Cerebral MRI findings and cognitive functioning: the Atherosclerosis Risk in Communities study.
To examine the association between prevalent cerebral abnormalities identified on MRI and cognitive functioning in a predominantly middle-aged, population-based study cohort. Cerebral MRI was performed on 1,538 individuals (aged 55 to 72) from the Atherosclerosis Risk in Communities (ARIC) cohort, with no history of stroke or TIA, at study sites in Forsyth County, NC, and Jackson, MS. White matter hyperintensities (WMHs), ventricular size, and sulcal size were graded by trained neuroradiologists on a semiquantitative, 10-point scale. Cognitive functioning was assessed using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). High ventricular grade was independently associated with significantly lower scores on the DWRT and DSST and greater risk (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.51 to 3.56) of impaired scores (i.e., < or =10th percentile) on the DWRT. High sulcal grade was associated with a modest decrement in scores on the DWRT. The presence of coexisting high grade WMHs and silent infarcts was independently associated with lower scores on all cognitive tests and greater risk of impaired functioning on the DSST (OR 2.91, 95% CI: 1.23 to 6.89) and WFT (OR 2.28, 95% CI 1.03 to 5.08). The presence of two or more high-grade abnormalities was associated with increased risk of impaired functioning on all cognitive tests (DWRT: OR 2.23, 95% CI 1.40 to 3.55; DSST: OR 2.06, 95% CI 1.13 to 3.76; WFT: OR 2.07, 95% CI 1.23 to 3.49) independent of multiple covariates and silent infarcts. Common changes in brain morphology are associated with diminished cognitive functioning in middle-aged and young-elderly individuals.


Protein-based profiling of the immune response to uropathogenic Escherichia coli in adult patients immediately following hospital admission for acute cystitis.
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are common infections in humans. Despite the substantial healthcare cost represented by these infections, the human immune response associated with the infection immediately following the onset of symptoms in patients remains largely undefined. We performed a prospective study aimed at defining the milieu of urinary cytokines in adult inpatients in the 24-48 h period immediately following hospital admission for acute cystitis due to UPEC. Urine samples, analyzed using 27-target multiplex protein assays, were used to generate immune profiles for patients and compared to age- and gender-matched healthy controls. The levels of multiple pro-inflammatory cytokines were significantly elevated in urine as a result of infection, an observation consistent with prior findings in murine models and clinical literature. We also identified significant responses for several novel factors not previously associated with the human response to UTI, including Interleukin (IL)-4, IL-7, IL-9, IL-17A, eotaxin, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and several growth factors. These data establish crucial parallels between the human immune response to UPEC and murine model UTI studies, and emphasize the complex but poorly defined nature of the human immune response to UPEC, particularly in the immediate period following the onset of symptoms for acute cystitis.


Immunological study of Melkersson-Rosenthal syndrome. Lack of response to food additive challenge.
A study was made of six patients with Melkersson-Rosenthal syndrome (MRS) to establish the aetiological role of foodstuffs and/or additives and the possible associated immunological alterations. In all cases Melkersson-Rosenthal syndrome (MRS) was diagnosed both clinically and histologically, excluding other causes of orofacial granulomatosis (OFG). A detailed study of possible triggering factors was performed in all patients. Blood analysis, x-rays and cultures, were always within normal limits, with the exception of the finding of circulating immune complexes (CICs) in three patients with facial palsy associated, and C-reactive protein positivity in two patients who presented persistent labial oedema. All patients were subjected to skin-prick tests with common inhalant allergens and with foods when sensitization to foods were suspected, and patch tests with European Standard Series and pastry components, organic dyes, perfumes and fragrances series. The results were negative in all cases. When asymptomatic, the patients were subjected to a double-blind oral challenge, under placebo control, with additives (monosodium glutamate, tartrazine, sulfites, erythrosine, paraoxybenzoate, sodium benzoate, lactose, aspirin, and annate), which was again negative. In no case did the patients refer the appearance of outbreaks with exposure to foods or contactants, and the course of the disease was unaffected by exclusion diets and the elimination of contactants. To conclude, we observed no sensitization to foods, additives or contactants in our patients. Likewise, there were no antecedents of atopy or hereditary predisposition related to the aetiopathogeny of MRS. The significance of the CIC encountered only in patients with facial paralysis remains to be established, due to the limited number of patients studied.


Human RECQL5 overcomes thymidine-induced replication stress.
Accurate DNA replication is essential to genome integrity and is controlled by five human RecQ helicases, of which at least three prevent cancer and ageing. Here, we have studied the role of RECQL5, which is the least characterised of the five human RecQ helicases. We demonstrate that overexpressed RECQL5 promotes survival during thymidine-induced slowing of replication forks in human cells. The RECQL5 protein relocates specifically to stalled replication forks and suppresses thymidine-induced RPA foci, CHK1 signalling, homologous recombination and gammaH2AX activation. It is unlikely that RECQL5 promotes survival through translesion synthesis as PCNA ubiquitylation is also reduced. Interestingly, we also found that overexpressing RECQL5 relieves cells of the cell cycle arrest normally imposed by thymidine, but without causing mutations. In conclusion, we propose that RECQL5 stabilises the replication fork allowing replication to overcome the effects of thymidine and complete the cell cycle.


Using evidence to change antimalarial drug policy in Kenya.
Chloroquine resistance was first detected in Kenya in 1978 and escalated during the 1980s. Chloroquine remained the treatment of choice for uncomplicated malaria infections until revised guidelines were launched in 1998 despite a plethora of scientific evidence on failure. This review analyses the range and quality of the evidence base that was used to change the drug policy in Kenya from chloroquine to SP and examines the process of consensus building and decision making. Our review illustrates the difficulties in translating sensitivity data with gross geographical, temporal and methodological variations into national treatment policy. The process was complicated by limited options, unknown adverse effects of replacement therapies, cost, as well as limited guidance on factors pertinent to changing the drug policy for malaria. Although > 50% of the studies showed parasitological failures by 1995, there was a general lack of consensus on the principles for assessing drug failures, the inclusion criteria for the study subjects and the relative benefits of parasitological and clinical assessments. A change in international recommendations for assessment of drug efficacy in 1996 from parasitological to clinical response further perplexed the decisions. There is an urgent need for international standards and evidence-based guidelines to provide a framework to assist the process by which decision-makers in malaria-endemic countries can make rational choices for antimalarial drug policy change.


Donor reactive regulatory T cells.
Donor reactive regulatory T cells (Treg) play an important role in tolerance induction and maintenance in experimental transplant models. In this review we focus on the formation of the donor reactive Treg pool and explore the potential of these cells for therapeutic application in clinical transplantation. Donor reactive Treg can arise by both conversion of alloreactive nonregulatory cells and expansion of naturally occurring Treg (nTreg) cross-reactive with donor alloantigen but the quantitative contribution of each of these pathways is at present unclear. However, the fact that donor reactive Treg can be driven both in vivo and ex vivo by alloantigen challenge of nonregulatory precursors is encouraging as it demonstrates that the functional potential of these cells for use in clinical transplantation will not be limited by fortuitous cross-reactivity between nTreg and donor alloantigens. Treg can be generated in vivo by transplantation or alloantigen challenge in combination with Treg-permissive immunosuppression, or ex vivo by phenotypic selection or by polyclonal or antigen-specific stimulation. A number of ex-vivo protocols exist for the enrichment of Treg in the laboratory and in many cases these cells have demonstrable function both in vitro and in relevant graft-versus-host disease (GVHD) or organ transplant models. The challenge now is to understand the clinical opportunities and limitations that these populations present. Combined with appropriate immunosuppression, Treg generated/expanded in vivo or ex vivo may hold the final key to operational tolerance in clinical setting.


Incorporating simulation into gynecologic surgical training.
Today's educational environment has made it more difficult to rely on the Halstedian model of "see one, do one, teach one" in gynecologic surgical training. There is decreased surgical volume, but an increased number of surgical modalities. Fortunately, surgical simulation has evolved to fill the educational void. Whether it is through skill generalization or skill transfer, surgical simulation has shifted learning from the operating room back to the classroom. This article explores the principles of surgical education and ways to introduce simulation as an adjunct to residency training. We review high- and low-fidelity surgical simulators, discuss the progression of surgical skills, and provide options for skills competency assessment. Time and money are major hurdles when designing a simulation curriculum, but low-fidelity models, intradepartmental cost sharing, and utilizing local experts for simulation proctoring can aid in developing a simulation program.


SNPs at SMG7 Associated with Time from Biochemical Recurrence to Prostate Cancer Death.
A previous genome-wide association study identified several loci with genetic variants associated with prostate cancer survival time in two cohorts from Sweden. Whether these variants have an effect in other populations or if their effect is homogenous across the course of disease is unknown. These variants were genotyped in a cohort of 1,298 patients. Samples were linked with age, PSA level, Gleason score, cancer stage at surgery, and times from surgery to biochemical recurrence to death from prostate cancer. SNPs rs2702185 and rs73055188 were tested for association with prostate cancer-specific survival time using a multivariate Cox proportional hazard model. SNP rs2702185 was further tested for association with time to biochemical recurrence and time from biochemical recurrence to death with a multi-state model. SNP rs2702185 at SMG7 was associated with prostate cancer-specific survival time, specifically the time from biochemical recurrence to prostate cancer death (HR, 2.5; 95% confidence interval, 1.4-4.5; P = 0.0014). Nine variants were in linkage disequilibrium (LD) with rs2702185; one, rs10737246, was found to be most likely to be functional based on LD patterns and overlap with open chromatin. Patterns of open chromatin and correlation with gene expression suggest that this SNP may affect expression of SMG7 in T cells. The SNP rs2702185 at the SMG7 locus is associated with time from biochemical recurrence to prostate cancer death, and its LD partner rs10737246 is predicted to be functional. These results suggest that future association studies of prostate cancer survival should consider various intervals over the course of disease.


