity limitation at follow-up. However, versus men without incident VF, those with incident radiographic-only VF also were significantly more likely at follow-up to report any back pain (70% versus 59%; PR, 1.2 [95% CI, 1.1 to 1.3]), severe back pain (8% versus 4%; PR, 1.9 [95% CI, 1.1 to 3.3]), bother from back pain most/all the time (22% versus 13%; PR, 1.7 [95% CI, 1.3 to 2.2]), and limited usual activity from back pain (34% versus 18%; PR, 1.9 [95% CI, 1.5 to 2.4]). Clinically undiagnosed, incident radiographic VFs were associated with an increased likelihood of back pain symptoms and associated activity limitation. Results suggest incident radiographic-only VFs often were symptomatic, and were associated with both new and worsening back pain. Preventing these fractures may reduce back pain and related disability in older men. © 2017 American Society for Bone and Mineral Research.


LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism.
Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V1a and V2 vasopressin receptor subtypes (V1a-R and V2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure-affinity and structure-efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.


Presence and characterization of prostaglandin D2-related molecules in nasal mucosa of patients with allergic rhinitis.
Prostaglandin D2 (PGD2) is the major prostanoid produced in the acute phase of allergic reactions. However, its pathophysiological role in addition to the pathway of production in allergic rhinitis remains unclear. We sought to determine the expression of synthases and receptors for PGD2 in human nasal mucosa. These expressions were compared between allergic and nonallergic patients. The expression and localization of hematopoietic-type (h)-PGD2 synthase (PGDS) and lipocalin-type (l)-PGDS were detected by immunohistochemistry. The expression of D prostanoid (DP) receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) was determined by quantitative real-time PCR. The h-PGDS but not l-PGDS was clearly expressed in nasal mucosa. The expression of h-PGDS in allergic patients was significantly higher than in control patients without mucosal hypertrophy. A variety of infiltrating cells including mast cells, eosinophils, macrophages, and lymphocytes as well as constitutive cells such as epithelial cells and fibroblasts expressed h-PGDS. The expression of both DP and CRTH2 was confirmed also. Although either the amount of DP or the amount of CRTH2 was not correlated with serum levels of IgE, the amount of CRTH2 but not DP was highly and significantly correlated with the number of eosinophils infiltrating into nasal musosa. These results suggest that PGD2 is released via the action of h-PGDS from various cells, and the expression of h-PGDS may be associated with the hypertrophic inflammation in the nose. In addition, ligation of PGD2 to CRTH2 appears to be selectively involved in eosinophil recruitment into the nose regardless of atopic status.


Effects of vitamins C and E on oxidative stress markers and endothelial function in patients with systemic lupus erythematosus: a double blind, placebo controlled pilot study.
Patients with systemic lupus erythematosus (SLE) experience excess morbidity and mortality due to coronary artery disease (CAD) that cannot be fully explained by the classical CAD risk factors. Among emerging CAD risk factors, oxidative stress is currently being emphasized. We evaluated the effects of longterm antioxidant vitamins on markers of oxidative stress and antioxidant defense and endothelial function in 39 patients with SLE. Patients were randomized to receive either placebo or vitamins (500 mg vitamin C and 800 IU vitamin E daily) for 12 weeks. Markers of oxidative stress included malondialdehyde (MDA) and allantoin. Antioxidants measured included erythrocyte superoxide dismutase and glutathione peroxidase, plasma total antioxidant power (as FRAP value), and ascorbic acid and vitamin E concentrations. Endothelial function was assessed by flow-mediated dilatation (FMD) of the brachial artery and plasma concentration of von Willebrand factor (vWF) and plasminogen activator inhibitor type 1 (PAI-1). Primary outcome of the study included the change in lipid peroxidation as revealed by MDA levels. Secondary outcomes included changes in allantoin and antioxidant levels and change in endothelial function. After treatment, plasma ascorbic acid and alpha-tocopherol concentrations were significantly (p < 0.05) increased only in the vitamin-treated group, associated with a significant decrease (p < 0.05) in plasma MDA. Other oxidative stress markers and antioxidant levels remained unchanged in both groups. FMD and vWF and PAI-1 levels remained unchanged in both groups. Combined administration of vitamins C and E was associated with decreased lipid peroxidation, but did not affect endothelial function in patients with SLE after 3 months of therapy.


Robust and Elastic Lunar and Martian Structures from 3D-Printed Regolith Inks.
Here, we present a comprehensive approach for creating robust, elastic, designer Lunar and Martian regolith simulant (LRS and MRS, respectively) architectures using ambient condition, extrusion-based 3D-printing of regolith simulant inks. The LRS and MRS powders are characterized by distinct, highly inhomogeneous morphologies and sizes, where LRS powder particles are highly irregular and jagged and MRS powder particles are rough, but primarily rounded. The inks are synthesized via simple mixing of evaporant, surfactant, and plasticizer solvents, polylactic-co-glycolic acid (30% by solids volume), and regolith simulant powders (70% by solids volume). Both LRS and MRS inks exhibit similar rheological and 3D-printing characteristics, and can be 3D-printed at linear deposition rates of 1-150 mm/s using 300 μm to 1.4 cm-diameter nozzles. The resulting LRS and MRS 3D-printed materials exhibit similar, but distinct internal and external microstructures and material porosity (~20-40%). These microstructures contribute to the rubber-like quasi-static and cyclic mechanical properties of both materials, with young's moduli ranging from 1.8 to 13.2 MPa and extension to failure exceeding 250% over a range of strain rates (10-1-102 min-1). Finally, we discuss the potential for LRS and MRS ink components to be reclaimed and recycled, as well as be synthesized in resource-limited, extraterrestrial environments.