Paradigmatic obstacles to improving the health of populations--implications for health policy.
While there are promising developments in public health, most interventions (both at the individual and community levels) remain focused on "downstream" tertiary treatments or one-on-one interventions. These efforts have their origins in the biomedical paradigm and risk factor epidemiology and the behavioral science research methods that serve as their handmaidens. This paper argues for a more appropriate balance of "downstream" efforts with a more appropriate whole population public health approach to health policy--what may be termed a social policy approach to healthy lifestyles rather than the current lifestyle approach to health policy. New, more appropriate research methods must be developed and applied to match these emerging levels of whole population intervention. We must avoid any disjunction between new upstream policy level interventions and the methods used to measure their effect--appropriate unto the intervention level must be the evaluation method thereof.


Fabrication of optical waveguides by imprinting: usage of positive tone resist as a mould for UV-curable polymer.
Optical ridge type waveguides based on UV-curable polymer were fabricated by imprinting method. Positive tone resist patterned on a silicon wafer was used as a mould. The characterization of waveguides was carried out by coupling TE-polarized light from a tapered fiber into a waveguide with 30 mm length and mapping the intensity distribution with another tapered fiber at the output facet of a waveguide. Proper single- or multimode operation was observed depending on the waveguide width being either 2 microm or 6 microm. Experimental observations on the mode profiles were also supported by the simulation results. Average power transmissions of 32% at 1530 nm wavelength and 45% at 1310 nm wavelength were characterized. The results suggest that the simple mould fabrication process might be a useful technique for device prototyping and that the performance of replicated waveguides can meet the requirements for certain applications.


Single-Center Experience With the Senning Procedure in the Current Era.
The Senning procedure is an operative technique for atrial inversion in congenital heart anomalies. We sought to evaluate our contemporary outcomes employing this technique. A retrospective analysis of all patients who underwent the Senning procedure at our institution was performed. Hospital records were reviewed, and follow-up data were obtained to evaluate outcomes. Overall, a total of 19 patients underwent a Senning procedure between August 2005 and July 2014. Median age at repair was 594 days (range: 5 days to 15 years). Of those, 7 patients underwent a combined Senning-Rastelli operation and 10 patients underwent a double switch operation (arterial switch or atrial switch). Primary diagnosis was congenitally corrected transposition of the great arteries (cc-TGA) in 17 patients. Associated lesions included ventricular septal defect (n = 10), pulmonary stenosis or atresia (n = 7), and Ebstein׳s anomaly of the tricuspid valve (n = 4). There was an operative death (5%). In all, 2 patients required superior vena cava baffle revision in the operating room. No new pulmonary venous or systemic venous baffle obstruction was observed during follow-up. A total of 5 (26%) patients developed heart block requiring pacemaker implantation. Actuarial survival was 81% at 5 years with a median follow-up of 38 months. The 2 patients in the cc-TGA group were subsequently transplanted. Surviving patients (n = 15) are all well at the last clinical follow-up, most with normal biventricular function. In conclusion, the Senning procedure offers excellent outcomes with regard to systemic and pulmonary venous baffle patency. Results in patients with cc-TGA, however, are affected by significant early mortality after Senning-Rastelli and incidence of left ventricular dysfunction after double switch; which should be considered during patient selection and surgical planning.


The 2011 survey on hypertensive disorders of pregnancy (HDP) in China: prevalence, risk factors, complications, pregnancy and perinatal outcomes.
Hypertensive disorders of pregnancy (HDP) are a group of medical complications in pregnancy and also a risk factor for severe pregnancy outcomes, but it lacks a large-scale epidemiological investigation in recent years. This survey represents a multicenter cross-sectional retrospective study to estimate the prevalence and analyze the risk factors for HDP among the pregnant women who had referred for delivery between January 1st 2011 and December 31st 2011 in China Mainland. A total of 112,386 pregnant women were investigated from 38 secondary and tertiary specialized or general hospitals randomly selected across the country, of which 5,869 had HDP, accounting for 5.22% of all pregnancies. There were significant differences in the prevalence of HDP between geographical regions, in which the North China showed the highest (7.44%) and Central China showed the lowest (1.23%). Of six subtypes of HDP, severe preeclampsia accounted for 39.96%, gestational hypertension for 31.40%, mild preeclampsia for 15.13%, chronic hypertension in pregnancy for 6.00%, preeclampsia superimposed on chronic hypertension for 3.68% and eclampsia for 0.89%. A number of risk factors for HDP were identified, including twin pregnancy, age of >35 years, overweight and obesity, primipara, history of hypertension as well as family history of hypertension and diabetes. The prevalence of pre-term birth, placental abruption and postpartum hemorrhage were significantly higher in women with HDP than those without HDP. The possible risk factors confirmed in this study may be useful for the development of early diagnosis and appropriate treatment of HDP.


In-depth analysis of the secretome identifies three major independent secretory pathways in differentiating human myoblasts.
Efficient muscle regeneration requires cross talk between multiple cell types via secreted signaling molecules. However, as yet there has been no comprehensive analysis of this secreted signaling network in order to understand how it regulates myogenesis in humans. Using integrated proteomic and genomic strategies, we show that human muscle cells release not only soluble secreted proteins through conventional secretory mechanisms but also complex protein and nucleic acid cargos via membrane microvesicle shedding. The soluble secretome of muscle cells contains 253 conventionally secreted signaling proteins, including 43 previously implicated in myogenesis, while others are known to modulate various cell types thus implying a much broader role for myoblasts in muscle remodeling. We also isolated and characterized two types of secreted membrane-derived vesicles: nanovesicles harboring typical exosomal features and larger, morphologically distinct, microvesicles. While they share some common features, their distinct protein and RNA cargos suggest independent functions in myogenesis. We further demonstrate that both types of microvesicles can dock and fuse with adjacent muscle cells but also deliver functional protein cargo. Thus, the intercellular signaling networks invoked during muscle differentiation and regeneration may employ conventional soluble signaling molecules acting in concert with muscle derived microvesicles delivering their cargos directly into target cells.


Growth-phase-dependent mobility of the lvh-encoding region in Legionella pneumophila strain Paris.
The lvh region of the Legionella pneumophila genome, which encodes a type IV secretion system, is located on a plasmid-like element in strains Paris (pP36) and Philadelphia (pLP45). The pP36 element has been described either integrated in the chromosome or excised as a multi-copy plasmid, in a similar manner to pLP45. In this paper, the chromosomal integration of pP36 in the Paris strain genome was described, occurring through site-specific recombination at the 3' end of a transfer-messenger RNA gene by recombination between attachment sites, in a similar manner to pathogenicity islands. This integration was growth-phase dependent, occurring during the exponential phase. Several pP36-borne genes were expressed during the lag phase of bacterial growth, coinciding with the peak amount of the episomal form of pP36. Expression of the same genes decreased during the exponential and stationary phases, owing to the integration phenomenon and a loss of episomal copies of pP36. A similar plasmid-like element was described in the Lens strain genome, suggesting that the mobility of the lvh region is a phenomenon widespread among Legionella sp.


An interdisciplinary memory clinic: a novel practice setting for pharmacists in primary care.
Pharmacists have developed innovative practices in various settings as singular providers or as members of multidisciplinary or interdisciplinary teams. Examples include pharmacists practicing in heart failure, hypertension, or hyperlipidemia clinics. There is a paucity of literature describing pharmacists in interdisciplinary memory clinics and specifically pharmacists practicing in interdisciplinary, primary care-based memory clinics. New practice models should be disseminated to guide others in the development of similar models given the complexity of this population. Patients with dementia are more difficult to manage because of cognitive impairment, behavioral and psychological symptoms, the common presence of multiple comorbidities, and related polypharmacy and caregiver issues. These challenges require expertise in neurodegenerative disorders and geriatrics. The purpose of this article is to describe the role of clinical pharmacists providing care to patients with cognitive complaints in a primary care-based, interdisciplinary memory clinic, with a focus on how the pharmacist practices and is integrated in this collaborative care setting. Patients are assessed using an interdisciplinary approach, with team consensus for assessment and planning of care. Pharmacists' activities include assessment of (1) appropriateness of medications based on frailty, (2) medications that can impair cognition and/or function, (3) medication adherence and management skills, and (4) vascular risk factor control. Pharmacists provide education regarding medications and diseases, ensure appropriate transitions in care, and conduct home visits. Pharmacist participation in this clinic represents a novel opportunity to advance pharmacy practice in primary care, interdisciplinary models. Work is ongoing to describe outcomes attributable to pharmacist participation in this clinic.


Making sense of qualitative data analysis: an introduction with illustrations from DIPEx (personal experiences of health and illness).
This paper outlines an approach to analysing qualitative textual data from interviews and discusses how to ensure analytic procedures are appropriately rigorous. Qualitative data analysis should begin at an early stage in data collection and be highly systematic. It is important to identify issues that emerge during the data collection and analysis as well as those that the researcher may have anticipated (from reading or experience). Analysis is very time-consuming, but careful sampling, the collection of rich material and analytic depth mean that a relatively small number of cases can generate insights that apply well beyond the confines of the study. One particular approach to thematic analysis is introduced with examples from the DIPEx (personal experiences of health and illness) project, which collects video- and audio-taped interviews that are freely accessible through http://www.dipex.org. Qualitative analysis of patients' perspectives of illness can illuminate numerous issues that are important for medical education, some of which are unlikely to arise in the clinical encounter. Qualitative studies can also cover a much broader range of experiences - of both common and rare disease - than clinicians will see in practice. The DIPEx website is based on qualitative analysis of collections of interviews, illustrated with hundreds of video and audio clips, and is an innovative resource for medical education.


Emerging strategies for exploiting cannabinoid receptor agonists as medicines.
Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.


TRPV4 in porcine lens epithelium regulates hemichannel-mediated ATP release and Na-K-ATPase activity.
In several tissues, transient receptor potential vanilloid 4 (TRPV4) channels are involved in the response to hyposmotic challenge. Here we report TRPV4 protein in porcine lens epithelium and show that TRPV4 activation is an important step in the response of the lens to hyposmotic stress. Hyposmotic solution (200 mosM) elicited ATP release from intact lenses and TRPV4 antagonists HC 067047 and RN 1734 prevented the release. In isosmotic solution, the TRPV4 agonist GSK1016790A (GSK) elicited ATP release. When propidium iodide (PI) (MW 668) was present in the bathing medium, GSK and hyposmotic solution both increased PI entry into the epithelium of intact lenses. Increased PI uptake and ATP release in response to GSK and hyposmotic solution were abolished by a mixture of agents that block connexin and pannexin hemichannels, 18α-glycyrrhetinic acid and probenecid. Increased Na-K-ATPase activity occurred in the epithelium of lenses exposed to GSK and 18α-glycyrrhetinic acid + probenecid prevented the response. Hyposmotic solution caused activation of Src family kinase and increased Na-K-ATPase activity in the lens epithelium and TRPV4 antagonists prevented the response. Ionomycin, which is known to increase cytoplasmic calcium, elicited ATP release, the magnitude of which was no greater when lenses were exposed simultaneously to ionomycin and hyposmotic solution. Ionomycin-induced ATP release was significantly reduced in calcium-free medium. TRPV4-mediated calcium entry was examined in Fura-2-loaded cultured lens epithelium. Hyposmotic solution and GSK both increased cytoplasmic calcium that was prevented by TRPV4 antagonists. The cytoplasmic calcium rise in response to hyposmotic solution or GSK was abolished when calcium was removed from the bathing solution. The findings are consistent with hyposmotic shock-induced TRPV4 channel activation which triggers hemichannel-mediated ATP release. The results point to TRPV4-mediated calcium entry that causes a cytoplasmic calcium increase which is an essential early step in the mechanism used by the lens to sense and respond to hyposmotic stress.


Gd(III)-EPTPAC16, a new self-assembling potential liver MRI contrast agent: in vitro characterization and in vivo animal imaging studies.
The recently reported amphiphilic chelate, [Gd(EPTPAC16)(H2O)]2-, forms supramolecular aggregates in aqueous solution by self-assembly of the monomers with a relaxometrically determined critical micellar concentration (CMC) of 0.34 mM. The effect of sonication on the aggregate size was characterized by dynamic light scattering and relaxometry, indicating the presence of premicellar aggregates and an overall decrease in aggregate size and polydispersity upon sonication, slightly below the CMC. [[153Sm](EPTPAC16)(H2O)]2- radiotracer was evaluated in vivo from gamma scintigraphy and biodistribution in Wistar rats. It was found to depend strongly on the sample concentration, below or above the CMC, and its sonication, in a way that correlates with the effect of the same factors on the size of the aggregates formed in solution. Below CMC, the very large aggregates of the [153Sm]3+ -labeled chelate were persistently and mainly taken up by the lungs, and also by the macrophage-rich liver and spleen. Sonication of this solution led to loss of the lung uptake. Above CMC, the metal chelate was mainly taken up by the liver, with very little uptake by the spleen and lungs. In vivo, dynamic contrast-enhanced (DCE)-MRI evaluation of the micellar [Gd(EPTPAC16)(H2O)]2- compound in Wistar rats showed a persistent hepatic positive-contrast effect in T1-weighted images, qualitatively similar to the clinically established Gd(III)-based hepatobiliary-selective agents. No enhancement effect was observed in the lungs because of the scarcity of mobile protons in this organ, despite the scintigraphic evidence of significant lung retention of the [153Sm]3+ -labeled chelate at concentrations below the CMC.


Comparative In Vitro Dissolution of Two Commercially Available Er-Zhi-Wan Herbal Medicinal Products.
In vitro dissolution test is an essential tool to assess the quality of herbal medicinal products in the solid dosage forms for oral use. Our work aimed to evaluate the dissolution behavior of Er-Zhi-Wan, in the formulations of water-honeyed pill and formula granule. Different media (water, 30% EtOH, 0.1 M HCl, acetate buffer, pH 4.5 and phosphate buffer, pH 6.8) were used following United States Pharmacopoeia and Chinese Pharmacopeia. An ultra-high performance liquid chromatography method was developed and validated to detect simultaneously six active ingredients for quantification and dissolution study (salidroside, specnuezhenide, nuezhenoside, luteolin, apigenin, oleanolic acid). As we observed, contents of main active ingredients were close in the two formulations for daily dose. In each medium, more ingredients dissolved from formula granule with higher Ymax and Ka. The mean dissolution time of the most ingredients in granule was significantly shorter than that in pill in acetate buffer, pH 4.5 and phosphate buffer, pH 6.8. Furthermore, salidroside, specnuezhenide and luteolin dissolved more than 80% in 30 min from formula granule, which indicated higher solubility along the intestinal tract according to biopharmaceutics classification system. The dissolution test developed and validated was adequate for its purposes and could be applied for quality control of herbal medicine. This work also can be used to provide necessary information on absorption for its biopharmaceutical properties.


Covalent binding studies on the 14C-labeled antitumor compound 2,5-bis(1-aziridinyl)-1,4-benzoquinone. Involvement of semiquinone radical in binding to DNA, and binding to proteins and bacterial macromolecules in situ.
2,5-Bis(1-aziridinyl)-1,4-benzoquinone (BABQ) is a compound from which several antitumour drugs are derived, such as Trenimone, Carboquone and Diaziquone (AZQ). The mechanism of DNA binding of BABQ was studied using 14C-labeled BABQ and is in agreement with reduction of the quinone moiety and protonation of the aziridine ring, followed by ring opening and alkylation. The one-electron reduced (semiquinone) form of BABQ alkylates DNA more efficiently than two-electron reduced or non reduced BABQ. Covalent binding to polynucleotides did not unambiguously reveal preference for binding to specific DNA bases. Attempts to elucidate further the molecular structure of DNA adducts by isolation of modified nucleosides from enzymatic digests of reacted DNA failed because of instability of the DNA adducts. The mechanism of covalent binding to protein (bovine serum albumin, BSA) appeared to be completely different from that of covalent binding to DNA. Binding of BABQ to BSA was not enhanced by reduction of the compound and was pH dependent in a way that is opposite to that of DNA alkylation. Glutathione inhibits binding of BABQ to BSA and forms adducts with BABQ in a similar pH dependence as the protein binding. The aziridine group therefore does not seem to be involved in the alkylation of BSA. Incubation of intact E. coli cells, which endogenously reduce BABQ, resulted in binding to both DNA and RNA, but also appreciable protein binding was observed.


Measuring spiritual belief: development and standardization of a Beliefs and Values Scale.
Higher levels of religious involvement are modestly associated with better health, after taking account of other influences, such as age, sex and social support. However, little account is taken of spiritual beliefs that are not tied to personal or public religious practice. Our objective was to develop a standardized measure of spirituality for use in clinical research. We characterized the core components of spirituality using narrative data from a purposive sample of people, some of whom were near the end of their lives. These data were developed into statements in a scale to measure strength of spiritual beliefs and its reliability, validity and factor structure were evaluated in order to reach a final version. Thirty-nine people took part in the qualitative study to define the nature of spirituality in their lives. These data were used to construct a 47-item instrument that was evaluated in 372 people recruited in medical and non-medical settings. Analysis of these statements led to a 24-item version that was evaluated in a further sample of 284 people recruited in similar settings. The final 20-item questionnaire performed with high test-retest and internal reliability and measures spirituality across a broad religious and non-religious perspective. A measure of spiritual belief that is not limited to religious thought, may contribute to research in psychiatry and medicine.


Optimal treatment of patients with NSTE-ACS in the Dutch health care system.
In the current daily practice of acute coronary syndromes, patients experiencing non-ST-elevation acute coronary syndrome (NSTE-ACS) represent the majority of this population. In these patients it is of utmost importance to estimate both ischaemic and bleeding risk, with subsequent, and preferably tailored pharmacological and, if indicated, invasive treatment. In this paper we describe the several risk scores and evaluate which are most applicable to the Dutch health-care system. Furthermore, we provide an overview of the recommended pharmacological treatment in keeping with the European Society of Cardiology guidelines. An important topic of this paper is how to decide between early or delayed invasive strategies. We describe the recommendations of the European Society of Cardiology and evaluate to which level these should be applied to the Dutch health-care system.


A preliminary transcriptome map of non-small cell lung cancer.
We constructed a genome-wide transcriptome map of non-small cell lung carcinomas based on gene-expression profiles generated by serial analysis of gene expression (SAGE) using primary tumors and bronchial epithelial cells of the lung. Using the human genome working draft and the public databases, 25,135 nonredundant UniGene clusters were mapped onto unambiguous chromosomal positions. Of the 23,056 SAGE tags that appeared more than once among the nine SAGE libraries, 11,156 tags representing 7,097 UniGene clusters were positioned onto chromosomes. A total of 43 and 55 clusters of differentially expressed genes were observed in squamous cell carcinoma and adenocarcinoma, respectively. The number of genes in each cluster ranged from 18 to 78 in squamous cell carcinomas and from 20 to 165 in adenocarcinomas. The size of these clusters varied from 1.8 Mb to 65.5 Mb in squamous cell carcinomas and from 1.6 Mb to 98.1 Mb in adenocarcinomas. Overall, the clusters with genes over-represented in tumors had an average of 3-4-fold increase in gene expression compared with the normal control. In contrast, clusters of genes with reduced expression had about 50-65% of the gene expression level compared with the normal. Examination of clusters identified in squamous cell lung cancer suggested that 9 of 15 clusters with overexpressed genes and 13 of 28 clusters with underexpressed genes were concordant with previously reported cytogenetic, comparative genomic hybridization or loss of heterozygosity studies. Therefore, at least a portion of the gene clusters identified via the transcriptome map most likely represented the transcriptional or genetic alterations occurred in the tumors. Integrating chromosomal mapping information with gene expression profiles may help reveal novel molecular changes associated with human lung cancer.


Divisive Hierarchical Clustering towards Identifying Clinically Significant Pre-Diabetes Subpopulations.
Type 2 Diabetes Mellitus is a progressive disease with increased risk of developing serious complications. Identifying subpopulations and their relevant risk factors can contribute to the prevention and effective management of diabetes. We use a novel divisive hierarchical clustering technique to identify clinically interesting subpopulations in a large cohort of Olmsted County, MN residents. Our results show that our clustering algorithm successfully identified clinically interesting clusters consisting of patients with higher or lower risk of diabetes than the general population. The proposed algorithm offers fine control over the granularity of the clustering, has the ability to seamlessly discover and incorporate interactions among the risk factors, and can handle non-proportional hazards, as well. It has the potential to significantly impact clinical practice by recognizing patients with specific risk factors who may benefit from an alternative management approach potentially leading to the prevention of diabetes and its complications.


Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes.
Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes. Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies. Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up. Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism. Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.


A pre-induction sporulation gene from Aspergillus nidulans.
Asexual sporulation in Aspergillus nidulans is an inducible developmental process controlled by genes that act before and after the inductive stimulus is applied. Genes that act before induction (pre-induction genes) potentially represent functions required for response to induction. This report describes the isolation and characterization of the acoB pre-induction gene which was cloned by complementation of a thermosensitive aconidial mutant followed by gene rescue. Genetic analysis and gene disruption confirmed the identity of the cloned gene. The mRNA of the acoB gene was present in uninduced vegetative hyphae, induced conidiating cultures and in both conidiospores and ascospores. An ORF in the nucleotide sequence of the acoB cDNA specifies a 327-residue protein unrelated to any known peptide sequence. Sequence analysis of the thermosensitive mutant allele, acoB202, revealed that the mutant phenotype is due to a frame-shift mutation that severely truncates the putative ACOB protein. Disruption of the acoB gene also produced a strain that was thermosensitive for conidiation. These properties suggest that acoB may be a gene that is required for sporulation only at elevated temperatures. Hybridization of acoB DNA with DNA from a variety of Aspergillus species showed that homology to this gene is largely restricted to sexually sporulating species that belong to the nidulans group.


On the origins of suboptimality in human probabilistic inference.
Humans have been shown to combine noisy sensory information with previous experience (priors), in qualitative and sometimes quantitative agreement with the statistically-optimal predictions of Bayesian integration. However, when the prior distribution becomes more complex than a simple Gaussian, such as skewed or bimodal, training takes much longer and performance appears suboptimal. It is unclear whether such suboptimality arises from an imprecise internal representation of the complex prior, or from additional constraints in performing probabilistic computations on complex distributions, even when accurately represented. Here we probe the sources of suboptimality in probabilistic inference using a novel estimation task in which subjects are exposed to an explicitly provided distribution, thereby removing the need to remember the prior. Subjects had to estimate the location of a target given a noisy cue and a visual representation of the prior probability density over locations, which changed on each trial. Different classes of priors were examined (Gaussian, unimodal, bimodal). Subjects' performance was in qualitative agreement with the predictions of Bayesian Decision Theory although generally suboptimal. The degree of suboptimality was modulated by statistical features of the priors but was largely independent of the class of the prior and level of noise in the cue, suggesting that suboptimality in dealing with complex statistical features, such as bimodality, may be due to a problem of acquiring the priors rather than computing with them. We performed a factorial model comparison across a large set of Bayesian observer models to identify additional sources of noise and suboptimality. Our analysis rejects several models of stochastic behavior, including probability matching and sample-averaging strategies. Instead we show that subjects' response variability was mainly driven by a combination of a noisy estimation of the parameters of the priors, and by variability in the decision process, which we represent as a noisy or stochastic posterior.


CT localization for a patient with a ground-glass opacity pulmonary nodule expecting thoracoscopy: a mixture of lipiodol and India ink.
Small and deeply seated pure ground-glass opacity (GGO) pulmonary nodules (PNs) are not discernible during video-assisted thoracoscopic surgery (VATS). Moreover, pathologists have difficulty in detecting these nodules due to insufficient localization. We percutaneously injected a mixture of lipiodol and India ink during preoperative CT-guided localization in a 52-year-old female patient presenting with a pure GGO PN. A black-pigmented tattoo lesion was clearly identified, and thoracoscopic wedge resection was performed without difficulty. Pathologic results were also discernible, thus allowing the target lesion to be identified without interruption for microscopic analysis. We introduce a novel method using a mixture of lipiodol and India ink with satisfactory results for preoperative localization of GGO PNs prior to VATS.


Clonal behaviour of myogenic precursor cells throughout the vertebrate lifespan.
To address questions of stem cell diversity during skeletal myogenesis, a Brainbow-like genetic cell lineage tracing method, dubbed Musclebow2, was derived by enhancer trapping in zebrafish. It is shown that, after initial formation of the primary myotome, at least 15 muscle precursor cells (mpcs) seed each somite, where they proliferate but contribute little to muscle growth prior to hatching. Thereafter, dermomyotome-derived mpc clones rapidly expand while some progeny undergo terminal differentiation, leading to stochastic clonal drift within the mpc pool. No evidence of cell-lineage-based clonal fate diversity was obtained. Neither fibre nor mpc death was observed in uninjured animals. Individual marked muscle fibres persist across much of the lifespan indicating low rates of nuclear turnover. In adulthood, early-marked mpc clones label stable blocks of tissue comprising a significant fraction of either epaxial or hypaxial somite. Fusion of cells from separate early-marked clones occurs in regions of clone overlap. Wounds are regenerated from several local mpcs; no evidence for specialised stem mpcs was obtained. In conclusion, our data indicate that most mpcs in muscle tissue contribute to local growth and repair and suggest that cellular turnover is low in the absence of trauma.


Titanium-Nitride-Oxide-Coated vs Everolimus-Eluting Stents in Acute Coronary Syndrome: 5-Year Clinical Outcomes of the TIDES-ACS Randomized Clinical Trial.
Titanium-nitride-oxide (TiNO)-coated stents show faster strut coverage compared with drug-eluting stents without excessive intimal-hyperplasia observed in bare metal stents. It is important to study long-term clinical outcomes after treatment of patients with an acute coronary syndrome (ACS) by TiNO-coated stents, which are neither drug-eluting stents nor bare metal stents. To compare the rate of main composite outcome of cardiac death, myocardial infarction (MI), or ischemia-driven target lesion revascularization at 5 years in patients with ACS randomized to receive either a TiNO-coated stent or a third-generation everolimus-eluting stent (EES). This multicenter, randomized, controlled, open-label trial was conducted in 12 clinical sites in 5 European countries and enrolled patients from January 2014 to August 2016. Patients presenting with ACS (ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina) with at least 1 de novo lesion were randomized to receive either a TiNO-coated stent or an EES. The present report analyzes the long-term follow-up for the main composite outcome and its individual components. Analysis took place between November 2022 to March 2023. The primary end point was a composite of cardiac death, MI, or target lesion revascularization at 12-month follow-up. A total of 1491 patients with ACS were randomly assigned to receive either TiNO-coated stents (989 [66.3%]) or EES (502 [33.7%]). The mean (SD) age was 62.7 (10.8) years, and 363 (24.3%) were female. At 5 years, the main composite outcome events occurred in 111 patients (11.2%) in the TiNO group vs 60 patients (12%) in the EES group (hazard ratio [HR], 0.94; 95% CI, 0.69-1.28; P = .69). The rate of cardiac death was 0.9% (9 of 989) vs 3.0% (15 of 502) (HR, 0.30; 95% CI, 0.13-0.69; P = .005), the rate of MI was 4.6% (45 of 989) vs 7.0% (35 of 502) (HR, 0.64; 95% CI, 0.41-0.99; P = .049), the rate of stent thrombosis was 1.2% (12 of 989) vs 2.8% (14 of 502) (HR, 0.43; 95% CI, 0.20-0.93; P = .034), and the rate of target lesion revascularization was 7.4% (73 of 989) vs 6.4% (32 of 502) (HR, 1.16; 95% CI, 0.77-1.76; P = .47) in the TiNO-coated stent arm and in the EES arm, respectively. In this study, patients with ACS had a main composite outcome that was not different 5 years after TiNO-coated stent or EES. ClinicalTrials.gov Identifier: NCT02049229.


Association of temperament with dental anxiety and behaviour of the preschool child during the initial dental visit.
The aim of this study was to investigate whether there is an association between temperament characteristics of preschool children, dental anxiety, and their dental behaviour. A total of 100 children, aged 3-5 yr, who were attending their initial dental visit accompanied by a parent, were included in this cross-sectional study. Dental anxiety of children was measured using the Facial Image Scale. The behaviour of children during the initial oral examination and oral prophylaxis was assessed using Frankl's behaviour rating scale. Temperament was assessed using Emotionality, Activity, Shyness Temperament Survey for Children (parental ratings). Statistically significant weak linear positive correlations were seen between the following: the percentage duration of definitely negative behaviour and shyness scores (rs = 0.28); anxiety level and emotionality scores (rs = 0.28); and anxiety level and shyness scores (rs = 0.26). Multinomial logistic regression analysis revealed that children with higher anxiety had higher odds of showing definitely negative behaviour, which decreased with increasing age of the child. Emotionality and shyness temperaments may be weakly associated with dental anxiety, and shyness may be weakly associated with the dental behaviour of the preschool child. Definitely negative dental behaviour is associated with dental anxiety and age of the child.


Djebelemur, a tiny pre-tooth-combed primate from the Eocene of Tunisia: a glimpse into the origin of crown strepsirhines.
Molecular clock estimates of crown strepsirhine origins generally advocate an ancient antiquity for Malagasy lemuriforms and Afro-Asian lorisiforms, near the onset of the Tertiary but most often extending back to the Late Cretaceous. Despite their inferred early origin, the subsequent evolutionary histories of both groups (except for the Malagasy aye-aye lineage) exhibit a vacuum of lineage diversification during most part of the Eocene, followed by a relative acceleration in diversification from the late Middle Eocene. This early evolutionary stasis was tentatively explained by the possibility of unrecorded lineage extinctions during the early Tertiary. However, this prevailing molecular view regarding the ancient origin and early diversification of crown strepsirhines must be viewed with skepticism due to the new but still scarce paleontological evidence gathered in recent years. Here, we describe new fossils attributable to Djebelemur martinezi, a≈50 Ma primate from Tunisia (Djebel Chambi). This taxon was originally interpreted as a cercamoniine adapiform based on limited information from its lower dentition. The new fossils provide anatomical evidence demonstrating that Djebelemur was not an adapiform but clearly a distant relative of lemurs, lorises and galagos. Cranial, dental and postcranial remains indicate that this diminutive primate was likely nocturnal, predatory (primarily insectivorous), and engaged in a form of generalized arboreal quadrupedalism with frequent horizontal leaping. Djebelemur did not have an anterior lower dentition as specialized as that characterizing most crown strepsirhines (i.e., tooth-comb), but it clearly exhibited a transformed antemolar pattern representing an early stage of a crown strepsirhine-like adaptation ("pre-tooth-comb"). These new fossil data suggest that the differentiation of the tooth-comb must postdate the djebelemurid divergence, a view which hence constrains the timing of crown strepsirhine origins to the Middle Eocene, and then precludes the existence of unrecorded lineage extinctions of tooth-combed primates during the earliest Tertiary.


[Raynaud's phenomenon; diagnosis and treatment].
Primary Raynaud's phenomenon (RP) is a relatively common disorder. Most patients with primary RP have only mild symptoms and do not develop complications. Distinguishing primary from secondary RP is important with respect to complications, and for prognosis and treatment. Secondary RP mainly manifests as part of systemic connective tissue disease. About 13% of patients diagnosed initially as having primary RP develop a systemic disorder within the following few years. Both auto-immune serology including antinuclear antibodies (ANA), and capillaroscopy are important diagnostic tools if one suspects the existence or development of a systemic disorder. Calcium antagonists are the cornerstone of RP pharmacotherapy.


Healing potentials of polymethylmethacrylate bone cement combined with platelet gel in the critical-sized radial bone defect of rats.
Polymethylmethacrylate (PMMA) is the most commonly used filler material that lacks biological properties and osteoconductivity or osteoinductivity. Platelet gel (PG) is a typical source of growth factors, cytokines and molecules efficient for bone formation and remodeling. The aim of this study was to evaluate bone healing and regeneration of bone defect in rat model by combining PMMA with PG. A total of 50 defects were created in the diaphysis of the radii of 25 male Sprague-Dawley rats. These defects were randomly divided into five groups (n = 10 defects for each group) and treated by autograft, plain PMMA, PG and PMMA-PG or left untreated. The rats were examined clinically and radiologically during the experiment and also after euthanasia at the 8th post-operative week, the healed defects were evaluated by gross morphology, histopathology, histomorphometry, computed tomography, scanning electron microscopy and biomechanical testing. PG could function as efficiently as autograft in promoting bone healing of the radial bones. Additionally, bone formation, and densities of cartilaginous and osseous tissues in the defects treated with autograft, PG and PMMA-PG were more satisfactory than the untreated and PMMA treated defects. Compared with the PMMA-PG implant, more PMMA residuals remained in the defect area and induced more intense inflammatory reaction. In conclusion, addition of PG could improve the bone regenerative properties of PMMA bone cement compared with PMMA alone in vivo. Therefore, the PG-PMMA can be proposed as a promising option to increase regenerative potential of PMMA, particularly when it is used as fixator, filler or adhesive in the dentistry, neurosurgery and bone tissue engineering applications.


Complement-Mediated Neutralisation Identified in Ebola Virus Disease Survivor Plasma: Implications for Protection and Pathogenesis.
The 2013-2016 Ebola virus (EBOV) epidemic in West Africa was unprecedented in case numbers and fatalities, and sporadic outbreaks continue to arise. Antibodies to the EBOV glycoprotein (GP) are strongly associated with survival and their use in immunotherapy is often initially based on their performance in neutralisation assays. Other immune effector functions also contribute to EBOV protection but are more complex to measure. Their interactions with the complement system in particular are comparatively under-researched and commonly excluded from cellular immunoassays. Using EBOV convalescent plasma samples from the 2013-2016 epidemic, we investigated antibody and complement-mediated neutralisation and how these interactions can influence immunity in response to EBOV-GP and its secreted form (EBOV-sGP). We defined two cohorts: one with low-neutralising titres in relation to EBOV-GP IgG titres (LN cohort) and the other with a direct linear relationship between neutralisation and EBOV-GP IgG titres (N cohort). Using flow cytometry antibody-dependent complement deposition (ADCD) assays, we found that the LN cohort was equally efficient at mediating ADCD in response to the EBOV-GP but was significantly lower in response to the EBOV-sGP, compared to the N cohort. Using wild-type EBOV neutralisation assays with a cohort of the LN plasma, we observed a significant increase in neutralisation associated with the addition of pooled human plasma as a source of complement. Flow cytometry ADCD was also applied using the GP of the highly virulent Sudan virus (SUDV) of the Sudan ebolavirus species. There are no licensed vaccines or therapeutics against SUDV and it overlaps in endemicity with EBOV. We found that the LN plasma was significantly less efficient at cross-reacting and mediating ADCD. Overall, we found a differential response in ADCD between LN and N plasma in response to various Ebolavirus glycoproteins, and that these interactions could significantly improve EBOV neutralisation for selected LN plasma samples. Preservation of the complement system in immunoassays could augment our understanding of neutralisation and thus protection against infection.


GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography.
Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain.


Cerebellar-cortical dysconnectivity in resting-state associated with sensorimotor tasks in schizophrenia.
Abnormalities of cerebellar function have been implicated in the pathophysiology of schizophrenia. Since the cerebellum has afferent and efferent projections to diverse brain regions, abnormalities in cerebellar lobules could affect functional connectivity with multiple functional systems in the brain. Prior studies, however, have not examined the relationship of individual cerebellar lobules with motor and nonmotor resting-state functional networks. We evaluated these relationships using resting-state fMRI in 30 patients with a schizophrenia-spectrum disorder and 37 healthy comparison participants. For connectivity analyses, the cerebellum was parcellated into 18 lobular and vermal regions, and functional connectivity of each lobule to 10 major functional networks in the cerebrum was evaluated. The relationship between functional connectivity measures and behavioral performance on sensorimotor tasks (i.e., finger-tapping and postural sway) was also examined. We found cerebellar-cortical hyperconnectivity in schizophrenia, which was predominantly associated with Crus I, Crus II, lobule IX, and lobule X. Specifically, abnormal cerebellar connectivity was found to the cerebral ventral attention, motor, and auditory networks. This cerebellar-cortical connectivity in the resting-state was differentially associated with sensorimotor task-based behavioral measures in schizophrenia and healthy comparison participants-that is, dissociation with motor network and association with nonmotor network in schizophrenia. These findings suggest that functional association between individual cerebellar lobules and the ventral attentional, motor, and auditory networks is particularly affected in schizophrenia. They are also consistent with dysconnectivity models of schizophrenia suggesting cerebellar contributions to a broad range of sensorimotor and cognitive operations.


Legal Feasibility of US Government Policies to Reduce Cancer Risk by Reducing Intake of Processed Meat.
Policy Points High-profile international evidence reviews by the World Health Organization, the World Cancer Research Fund, the American Institute for Cancer Research, and the American Cancer Society concluded that processed meat consumption increases the risk of cancer. The red meat and processed meat industries are influential in the United States and in several other nations. The US federal government supports public-private partnerships for commodity meat promotion and advertising. Four potential policy options to affect consumption of processed meat are taxation, reduced processed meat quantities in school meal standards, public service announcements, and warning labels. Feasibility of these options would be enhanced by an explicit and science-based statement on processed meat in the 2020-2025 Dietary Guidelines for Americans. The World Health Organization, the World Cancer Research Fund, and the American Cancer Society have each in recent years concluded that processed meats are probable carcinogens. The 2015-2020 Dietary Guidelines for Americans did not separately evaluate health effects of processed meat, although it mentioned lower processed meat intakes among characteristics of healthy diets. We summarized the international scientific literature on meat intake and cancer risk; described the scientific and political processes behind the periodic Dietary Guidelines for Americans; described the US red meat and processed meat industries and the economic structure of government-supported industry initiatives for advertising and promotion; and reviewed and analyzed specific factors and precedents that influence the feasibility of four potential policy approaches to reduce processed meat intake. Based on a review of 800 epidemiological studies, the World Health Organization found sufficient evidence in humans that processed meat is carcinogenic, estimating that each 50-gram increase in daily intake increases the risk of colorectal cancer by 18%. Among the four policy responses we studied, legal feasibility is highest in the US for three policy options: reducing processed meat in school meals and other specific government-sponsored nutrition programs; a local, state, or federal tax on processed meat; and public service announcements on health harms of processed meats by either the government or private sector entities. Legal feasibility is moderate for a fourth policy option, mandatory warning labels, due to outstanding legal questions about the minimum evidence required to support this policy. Political feasibility is influenced by the economic and political power of the meat industries and also depends on decisions in the next round of the Dietary Guidelines for Americans about how to assess and describe the link between processed meat consumption and cancer risk. Public policy initiatives to reduce processed meat intake have a strong scientific and public health justification and are legally feasible, but political feasibility is influenced by the economic and political power of meat industries and also by uncertainty about the likely treatment of processed meat in the 2020-2025 Dietary Guidelines for Americans.


[Immunosuppressants for therapy of patients with ulcerative colitis].
Ulcerative colitis (UC) has been known as inflammatory bowel disease. Progress in UC management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. We here review about immunosuppressants in management of UC; Cyclosporine A (CsA) has been used for the induction therapy in steroid resistant refractory UC. Although it has been reported that CsA has high response rate in severe UC, long-term efficacy (maintenance of remission) has not been proven. To improve maintenance therapy, immunosuppressant has been re-considered in management of UC. In recent years, it has been reported that efficacy of 6-mercaptopurine/azathioprine in maintenance of remission of UC is superior to 5-aminosalicylate (5-ASA). Pharmacological studies have indicated thiopurine methyltransferase (TPMT) activity is essential for maintenance of blood concentration of 6-thioguanine nucleotide (6-TG).


Experimental approach and initial forest response to a simulated ice storm experiment in a northern hardwood forest.
Ice storms are a type of extreme winter weather event common to north temperate and boreal forests worldwide. Recent climate modelling studies suggest that these storms may become more frequent and severe under a changing climate. Compared to other types of storm events, relatively little is known about the direct and indirect impacts of these storms on forests, as naturally occurring ice storms are inherently difficult to study. Here we describe a novel experimental approach used to create a suite of ice storms in a mature hardwood forest in New Hampshire, USA. The experiment included five ice storm intensities (0, 6.4, 12.7 and 19.1 mm radial ice accretion) applied in a single year, and one ice storm intensity (12.7 mm) applied in two consecutive years. Results demonstrate the feasibility of this approach for creating experimental ice storms, quantify the increase in fine and coarse woody debris mass and nutrients transferred from the forest canopy to the soil under the different icing conditions, and show an increase in the damage to the forest canopy with increasing icing that evolves over time. In this forest, little damage occurred below 6.4 mm radial ice accretion, moderate damage occurred with up to 12.7 mm of accretion, and significant branch breakage and canopy damage occurred with 19.1 mm of ice. The icing in consecutive years demonstrated an interactive effect of ice storm frequency and severity such that some branches damaged in the first year of icing appeared to remain in the canopy and then fall to the ground in the second year of icing. These results have implications for National Weather Service ice storm warning levels, as they provide a quantitative assessment of ice-load related inputs of forest debris that will be useful to municipalities creating response plans for current and future ice storms.


Genome-Wide Association Studies of 11 Agronomic Traits in Cassava (Manihot esculenta Crantz).
Cassava (Manihot esculenta Crantz) is a major tuberous crop produced worldwide. In this study, we sequenced 158 diverse cassava varieties and identified 349,827 single-nucleotide polymorphisms (SNPs) and indels. In each chromosome, the number of SNPs and the physical length of the respective chromosome were in agreement. Population structure analysis indicated that this panel can be divided into three subgroups. Genetic diversity analysis indicated that the average nucleotide diversity of the panel was 1.21 × 10-4 for all sampled landraces. This average nucleotide diversity was 1.97 × 10-4, 1.01 × 10-4, and 1.89 × 10-4 for subgroups 1, 2, and 3, respectively. Genome-wide linkage disequilibrium (LD) analysis demonstrated that the average LD was about ∼8 kb. We evaluated 158 cassava varieties under 11 different environments. Finally, we identified 36 loci that were related to 11 agronomic traits by genome-wide association analyses. Four loci were associated with two traits, and 62 candidate genes were identified in the peak SNP sites. We found that 40 of these genes showed different expression profiles in different tissues. Of the candidate genes related to storage roots, Manes.13G023300, Manes.16G000800, Manes.02G154700, Manes.02G192500, and Manes.09G099100 had higher expression levels in storage roots than in leaf and stem; on the other hand, of the candidate genes related to leaves, Manes.05G164500, Manes.05G164600, Manes.04G057300, Manes.01G202000, and Manes.03G186500 had higher expression levels in leaves than in storage roots and stem. This study provides basis for research on genetics and the genetic improvement of cassava.


Temporal and Geospatial Trends of Hypertension Management in Korea: a Nationwide Study 2002-2016.
Geographic distribution of hypertension management in Korea has never been reported. We investigated temporal and regional trends of hypertension management in Korea. For each calendar year from 2002 to 2016, we identified 2,423,245 to 7,549,989 persons aged ≥30 years treated for hypertension (total 80,564,109 cases). We calculated yearly age-sex standardized rates for medication adherence, combination therapy, blood test, and urine test according to geographic regions. We then used multivariate logistic regression to calculate odds ratios for hypertension management adjusted for individual-level sociodemographic factors. Adherence rates have markedly increased from 24.4% (2002) to 71.6% (2016) nationwide. Regional difference was prominent in 2002 (highest, 31.7% in Seoul; lowest, 14.4% in Jeonbuk), but has become less noticeable over 15 years (highest, 73.1% in Daejeon; lowest, 69.0% in Jeonnam, 2016). Combination therapy rates increased from 42.8% (2002) to 61.0% (2011), but are in decreasing trend after 2011. Blood test rates were 58.8% in 2016, whereas urine test rates have been stagnant below 50% across all regions. Geographic variations of combination therapy and complication screening rates were not profound. Results from multivariable logistic regression, adjusted for age and sex, were in agreement with trends observed by standardized rates. The odds ratios remained unchanged when the models were further adjusted for employment status and household income. Regional difference in hypertension management was evident in the past, but has become less apparent over the last 15 years in Korea.


Design and Evaluation of Interactive Proofreading Tools for Connectomics.
Proofreading refers to the manual correction of automatic segmentations of image data. In connectomics, electron microscopy data is acquired at nanometer-scale resolution and results in very large image volumes of brain tissue that require fully automatic segmentation algorithms to identify cell boundaries. However, these algorithms require hundreds of corrections per cubic micron of tissue. Even though this task is time consuming, it is fairly easy for humans to perform corrections through splitting, merging, and adjusting segments during proofreading. In this paper we present the design and implementation of Mojo, a fully-featured single-user desktop application for proofreading, and Dojo, a multi-user web-based application for collaborative proofreading. We evaluate the accuracy and speed of Mojo, Dojo, and Raveler, a proofreading tool from Janelia Farm, through a quantitative user study. We designed a between-subjects experiment and asked non-experts to proofread neurons in a publicly available connectomics dataset. Our results show a significant improvement of corrections using web-based Dojo, when given the same amount of time. In addition, all participants using Dojo reported better usability. We discuss our findings and provide an analysis of requirements for designing visual proofreading software.


Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria.
Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 +/- 25 hours (mean +/- 1 S.D.) after treatment was begun and then declining. Quinine total clearances (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 0.92 +/- 0.42 compared with 1.35 +/- 0.6 ml/min/kg, p = 0.03; Vd, 1.18 +/- 0.37 compared with 1.67 +/- 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.


Experienced speech-language pathologists' responses to ethical dilemmas: an integrated approach to ethical reasoning.
To investigate the approaches of experienced speech-language pathologists (SLPs) to ethical reasoning and the processes they use to resolve ethical dilemmas. Ten experienced SLPs participated in in-depth interviews. A narrative approach was used to guide participants' descriptions of how they resolved ethical dilemmas. Individual narrative transcriptions were analyzed by using the participant's words to develop an ethical story that described and interpreted their responses to dilemmas. Key concepts from individual stories were then coded into group themes to reflect participants' reasoning processes. Five major themes reflected participants' approaches to ethical reasoning: (a) focusing on the well-being of the client, (b) fulfilling professional roles and responsibilities, (c) attending to professional relationships, (d) managing resources, and (e) integrating personal and professional values. SLPs demonstrated a range of ethical reasoning processes: applying bioethical principles, casuistry, and narrative reasoning when managing ethical dilemmas in the workplace. The results indicate that experienced SLPs adopted an integrated approach to ethical reasoning. They supported clients' rights to make health care choices. Bioethical principles, casuistry, and narrative reasoning provided useful frameworks for facilitating health professionals' application of codes of ethics to complex professional practice issues.


Photoelectrochemical hydrogen production in alkaline solutions using Cu2O coated with earth-abundant hydrogen evolution catalysts.
The splitting of water into hydrogen and oxygen molecules using sunlight is an attractive method for solar energy storage. Until now, photoelectrochemical hydrogen evolution is mostly studied in acidic solutions, in which the hydrogen evolution is more facile than in alkaline solutions. Herein, we report photoelectrochemical hydrogen production in alkaline solutions, which are more favorable than acidic solutions for the complementary oxygen evolution half-reaction. We show for the first time that amorphous molybdenum sulfide is a highly active hydrogen evolution catalyst in basic medium. The amorphous molybdenum sulfide catalyst and a Ni-Mo catalyst are then deposited on surface-protected cuprous oxide photocathodes to catalyze sunlight-driven hydrogen production in 1 M KOH. The photocathodes give photocurrents of -6.3 mA cm(-2) at the reversible hydrogen evolution potential, the highest yet reported for a metal oxide photocathode using an earth-abundant hydrogen evolution reaction catalyst.


Law as Clinical Evidence: A New ConstitutiveModel of Medical Education and Decision-Making.
Over several decades, ethics and law have been applied to medical education and practice in a way that reflects the continuation during the twentieth century of the strong distinction between facts and values. We explain the development of applied ethics and applied medical law and report selected results that reflect this applied model from an empirical project examining doctors' decisions on withdrawing/withholding treatment from patients who lack decision-making capacity. The model is critiqued, and an alternative "constitutive" model is supported on the basis that medicine, medical law, and medical ethics exemplify the inevitable entanglement of facts and values. The model requires that ethics and law be taught across the medical education curriculum and integrated with the basic and clinical sciences and that they be perceived as an integral component of medical evidence and practice. Law, in particular, would rank as equal in normative authority to the relevant clinical scientific "facts" of the case, with graduating doctors having as strong a basic command of each category as the other. The normalization of legal knowledge as part of the clinician's evidence base to be utilized in practice may provide adequate consolation for clinicians who may initially resent further perceived incursions on their traditional independence and discretion.


Effectiveness of composite bone graft substitute plugs in the treatment of chondral and osteochondral lesions of the talus.
A review of outcomes in 13 patients with talar dome osteochondral or chondral lesions treated with a bone graft substitute plug was undertaken in an effort to evaluate its effectiveness in comparison with other reported surgical techniques. Mean patient age was 36.4 (range 16 to 57) years. Mean follow-up was 30.1 (range 7 to 43) months. Medial malleolar osteotomy was performed in 9 (69.23%) cases. Average defect diameter was 9.8 (range 5 to 20) mm. Pain decreased significantly from 6.2 (range 3 to 9) to 4.0 (range 0 to 9) (P = .009). Postoperative American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scores averaged 67.3 (range 26 to 100). Younger age, smaller defect size, and avoidance of medial malleolar osteotomy resulted in better outcomes. Mean Short Form-36 scores for the study group fell below US norms in all categories, and 12 (92.31%) ankles demonstrated persistent lesions radiographically. Postoperative magnetic resonance imaging in 2 (15.39%) patients demonstrated enlarged lesions, and 4 (30.77%) patients underwent revision surgery that revealed abnormal cartilage around the implant site. Complications included 1 (7.69%) deep venous thrombosis, 1 (7.69%) arthrofibrosis, and 1 (7.69%) superficial neuritis. Despite some improvement in pain, comparison of functional outcome showed bone graft substitute plug implantation to be less effective overall than other operative interventions. Future investigations with more specific selection criteria are warranted to gain further insight into the efficacy of these bone graft substitute plugs.


The fine structure of the Purkinje cell.
This paper describes the fine structure of the Purkinje cell of the rat cerebellum after fixation by perfusion with 1 per cent buffered osmium tetroxide. Structures described include a large Golgi apparatus, abundant Nissl substance, mitochondria, multivesicular bodies, osmiophilic granules, axodendritic and axosomatic synapses, the nucleus, the nucleolus, and the nucleolar body. A new and possibly unique relationship between mitochondria and subsurface cisterns is described. Possible functional correlations are discussed.


Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice.
TERMINOLOGY AND PRINCIPLES OF COMBINING ANTIPSYCHOTICS WITH A SECOND MEDICATION: The term "combination" includes virtually all the ways in which one medication may be added to another. The other commonly used terms are "augmentation" which implies an additive effect from adding a second medicine to that obtained from prescribing a first, an "add on" which implies adding on to existing, possibly effective treatment which, for one reason or another, cannot or should not be stopped. The issues that arise in all potential indications are: a) how long it is reasonable to wait to prove insufficiency of response to monotherapy; b) by what criteria that response should be defined; c) how optimal is the dose of the first monotherapy and, therefore, how confident can one be that its lack of effect is due to a truly inadequate response? Before one considers combination treatment, one or more of the following criteria should be met; a) monotherapy has been only partially effective on core symptoms; b) monotherapy has been effective on some concurrent symptoms but not others, for which a further medicine is believed to be required; c) a particular combination might be indicated de novo in some indications; d) The combination could improve tolerability because two compounds may be employed below their individual dose thresholds for side effects. Regulators have been concerned primarily with a and, in principle at least, c above. In clinical practice, the use of combination treatment reflects the often unsatisfactory outcome of treatment with single agents. ANTIPSYCHOTICS IN MANIA: There is good evidence that most antipsychotics tested show efficacy in acute mania when added to lithium or valproate for patients showing no or a partial response to lithium or valproate alone. Conventional 2-armed trial designs could benefit from a third antipsychotic monotherapy arm. In the long term treatment of bipolar disorder, in patients responding acutely to the addition of quetiapine to lithium or valproate, this combination reduces the subsequent risk of relapse to depression, mania or mixed states compared to monotherapy with lithium or valproate. Comparable data is not available for combination with other antipsychotics. ANTIPSYCHOTICS IN MAJOR DEPRESSION: Some atypical antipsychotics have been shown to induce remission when added to an antidepressant (usually a SSRI or SNRI) in unipolar patients in a major depressive episode unresponsive to the antidepressant monotherapy. Refractoriness is defined as at least 6 weeks without meeting an adequate pre-defined treatment response. Long term data is not yet available to support continuing efficacy. SCHIZOPHRENIA: There is only limited evidence to support the combination of two or more antipsychotics in schizophrenia. Any monotherapy should be given at the maximal tolerated dose and at least two antipsychotics of different action/tolerability and clozapine should be given as a monotherapy before a combination is considered. The addition of a high potency D2/3 antagonist to a low potency antagonist like clozapine or quetiapine is the logical combination to treat positive symptoms, although further evidence from well conducted clinical trials is needed. Other mechanisms of action than D2/3 blockade, and hence other combinations might be more relevant for negative, cognitive or affective symptoms. OBSESSIVE-COMPULSIVE DISORDER: SSRI monotherapy has moderate overall average benefit in OCD and can take as long as 3 months for benefit to be decided. Antipsychotic addition may be considered in OCD with tic disorder and in refractory OCD. For OCD with poor insight (OCD with "psychotic features"), treatment of choice should be medium to high dose of SSRI, and only in refractory cases, augmentation with antipsychotics might be considered. Augmentation with haloperidol and risperidone was found to be effective (symptom reduction of more than 35%) for patients with tics. For refractory OCD, there is data suggesting a specific role for haloperidol and risperidone as well, and some data with regard to potential therapeutic benefit with olanzapine and quetiapine. ANTIPSYCHOTICS AND ADVERSE EFFECTS IN SEVERE MENTAL ILLNESS: Cardio-metabolic risk in patients with severe mental illness and especially when treated with antipsychotic agents are now much better recognized and efforts to ensure improved physical health screening and prevention are becoming established.


The point prevalence of respiratory syncytial virus in hospital and community-based studies in children from Northern Australia: studies in a 'high-risk' population.
Respiratory syncytial virus (RSV) is the leading viral cause of acute lower respiratory infections globally, accounting for high morbidity and mortality burden among children aged less than 5 years. As candidate RSV vaccine trials in pregnant women and infants are underway a greater understanding of RSV epidemiology is now needed, especially in paediatric populations with high rates of acute and chronic respiratory disease. The objective was to identify RSV prevalence in children living in northern Australia, a region with a high respiratory disease burden. Data were sourced from 11 prospective studies (four hospital and seven community-based) of infants and children with acute and chronic respiratory illnesses, as well as otitis media, conducted between 1996 and 2017 inclusive. The data from northern Australian children in these trials were extracted and, where available and consented, their nasopharyngeal swabs (biobanked at -80ºC) were tested by polymerase chain reaction assays for RSV-A and B, 16 other viruses and atypical respiratory bacterial pathogens. Overall, 1127 children were included. Their median age was 1.8 years (interquartile range 0.5-4.9); 58% were male and 90% Indigenous, with 81% from remote communities. After human rhinoviruses (HRV), RSV was the second most prevalent virus (15%, 95% confidence interval (CI) 13-18). RSV prevalence was greatest amongst children aged less than 2 years hospitalised with bronchiolitis (47%, 95%CI 41.4-52.4), with more than two-thirds with RSV aged less than 6 months. In contrast, the prevalence of RSV was only 1-3.5% in other age groups and settings. In one-third of RSV cases, another respiratory virus was also detected. Individual viruses other than RSV and HRV were uncommon (0-9%). Combined data from 11 hospital and community-based studies of children aged less than 18 years who lived in communities with a high burden of acute and chronic respiratory illness showed that RSV was second only to HRV as the most prevalent virus detected across all settings. RSV was the most frequently detected virus in infants hospitalised with bronchiolitis, including those aged less than 6 months. In contrast, RSV was uncommonly detected in children in community settings. In northern Australia, effective maternal and infant RSV vaccines could substantially reduce RSV bronchiolitis-related hospitalisations, including admissions of Indigenous infants from remote communities.


Do brain lesions in stroke affect basic emotions and attachment?
The aim of the current study was to investigate basic emotions and attachment in a sample of 86 stroke patients. We included a control group of 115 orthopedic patients (matched for age and cognitive status) without brain lesions to control for unspecific general illness effects of a traumatic recent event on basic emotions and attachment. In order to measure basic emotions and attachment style we applied the Affective Neuroscience Personality Scale (ANPS) and the Attachment Style Questionnaire (ASQ). The stroke patients showed significantly different scores in the SEEKING, SADNESS, and ANGER subscales of the ANPS as well as in the Relationship as Secondary Attachment dimension of the ASQ when compared to the control group. These differences show a pattern influenced by lesion location mainly as concerns basic emotions. Anterior, medial, left, and subcortical patients provide scores significantly lower in ANPS-SEEKING than the control group; ANPS-SADNESS scores in anterior, right, medial, and subcortical patients were significantly higher than those of the control group. ANPS-ANGER scores in posterior, right, and lateral patients were significantly higher than those in the control group; finally, the ANPS-FEAR showed slightly lower scores in posterior patients than in the control group. Minor effects on brain lesions were also individuated in the attachment style. Anterior lesion patients showed a significantly higher average score in the ASQ-Need for Approval subscale than the control group. ASQ-Confidence subscale scores differed significantly in stroke patients with lesions in medial brain regions when compared to control subjects. Scores at ANPS and ASQ subscales appear significantly more correlated in stroke patients than in the control group. Such finding of abnormalities, especially concerning basic emotions in stroke brain-lesioned patients, indicates that the effect of brain lesions may enhance the interrelation between basic emotions and attachment with respect to the control group.


Global longitudinal strain and left atrial volume index improve prediction of appropriate implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy patients.
Accurate predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in hypertrophic cardiomyopathy (HCM) patients are lacking. Both left atrial volume index (LAVI) and global longitudinal strain (GLS) have been proposed as prognostic markers in HCM patients. The specific value of LAVI and GLS to predict appropriate ICD therapy in high-risk HCM patients was studied. LAVI and 2-dimensional speckle tracking-derived GLS were assessed in 92 HCM patients undergoing ICD implantation (69 % men, mean age 50 ± 14 years). During long-term follow-up, appropriate ICD therapies, defined as antitachycardia pacing and/or shock for ventricular arrhythmia, were recorded. Appropriate ICD therapy occurred in 21 patients (23 %) during a median follow-up of 4.7 (2.2-8.2) years. Multivariate analysis revealed LAVI (p = 0.03) and GLS (p = 0.04) to be independent predictors of appropriate ICD therapy. Both LAVI and GLS showed higher accuracy to predict appropriate ICD therapy compared to presence of ≥1 conventional sudden cardiac death (SCD) risk factor(s) [area under the curve 0.76 (95 % CI 0.65-0.87) and 0.65 (95 % CI 0.54-0.77) versus 0.52 (95 % CI 0.43-0.58) respectively, p < 0.001]. No patient with both LAVI <34 mL/m(2) and GLS <-14 % experienced appropriate ICD therapy. Assessment of both LAVI and GLS on top of conventional SCD risk factors provided incremental clinical predictive value for appropriate ICD therapy, as shown by likelihood ratio test (p < 0.001) and integrated discrimination improvement index (0.17, p < 0.001). LAVI and GLS provide high negative predictive value for appropriate ICD therapy in high-risk HCM patients. Additionally to conventional SCD risk factors, both parameters may be useful to optimize criteria and timing for ICD implantation in these patients.


Liposomes and nanotechnology in drug development: focus on neurological targets.
Neurological diseases represent a medical, social, and economic problem of paramount importance in developed countries. Although their etiology is generally known, developing therapeutic interventions for the central nervous system is challenging due to the impermeability of the blood-brain barrier. Thus, the fight against neurological diseases usually struggles "at the gates" of the brain. Flooding the bloodstream with drugs, where only a minor fraction reaches its target therapeutic site, is an inefficient, expensive, and dangerous procedure, because of the risk of side effects at nontargeted sites. Currently, advances in the field of nanotechnology have enabled development of a generation of multifunctional molecular platforms that are capable of transporting drugs across the blood-brain barrier, targeting specific cell types or functional states within the brain, releasing drugs in a controlled manner, and enabling visualization of processes in vivo using conventional imaging systems. The marriage between drug delivery and molecular imaging disciplines has resulted in a relatively new discipline, known as theranostics, which represents the basis of the concept of personalized medicine. In this study, we review the concepts of the blood-brain barrier and the strategies used to traverse/bypass it, the role of nanotechnology in theranostics, the wide range of nanoparticles (with emphasis on liposomes) that can be used as stealth drug carriers, imaging probes and targeting devices for the treatment of neurological diseases, and the targets and targeting strategies envisaged in the treatment of different types of brain pathology.


Hand hygiene in health care settings: the citizens' point of view.
The infection risk prevention is one of the main objectives of all health and sanitary systems, since the reduction of the healthcare associated infections is attainable goals through appropriate prevention strategies. Among these, proper hand hygiene of health care professionals and citizens (visitors/outpatients/caregivers, volunteers) is fundamental to reduce the spreading of micro organisms and prevent infections. The purpose of the study is indeed to explore the self-reported hand washing behavior of citizens who access to health facilities and the variables involved in it, using in particular the Theory of Planned Behaviour. A quantitative research was lead using an anonymous questionnaire, filled out online by 195 citizens (53.6% Female). In the survey were included all the associations of volunteers, relatives and caregivers who cooperate in health care settings of Emilia Romagna Region (Italy). This study has shown that hand hygiene is influenced by different socio-demographic (e.g. gender, age, education) and socio-cognitive variables (intention, attitude, subjective norms, control beliefs). In particular, citizens have a favorable attitude toward hands hygiene in healthcare settings, but they wash their hands more frequently in other contexts or in case of global infectious diseases. The study confirms that the Theory of Planned Behavior adequately explains the hand hygiene behavior in health care settings. Furthermore the threat of infection has a significant impact both on the intention and on the behavior. The results mostly interested those are involved in infectious risk giving the opportunity to intervene with targeted programs for the citizenship.


Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors.
Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB(1) and CB(2)), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB(1) and the CB(2) receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB(1)/CB(2) agonist WIN-55,212-2 or the selective CB(2) agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.


The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex.
The metalloproteinase and major amyloid precursor protein (APP) alpha-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors. Adam10(-/-) mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. To investigate the function of ADAM10 in brain, we generated Adam10 conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived from Adam10 cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. We found that Notch-1 processing was affected, leading to downregulation of several Notch-regulated genes in Adam10 cKO brains, in accordance with the central role of ADAM10 in this signaling pathway and explaining the neurogenic phenotype. Finally, we found that alpha-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP alpha-secretase in brain. Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP.