Effectiveness of discharge education strategies versus usual care on clinical outcomes in acute coronary syndrome patients: a systematic review.
The objective of this review was to systematically review studies that evaluated the clinical effectiveness of hospital discharge education strategies provided to patients with acute coronary syndrome (ACS). In an era of shortening lengths of stay for patients with ACS, bedside education opportunities are diminishing; however, the importance of discharge education on medication management, emergency procedures and safe recovery remains vital to prevent rehospitalization. The following studies were considered for inclusion: English-language randomized controlled trials (RCTs) measuring educational strategies provided to adults with ACS as the only intervention prior to discharge or post-discharge from acute care, compared to usual care. An electronic search was performed by an experienced research librarian. MEDLINE, CINAHL, PsycINFO, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov and WHO International Clinical Trial Registry Platform were searched for studies published between 2000 and 2017. All citations were collated and uploaded into EndNote where duplicates were removed. Titles and abstracts were screened by two independent reviewers. The reference lists of all included studies were screened for additional references. Risk of bias was assessed using the JBI critical appraisal instrument for all included studies. In the case of missing or incomplete data, corresponding authors were contacted. The primary outcomes of interest were knowledge relating to ACS diagnosis, treatment and procedures. Secondary outcomes included lifestyle modifications, medication adherence/knowledge, general practitioner follow-up, attendance to cardiac rehabilitation (CR), readmission and mortality (up to 12 months). As data were collected using different instruments in each study, meta-analysis was not performed. The electronic search identified 3445 records. Following deduplication, 2093 citations were screened with 47 papers selected for assessment of eligibility. Three RCTs involving 175 participants were identified for inclusion. The certainty of this evidence (Grading of Recommendations, Assessment, Development and Evaluation) was rated as low to moderate. The risk of bias for all included studies was moderate. In all studies, the impact of inpatient educational interventions was assessed in relation to attendance to a CR program, exercise rates and medication adherence. Interventions included targeted educational sessions (15-40 minutes) where participants prioritized their learning needs and were provided tailored cardioprotective risk factor and lifestyle modification advice and invited to attend a CR program. One study presented the education in animation. In one study, intervention groups reported increased attendance to CR compared to control (47.3%; n = 9, versus 21.1%; n = 4) and another demonstrated significantly increased exercise rates from baseline to follow-up. No significant difference was reported between the intervention and control for medication adherence, and none of the studies reported readmission or mortality rates. The current review found little to no evidence for the effectiveness of current discharge practices on clinical outcomes. There has been limited research on modes of delivery or what the essential components for ACS discharge education should be. This review has highlighted the need for comprehensive effectiveness studies to provide a strong evidence-base to support ACS discharge practices. PROSPERO CRD42018094781.


Observation of tt[over ¯]H Production.
The observation of Higgs boson production in association with a top quark-antiquark pair is reported, based on a combined analysis of proton-proton collision data at center-of-mass energies of sqrt[s]=7, 8, and 13 TeV, corresponding to integrated luminosities of up to 5.1, 19.7, and 35.9 fb^{-1}, respectively. The data were collected with the CMS detector at the CERN LHC. The results of statistically independent searches for Higgs bosons produced in conjunction with a top quark-antiquark pair and decaying to pairs of W bosons, Z bosons, photons, τ leptons, or bottom quark jets are combined to maximize sensitivity. An excess of events is observed, with a significance of 5.2 standard deviations, over the expectation from the background-only hypothesis. The corresponding expected significance from the standard model for a Higgs boson mass of 125.09 GeV is 4.2 standard deviations. The combined best fit signal strength normalized to the standard model prediction is 1.26_{-0.26}^{+0.31}.


Association studies with imputed variants using expectation-maximization likelihood-ratio tests.
Genotype imputation has become standard practice in modern genetic studies. As sequencing-based reference panels continue to grow, increasingly more markers are being well or better imputed but at the same time, even more markers with relatively low minor allele frequency are being imputed with low imputation quality. Here, we propose new methods that incorporate imputation uncertainty for downstream association analysis, with improved power and/or computational efficiency. We consider two scenarios: I) when posterior probabilities of all potential genotypes are estimated; and II) when only the one-dimensional summary statistic, imputed dosage, is available. For scenario I, we have developed an expectation-maximization likelihood-ratio test for association based on posterior probabilities. When only imputed dosages are available (scenario II), we first sample the genotype probabilities from its posterior distribution given the dosages, and then apply the EM-LRT on the sampled probabilities. Our simulations show that type I error of the proposed EM-LRT methods under both scenarios are protected. Compared with existing methods, EM-LRT-Prob (for scenario I) offers optimal statistical power across a wide spectrum of MAF and imputation quality. EM-LRT-Dose (for scenario II) achieves a similar level of statistical power as EM-LRT-Prob and, outperforms the standard Dosage method, especially for markers with relatively low MAF or imputation quality. Applications to two real data sets, the Cebu Longitudinal Health and Nutrition Survey study and the Women's Health Initiative Study, provide further support to the validity and efficiency of our proposed methods.


Regulation of alpha 1-adrenergic receptor-coupled calcium flux in cultured vascular smooth muscle cells.
To study the role of the alpha-adrenergic receptor (AAR) pathway in the regulation of catecholamine-induced vascular contraction, we developed methods for the direct evaluation of AAR and AAR-coupled calcium efflux in cultured vascular smooth muscle cells derived from the rabbit aorta by enzymatic dissociation. AAR were characterized by the binding of the alpha 1- and alpha 2-selective radioligands [3H]-prazosin and [3H]-yohimbine, respectively. Norepinephrine-stimulated efflux of 45calcium from preloaded cells was measured as an index of AAR-mediated calcium flux. The [3H]-prazosin binding was of high affinity (Kd = 0.15 nM), saturable (Bmax = 75-125 fmol/mg protein), and competed for by agonists and antagonists in the order expected for an alpha 1 receptor. There was no specific binding of [3H]-yohimbine. Norepinephrine-stimulated 45Ca efflux was concentration-dependent (EC50 congruent to 100 nM), and potently blocked by prazosin (IC50 congruent to 0.1 nM), but not yohimbine (IC50 greater than 100 nM), indicating, together with the binding data, that norepinephrine-stimulated 45Ca efflux in this system is alpha 1 mediated. Following treatment of cells with 1-norepinephrine (0.1 nM) for 24 hours, the density of AAR and maximal norepinephrine-stimulated 45Ca efflux were decreased by 72% +/- 14% and 91% +/- 9%, respectively. This cultured cell system offers several advantages for study of the mechanisms of coupling and regulation of alpha-adrenergic receptors in vascular smooth muscle.


Trial participants' experiences of early enhanced speech and language therapy after stroke compared with employed visitor support: a qualitative study nested within a randomized controlled trial.
To explore trial participants' experiences of the process and outcomes of early, enhanced speech and language therapy after stroke with support from an employed visitor. Qualitative study nested within a randomized controlled trial. Twney-two people who, after stroke, had a diagnosis of aphasia (12), dysarthria (5) or both (5) and who participated in the ACT NoW study. Eight English NHS usual care settings. Individual interviews. Thematic content analysis assisted by a bespoke data transformation protocol for incorporating non-verbal and semantically ambiguous data. Participants highly regarded regular and sustained contact with someone outside of immediate family/friends who engaged them in deliberate activities/communication in the early months after stroke. Participants identified differences in the process of intervention between speech and language therapists and employed visitors. But no major discriminations were made between the impact or value of this contact according to whether provided by a speech and language therapist or employed visitor. Participant-defined criteria for effectiveness of contact included: impact on mood and confidence, self-recognition of progress and the meeting of individual needs. As in the randomized controlled trial, participants reported no evidence of added benefit of early communication therapy beyond that from attention control. The findings do not imply that regular contact with any non-professional can have beneficial effects for someone with aphasia or dysarthria in the early weeks following a stroke. The study points to specific conditions that would have to be met for contact to have a positive effect.


Role of FN1 and GREB1 gene polymorphisms in endometriosis.
Endometriosis is a complex gynecological disorder, affecting up to 10% of women of childbearing age, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic, epigenetic and environmental factors, with an overall heritability estimated at approximately 50%. The aim of the present study was to evaluate the association of rs1250248 and rs11674184 single nucleotide polymorphisms (SNPs), mapping to fibronectin 1 (FN1) and growth regulation by estrogen in breast cancer 1 (GREB1) genetic loci, respectively, with the risk of endometriosis. A total of 166 women with endometriosis (stages I-IV) who were hospitalized for the condition, diagnosed by laparoscopic intervention and histologically confirmed, and 168 normal controls were recruited and genotyped. Genotyping of the rs1250248 and rs11674184 SNPs was performed with TaqMan primer/probe sets. A significant association was detected with the A allele, as well as the AA and AG genotypes of rs1250248 (FN1) in patients with endometriosis, as well as in patients with stage I and II of the disease only. The rs11674184 SNP of the GREB1 gene was not found to be associated with an increased susceptibility to endometriosis either for all patients (stages I-IV) or for subgroups of stage I and II or III and IV of the disease only. Our results demonstrated a genetic association between the rs1250248 (FN1) SNP and endometriosis at both the genotypic and allelic level. However, although rs11674184 of GREB1 constitutes one of the most consistently associated SNPs with endometriosis in European ancestry populations, it was not found to be associated with endometriosis in this study.


Prognostic significance of Jab1 expression in laryngeal squamous cell carcinomas.
Jun activation domain-binding protein 1 (Jab1) is known as a coactivator of AP1 transcription factor, which contributes to tumor progression by degrading the p27kip1 protein. The purpose of this study is to investigate whether Jab1 expression is correlated with p27kip1 level and cell proliferation, as well as whether Jab1 expression is associated with clinicopathologic variables and prognosis of laryngeal squamous cell carcinoma (LSCC). Immunohistochemical and/or Western blot analysis was done in HEp-2 cells and 102 cases of LSCCs. Jab1 expression was negatively associated with p27kip1 expression and was positively associated with cell proliferation both in HEp-2 cells and LSCCs. Jab1 overexpression was detected in 51% LSCCs and was significantly associated with unfavorable clinicopathologic variables. Survival analysis revealed that Jab1 overexpression is significantly associated with short disease-free and overall survival (P = 0.0036 and P = 0.0001, respectively). When Jab1 and p27kip1 are combined, patients with Jab1(+)/p27kip1(-) revealed poor disease-free and overall survival (P= 0.0008 and P < 0.0001, respectively). When Jab1 expression and lymph node status are combined, patients with Jab1(+)/lymph node(+) revealed poorer disease-free andoverall survival than others (P < 0.0001 and P < 0.0001, respectively). Furthermore, patients with the phenotype of Jab1(+)/p27kip1(-)/lymph node(+) revealed the worst disease-free and overall survival (P < 0.0001 and P < 0.0001, respectively). Multivariate analysis revealed that Jab1 protein is an independent prognostic indicator for overall survival. These findings suggested that Jab1 protein may contribute to the tumor progression and represent a novel prognostic indicator for LSCCs.


Evaluation of bone mineral density of the lumbar spine using a novel phantomless dual-energy CT post-processing algorithm in comparison with dual-energy X-ray absorptiometry.
Current techniques for evaluation of bone mineral density (BMD) commonly require phantom calibration. The purpose of this study was to evaluate a novel algorithm for phantomless in vivo dual-energy computed tomography (DECT)-based assessment of BMD of the lumbar spine in comparison with dual-energy X-ray absorptiometry (DEXA). Data from clinically indicated DECT and DEXA examinations within two months comprising the lumbar spine of 47 patients were retrospectively evaluated. By using a novel automated dedicated post-processing algorithm for DECT, the trabecular bone of lumbar vertebrae L1-L4 was selected and analysed. Linear correlation was analysed using Pearson's product-moment correlation coefficient for the comparison of the results from DECT and DEXA. A total of 186 lumbar vertebrae in 47 patients (mean age, 58 years; age range, 24-85 years) were analysed, 24 men (mean age, 55 years; age range, 24-85 years) and 23 women (mean age, 59 years; age range, 31-80 years). Mean BMD of L1-L4 determined with DEXA was 0.985 g/cm2 and 20/47 patients (42.6%) showed an osteoporotic BMD (T score lower than - 2.5) of at least two vertebrae. Average DECT-based BMD of L1-L4 was 86.8 mg/cm3. Regression analysis demonstrated a lack of correlation between DECT- and DEXA-based BMD values with a Pearson's product-moment correlation coefficient r = 0.4205. Dedicated post-processing of DECT data using a novel algorithm for retrospective phantomless BMD assessment of the trabecular bone of lumbar vertebrae from clinically indicated DECT examinations is feasible.


Cytolysis of mammary tumor targets by resting, interleukin-2 stimulated and in vitro cultured peripheral blood lymphocytes from breast cancer patients.
The cytotoxic capacity of resting, interleukin-2 (IL-2)-stimulated and in vitro cultured (3-5 days in 10 U/ml IL-2 containing media) peripheral blood lymphocytes (PBLs) from breast cancer patients to a panel of established mammary tumor cell lines was ascertained. Significant cytolysis (ranging from 7.8 to 12.4%, at an effector: target ratio of 20:1) of all mammary tumor targets (MCF-7, 734B, ZR-75-1, ZR-75-30, BT-20 and Hs578T) by PBLs was demonstrable in 18 h chromium release assays. Natural killer (NK) cytotoxicity was distinct from IL-2 stimulated (5 U/ml) and in vitro cultured PBL cytotoxicity in that resting PBLs were not cytolytic to RAJI cells, normal breast epithelia (Hs578Bst) and fibroblasts. Basal NK activity against mammary tumor targets was significantly reduced in patients receiving chemotherapy when compared to both untreated patients and normal controls. In criss-cross cold target inhibition studies, ZR-75-1 and K562 targets were not mutually competitive in NK cell assays (using resting PBLs) but were mutually competitive in lymphokine-activated killer (LAK) assays (using in vitro cultured PBLs). In eleven independent experiments, basal NK activity of ZR-75-1 cells was increased by a cold target excess of K562 (8.2 +/- 2.4% vs 30.5 +/- 5.2%, mean +/- SE, p greater than 0.01, cold:hot target ratio = 10:1). Interestingly, no such parallel increase of cytolysis of 734B targets by K562 cells was observed. Basal cytotoxicity against ZR-75-1 and K562 targets was serologically depleted using antibodies to natural killer cells HNK-1 and Leu 11b. Thus mammary tumor cell lines parallel autologous tumor cells, yet show features that are distinct from NK-resistant and sensitive lymphoid cell lines in their susceptibility to natural resistant cytolytic mechanisms.


Invasion of epithelial cells by Shigella flexneri induces tyrosine phosphorylation of cortactin by a pp60c-src-mediated signalling pathway.
Shigella flexneri causes bacillary dysentery in humans by invading epithelial cells of the colon. Cell invasion occurs via bacterium-directed phagocytosis, a process requiring polymerization of actin at the site of bacterial entry. We show that invasion of HeLa cells by S.flexneri induces tyrosine phosphorylation of cortactin, a host cell protein previously identified as a cytoskeleton-associated protein tyrosine kinase (PTK) substrate for the proto-oncoprotein pp60c-src. Immunolocalization experiments indicate that cortactin is recruited to submembranous actin filaments formed during bacterial entry. In particular, cortactin is highly enriched in membrane ruffles of the entry structure, which engulf entering bacteria, and also in the periphery of the phagosome early after bacterial internalization. The proto-oncoprotein pp60c-src appears to mediate tyrosine phosphorylation of cortactin, since overexpression of this PTK in HeLa cells specifically increases the level of cortactin tyrosine phosphorylation induced during bacterial entry. Immunolocalization studies in pp60c-src-overexpressing HeLa cells indicate that pp60c-src is recruited to the entry structure and to the periphery of the phagosome, where pp60c-src appears to accumulate in association with the membrane. Our results suggest that epithelial cell invasion by S.flexneri involves recruitment and kinase activation of pp60c-src. Signalling by the proto-oncoprotein pp60c-src may play a role in cytoskeletal changes that facilitate S.flexneri uptake into epithelial cells, since transient overexpression of pp60c-src in HeLa cells can provoke membrane ruffling and appears also to stimulate bacterial uptake of a non-invasive S.flexneri strain.


Identification and distribution of microsymbionts associated with soybean nodulation in Mozambican soils.
Indigenous soybean rhizobial strains were isolated from root nodules sampled from farmers' fields in Mozambique to determine their identity, distribution and symbiotic relationships. Plant infection assays revealed variable nodulation and symbiotic effectiveness among the 43 bacterial isolates tested. Strains from Ruace generally promoted greater whole-plant growth than the others. 16S rRNA-RFLP analysis of genomic DNA extracted from the rhizobial isolates produced different banding patterns, a clear indication of high bacterial diversity. However, the multilocus sequence analysis (MLSA) data showed alignment of the isolates with B. elkanii species. The 16S rRNA sequences of representative soybean isolates selected from each 16S rRNA-RFLP cluster showed their relatedness to B. elkanii, as well as to other Bradyrhizobium species. But a concatenated phylogeny of two housekeeping genes (glnII and gyrB) identified the soybean nodulating isolates as Bradyrhizobium, with very close relatedness to B. elkanii. The nifH and nodC sequences also showed that the majority of the test soybean isolates were closely related to B. elkanii, albeit the inconsistency with some isolates. Taken together, these findings suggest that the B. elkanii group are the preferred dominant microsymbiont of soybean grown in Mozambican soils. Furthermore, the distribution of soybean rhizobia in the agricultural soils of Mozambique was found to be markedly influenced by soil pH, followed by the concentrations of plant-available P and Mn. This study suggested that the identified isolates TUTMJM5, TUTMIITA5A and TUTLBC2B can be used as inoculants for increased soybean production in Mozambique.


Responsive cell-material interfaces.
Major design aspects for novel biomaterials are driven by the desire to mimic more varied and complex properties of a natural cellular environment with man-made materials. The development of stimulus responsive materials makes considerable contributions to the effort to incorporate dynamic and reversible elements into a biomaterial. This is particularly challenging for cell-material interactions that occur at an interface (biointerfaces); however, the design of responsive biointerfaces also presents opportunities in a variety of applications in biomedical research and regenerative medicine. This review will identify the requirements imposed on a responsive biointerface and use recent examples to demonstrate how some of these requirements have been met. Finally, the next steps in the development of more complex biomaterial interfaces, including multiple stimuli-responsive surfaces, surfaces of 3D objects and interactive biointerfaces will be discussed.


Theory-Guided Development of Fertility Care Implementation Strategies for Adolescent and Young Adult Cancer Survivors.
Purpose: Oncofertility care at cancer diagnosis remains underimplemented across oncology and fertility care settings, with limited tools to scale up effective implementation strategies. Using implementation science theory, we systematically assessed factors that influence oncofertility care implementation and mapped scalable strategies, particularly electronic health record (EHR)-enabled ones, that fit adult and pediatric oncology care contexts. Methods: Using purposeful sampling, we recruited health care providers and female, reproductive-aged survivors of adolescent and young adult (AYA) cancers (AYA survivors) from a comprehensive cancer center and a freestanding children's hospital to semistructured interviews and focus groups. Using thematic analysis combining inductive codes with deductive codes using the Consolidated Framework for Implementation Research (CFIR), we characterized barriers and facilitators to care and designed responsive strategies. Two coders independently coded each transcript. Results: We recruited 19 oncology and fertility providers and 9 cancer survivors. We identified barriers and facilitators to oncofertility care in the CFIR domains of individual, inner setting, outer setting, and process, allowing us to conceptualize oncofertility care to encompass three core components (screening, referral, and fertility preservation counseling) and map five strategies to these components that fit an adult and a children's context and bridge oncology and fertility practices. The strategies were screening using a best practice advisory, referral order, telehealth fertility counseling, provider audit and feedback, and provider education. All but provider education were EHR tools with embedded efficiencies. Conclusion: An implementation science approach systematically assessed oncofertility care and mapped strategies to provide a theory-based approach and scalable EHR tools to support wider dissemination.


Neurosubstrates of remission following prolonged exposure therapy in veterans with posttraumatic stress disorder.
Prolonged exposure (PE) therapy is the first-line treatment for posttraumatic stress disorder (PTSD) in combat veterans. The underlying brain changes of treatment effect in PTSD are currently unknown. A total of 31 veterans with PTSD completed an fMRI scan performing an affective anticipation task at baseline and were enrolled in PE therapy. Of these, 7 prematurely terminated therapy, while 24 individuals completed PE therapy and an identical follow-up fMRI scan. At follow-up, 15 of the 24 completers still had diagnosable PTSD (NR-PTSD) and 9 of the 24 completers showed complete remission from PTSD (R-PTSD), i.e. they did not meet diagnostic criteria for PTSD. The left anterior insula showed a significant group by scan session interaction. Specifically, the R-PTSD group showed decreased activation during anticipation of negative images from pre- to posttreatment scans, while the NR-PTSD group showed increased activation during anticipation of positive images in this region. Furthermore, the change in functional activation in the insula co-occurred with increased connectivity between this insular region and the right cingulate and right mid-posterior insular region in R-PTSD. These findings suggest that the capacity to effectively remit from PTSD symptoms after PE treatment requires the ability to connect with physiological signals and moderate the discomfort of anticipatory anxiety of exposure therapy. These processes appear to be controlled by a network where the anterior insula is connected with the cingulate and the mid-posterior insula.


A Specialized Diacylglycerol Acyltransferase Contributes to the Extreme Medium-Chain Fatty Acid Content of Cuphea Seed Oil.
Seed oils of many Cuphea sp. contain >90% of medium-chain fatty acids, such as decanoic acid (10:0). These seed oils, which are among the most compositionally variant in the plant kingdom, arise from specialized fatty acid biosynthetic enzymes and specialized acyltransferases. These include lysophosphatidic acid acyltransferases (LPAT) and diacylglycerol acyltransferases (DGAT) that are required for successive acylation of medium-chain fatty acids in the sn-2 and sn-3 positions of seed triacylglycerols (TAGs). Here we report the identification of a cDNA for a DGAT1-type enzyme, designated CpuDGAT1, from the transcriptome of C. avigera var pulcherrima developing seeds. Microsomes of camelina (Camelina sativa) seeds engineered for CpuDGAT1 expression displayed DGAT activity with 10:0-CoA and the diacylglycerol didecanoyl, that was approximately 4-fold higher than that in camelina seed microsomes lacking CpuDGAT1. In addition, coexpression in camelina seeds of CpuDGAT1 with a C. viscosissima FatB thioesterase (CvFatB1) that generates 10:0 resulted in TAGs with nearly 15 mol % of 10:0. More strikingly, expression of CpuDGAT1 and CvFatB1 with the previously described CvLPAT2, a 10:0-CoA-specific Cuphea LPAT, increased 10:0 amounts to 25 mol % in camelina seed TAG. These TAGs contained up to 40 mol % 10:0 in the sn-2 position, nearly double the amounts obtained from coexpression of CvFatB1 and CvLPAT2 alone. Although enriched in diacylglycerol, 10:0 was not detected in phosphatidylcholine in these seeds. These findings are consistent with channeling of 10:0 into TAG through the combined activities of specialized LPAT and DGAT activities and demonstrate the biotechnological use of these enzymes to generate 10:0-rich seed oils.


An Extended Depth-at-Field Volumetric Near-Eye Augmented Reality Display.
We introduce an optical design and a rendering pipeline for a full-color volumetric near-eye display which simultaneously presents imagery with near-accurate per-pixel focus across an extended volume ranging from 15cm (6.7 diopters) to 4M (0.25 diopters), allowing the viewer to accommodate freely across this entire depth range. This is achieved using a focus-tunable lens that continuously sweeps a sequence of 280 synchronized binary images from a high-speed, Digital Micromirror Device (DMD) projector and a high-speed, high dynamic range (HDR) light source that illuminates the DMD images with a distinct color and brightness at each binary frame. Our rendering pipeline converts 3-D scene information into a 2-D surface of color voxels, which are decomposed into 280 binary images in a voxel-oriented manner, such that 280 distinct depth positions for full-color voxels can be displayed.


Increased depression-related behavior during the postpartum period in inbred BALB/c and C57BL/6 strains.
Pregnancy and lactation are characterized by dramatic changes in the endocrine system and brain in mammalian females. These changes, with stress before pregnancy, are potential risk factors for the development of postpartum depression (PPD). A valid animal model of PPD is needed to understand the neurobiological basis of the depressive state of females. To explore a mouse model of PPD, we first assessed anxiety-like and depression-related behaviors in nulliparous (virgin), nonlactating primiparous, and lactating primiparous females in four inbred strains of mice (C57BL/6J, C57BL/6JJcl, BALB/cAnNCrlCrlj, and BALB/cAJcl). Pups from the nonlactating female group were removed one day after parturition to examine the effects of physical interaction with pups on the postpartum behaviors. Second, we investigated the additional effects of prepregnancy stress (restraint stress for 6 h/day for 21 days) on postpartum behaviors in the BALB/cAJcl strain. We found that females of the two BALB/c substrains showed decreased locomotor activity and increased anxiety-like and depression-related behaviors compared with females of the two C57BL/6 substrains. Behavioral differences were also observed between the two substrains of each strain. Additionally, pregnancy- and lactation-dependent behavioral differences were found in some strains: lactating BALB/cAJcl females traveled shorter distance than the females of the other reproductive state groups, while nonlactating and lactating BALB/cAJcl and C57BL/6J females showed increased depression-related behavior compared with nulliparous females. Lactating BALB/cAJcl and C57BL/6JJcl females exhibited decreased sucrose preference or anhedonia-like behavior compared with nulliparous and nonlactating females, although these results did not reach statistical significance after correction for multiple testing. An additional independent experiment replicated the marked behavioral changes in lactating BALB/cAJcl females. Moreover, increased anxiety-like behavior was observed in lactating BALB/cAJcl females that experienced prepregnancy stress. These results suggest genetic contributions to the regulation of anxiety-like and depression-related behaviors in female mice. Furthermore, this study suggests that pregnancy and lactation cause decreased locomotor activity and increased depression-related behaviors, which was consistently found in our results, and that prepregnancy stress enhances anxiety-like behavior in the BALB/cAJcl strain. The inbred strain of female mice may be used as a potential model of PPD to further study the genetic and neurobiological mechanisms underlying the development of this disorder.


Biological activity of propolis-honey balm in the treatment of experimentally-evoked burn wounds.
Medicines of biogenic origin with micro-organic, regenerative and analgesic properties are becoming more and more significant in the treatment of burn wounds. These properties are found in apitherapeutics such as propolis and honey--products collected and processed by a honey bee. Their effect on the course of the healing processes is multidirectional. The aim of the study was a histopathological and biochemical analysis of the processes of scar formation in experimentally evoked burn wounds in white pigs treated with the 1% and 3% Sepropol balms containing standardized extracts of propolis and honey. The results were compared with the therapeutic effects obtained with dermazin cream (1% silver sulfadiazine). The level of collagen was determined in the wounds treated with 1% and 3% Sepropol and compared with the collagen level in healthy skin and wounds treated with dermazin. Granulation and regenerated epithelium formation times were compared, with the 3% Sepropol being by far the most effective. The 3% Sepropol also increased the collagen level to 116% with the control sub-groups scoring between 80% and 98%. The results show the healing process of burn wounds in pigs treated with the Sepropol balm starts earlier and has a faster course than the standard dermazin therapy.


The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review.
Tonsillectomy (TE) or adenotonsillectomy (ATE) may have a beneficial effect on the clinical course in children with the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. However, an immunological reason for this effect remains unknown. This literature review summarizes the current knowledge regarding the immunological role of the tonsils in the PFAPA syndrome. We searched PubMed, Medline, EMBASE and Cochrane for papers written in English dated from 1 January 1987 to 30 April 2019. The search included all studies reporting histological, immunological or microbiological workup of tonsil specimens from children aged 0-18 years with PFAPA. Thirteen articles reported histological, immunological or microbiological workup of tonsil specimens in children with PFAPA. The histology of tonsil specimens from children with PFAPA displayed chronic tonsillar inflammation with lymphoid hyperplasia. No uniform immunological pattern was identified, but some studies found fewer B-lymphocytes and smaller germinal centers in PFAPA compared to controls. A difference in tonsillar microbiota between PFAPA and controls was found in one study. A uniform immunological or microbiological pattern explaining the clinical effect of TE in children with PFAPA has not been revealed. Future targeted immunological studies of tonsils in PFAPA patients could possibly illuminate the understanding of the immunology in this disease.


A novel mechanism of fluconazole: fungicidal activity through dose-dependent apoptotic responses in Candida albicans.
Fluconazole (FLC) is a well-known fungistatic agent that inhibits ergosterol biosynthesis. We showed that FLC exhibits dose-dependent fungicidal activity, and investigated the fungicidal mechanism of FLC on Candida albicans. To confirm the relationship between fungicidal activity and the inhibition of ergosterol, we assessed membrane dysfunctions via propidium iodide influx and potassium leakage, as well as morphological change. Interestingly, while membrane disruption was not observed at all tested concentrations of FLC, potassium efflux and cell shrinkage were observed at high dosages of FLC (HDF). Low-dosage FLC (LDF) treatment did not induce significant changes. Next, we examined whether the fungicidal activity of FLC was associated with apoptosis in C. albicans. FLC caused dose-dependent apoptotic responses, including phosphatidylserine externalization and DNA fragmentation. It was also involved in glutathione depletion followed by oxidative damage. In particular, unlike LDF, HDF leads to the disruption of mitochondrial homeostasis, including mitochondrial membrane depolarization and accumulation of calcium and reactive oxygen species. HDF-induced mitochondrial dysfunction promoted the release of cytochrome c from mitochondria to the cytosol, and activated intracellular metacaspase. In conclusion, the dose-dependent fungicidal activity of FLC was due to an apoptotic response in C. albicans.


Meta-analysis of the association between progression-free survival and overall survival in metastatic colorectal cancer.
The validity of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in metastatic colorectal cancer (mCRC) trials has been studied, primarily in first-line treatment. The relationship between PFS and OS has not been well studied in later lines of treatment. We conducted a systematic literature review of mCRC phase 2 and 3 clinical trials that reported OS and PFS (or time-to-progression [TTP]) data. Correlation between endpoints (either PFS alone or PFS aggregated with TTP [PFS_TTP]) was estimated within treatment arms. Treatment effect was the ratio of the median time to OS, PFS, or PFS_TTP in the "control" versus "experimental" arm. We conducted meta-regression analyses and performed receiver-operating characteristic (ROC) analysis. We analyzed data from 62 articles (23,527 patients). A high positive correlation was found between median PFS_TTP and median OS within treatment arms (r = 0.87; 95% confidence interval [CI], 0.82-0.91) and also between the median OS and median PFS (r = 0.89, 95% CI, 0.83-0.93)]. R(2) was 0.48 for PFS_TTP and 0.59 for PFS; R (2) for PFS_TTP was higher for first-line (R(2) = 0.54) than second-line studies (R(2) = 0.38). The ROC analysis is presented as a conceptual tool for evaluating the performance of PFS as a surrogate for OS at various thresholds. The correlation of PFS, alone or aggregated with TTP, with OS in clinical trials of patients with mCRC is robust across lines of therapy and provides a useful means of predicting improvements in OS using PFS data.


Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice.
We previously found that chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, we examined the effects of chronic alcohol consumption on the functionality and regulation of these cells in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-gamma producing T cells in the tumor-bearing mice. Foxp3(+)CD4(+)CD25(+) regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation as determined by carboxyfluorescein succinimidyl ester labeling experiments in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-gamma producing CD8(+) T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival.


Comparative analysis of in vitro fertilization methods for establishing successful embryo transfer clinics.
A review of the laboratory methods and embryo transfer procedures used by seven of the foremost clinics in the world are discussed and evaluated in this article. Based on these facts an in vitro fertilization clinic was launched in 1983. In the second part of the paper the latest laboratory methods, i.e. ovulation induction plans and the embryo transfer technique of Tygerberg Hospital, are described. One hundred and thirty laparoscopies were performed since 1 May 1984-30 November 1984. Six hundred and one follicles were aspirated, 482 oocytes were obtained, 84% of all oocytes were fertilized, 112 patients reached the transfer stage and 28 pregnancies resulted. A clinical pregnancy rate of 21,4% per transfer and 18,5% per laparoscopy resulted.


Targeting SR-BI for Cancer Diagnostics, Imaging and Therapy.
Scavenger receptor class B type I (SR-BI) plays an important role in trafficking cholesteryl esters between the core of high density lipoprotein and the liver. Interestingly, this integral membrane protein receptor is also implicated in the metabolism of cholesterol by cancer cells, whereby overexpression of SR-BI has been observed in a number of tumors and cancer cell lines, including breast and prostate cancers. Consequently, SR-BI has recently gained attention as a cancer biomarker and exciting target for the direct cytosolic delivery of therapeutic agents. This brief review highlights these key developments in SR-BI-targeted cancer therapies and imaging probes. Special attention is given to the exploration of high density lipoprotein nanomimetic platforms that take advantage of upregulated SR-BI expression to facilitate targeted drug-delivery and cancer diagnostics, and promising future directions in the development of these agents.


Alien knowledge: preparing student midwives for learning about infant feeding--education practice at a UK university.
Infant feeding education forms a key element in undergraduate midwifery education in the UK. Students must be prepared to provide women with support and information to make appropriate health choices for themselves and their infants. However, student midwives may already have developed opinions about infant feeding prior to commencing a midwifery education programme. The education literature suggests that existing attitudes may present a barrier to learning for some students. This particularly applies to learning in relation to sensitive or emotionally laden subjects. A review of the literature was undertaken to identify potential teaching approaches which might help students to overcome barriers to learning. Following this the evidence was utilised at a UK university to develop activities which prepare student midwives for effective learning around infant feeding. Students enrolled in the midwifery education programme were introduced to a number of activities aimed at encouraging them to accommodate unfamiliar ideas or 'alien knowledge'. These included placing students in situations which challenged their ideas, as well as engaging in group discussions and reflective exercises. The impact of these educational interventions was identified through formative and summative assessment, and through evaluation of the teaching strategy at the end of the programme. This demonstrated that, amongst those students with previously negative attitudes towards infant feeding, there was a move towards more positive attitudes and a greater confidence in providing evidence based information to parents.


Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia.
We reported before that the minimal alveolar concentration (MAC) of isoflurane is decreased in complex I-deficient mice lacking the NDUFS4 subunit of the respiratory chain (RC) (1.55 and 0.81% at postnatal (PN) 22-25 days and 1.68 and 0.65% at PN 31-34 days for wildtype (WT) and CI-deficient KO, respectively). A more severe respiratory depression was caused by 1.0 MAC isoflurane in KO mice (respiratory rate values of 86 and 45 at PN 22-25 days and 69 and 29 at PN 31-34 days for anesthetized WT and KO, respectively). Here, we address the idea that isoflurane anesthesia causes a much larger decrease in brain mitochondrial ATP production in KO mice thus explaining their increased sensitivity to this anesthetic. Brains from WT and KO mice of the above study were removed immediately after MAC determination at PN 31-34 days and a mitochondria-enriched fraction was prepared. Aliquots were used for measurement of maximal ATP production in the presence of pyruvate, malate, ADP and creatine and, after freeze-thawing, the maximal activity of the individual RC complexes in the presence of complex-specific substrates. CI activity was dramatically decreased in KO, whereas ATP production was decreased by only 26% (p < 0.05). The activities of CII, CIII, and CIV were the same for WT and KO. Isoflurane anesthesia decreased the activity of CI by 30% (p < 0.001) in WT. In sharp contrast, it increased the activity of CII by 37% (p < 0.001) and 50% (p < 0.001) and that of CIII by 37% (p < 0.001) and 40% (p < 0.001) in WT and KO, respectively, whereas it tended to increase that of CIV in both WT and KO. Isoflurane anesthesia increased ATP production by 52 and 69% in WT (p < 0.05) and KO (p < 0.01), respectively. Together these findings indicate that isoflurane anesthesia interferes positively rather than negatively with the ability of CI-deficient mice brain mitochondria to convert their main substrate pyruvate into ATP.


Habitat-specific locomotor variation among Chinese hook snout carp (Opsariichthys bidens) along a river.
The Wujiang River is a tributary of the upper Yangtze River that shows great variations in its flow regime and habitat condition. Dams have been built along the Wujiang River and have altered the habitats profoundly enough that they may give rise to reproductive isolation. To test whether the swimming performance and morphology of the Chinese hook snout carp (Opsariichthys bidens), varied among habitats and whether the possible differences had a genetic basis, we measured the steady and unsteady swimming performance, external body shape and genetic distance among fish collected from both the main and tributary streams of the upper, middle and lower reaches along the river. We also measured the routine energy expenditure (RMR), maximum metabolic rate (MMR), cost of transport (COT) and calculated the optimal swimming speed. The steady swimming capacity, RMR, MMR and optimal swimming speed were all higher and the COT was lower in the upper reach or tributary streams compared with the lower reach or main stream. However, unsteady swimming performance showed no variation among collecting sites. Flow regimes as suggested by river slope and water velocity were positively correlated with steady swimming performance but not with unsteady swimming performance. Predation stress were significantly related with body morphology and hence energy cost during swimming but not U(crit) value. The fish from only one population (Hao-Kou) showed relatively high genetic differentiation compared with the other populations. Fish from the upper reach or tributary streams exhibited improved steady swimming performance through improved respiratory capacity and lower energy expenditure during swimming at the cost of higher maintenance metabolism. There was no correlation between the steady and unsteady swimming performance at either the population or the individual levels. These results suggest that a trade-off between steady and unsteady swimming does not occur in O. bidens.


Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques.
Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.


Evolution of alternative and constitutive regions of mammalian 5'UTRs.
Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized. We evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation. The findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation.


Multivariate patterns of gray matter volume in thalamic nuclei are associated with positive schizotypy in healthy individuals.
Previous models suggest biological and behavioral continua among healthy individuals (HC), at-risk condition, and full-blown schizophrenia (SCZ). Part of these continua may be captured by schizotypy, which shares subclinical traits and biological phenotypes with SCZ, including thalamic structural abnormalities. In this regard, previous findings have suggested that multivariate volumetric patterns of individual thalamic nuclei discriminate HC from SCZ. These results were obtained using machine learning, which allows case-control classification at the single-subject level. However, machine learning accuracy is usually unsatisfactory possibly due to phenotype heterogeneity. Indeed, a source of misclassification may be related to thalamic structural characteristics of those HC with high schizotypy, which may resemble structural abnormalities of SCZ. We hypothesized that thalamic structural heterogeneity is related to schizotypy, such that high schizotypal burden would implicate misclassification of those HC whose thalamic patterns resemble SCZ abnormalities. Following a previous report, we used Random Forests to predict diagnosis in a case-control sample (SCZ = 131, HC = 255) based on thalamic nuclei gray matter volumes estimates. Then, we investigated whether the likelihood to be classified as SCZ (π-SCZ) was associated with schizotypy in 174 HC, evaluated with the Schizotypal Personality Questionnaire. Prediction accuracy was 72.5%. Misclassified HC had higher positive schizotypy scores, which were correlated with π-SCZ. Results were specific to thalamic rather than whole-brain structural features. These findings strengthen the relevance of thalamic structural abnormalities to SCZ and suggest that multivariate thalamic patterns are correlates of the continuum between schizotypy in HC and the full-blown disease.


[Fluorine as a factor in premature aging].
The use of fluorine compounds in various areas of medicine, particularly in dentistry, as well as in agriculture and industry became very popular in the second half of the 20th century. Fluorine owed this widespread acceptance to observations that its compounds stimulate ossification processes and reduce the prevalence of caries. Unfortunately, growing expectations overshadowed the truth regarding interactions of fluoride on the molecular level. The fact was often ignored that fluoride is toxic, even though laboratory data stood for a careful approach to the benefits of usage. Excessive exposure to fluoride may lead to acute poisoning, hyperemia, cerebral edema, and degeneration of the liver and kidneys. Acute intoxication through the airways produces coughing, choking, and chills, followed by fever and pulmonary edema. Concentrated solutions of fluorine compounds produce difficult to heal necrotic lesions. In spite of these dramatic symptoms, acute intoxications are relatively rare; the more common finding is chronic intoxication attributable to the universal presence of fluorine compounds in the environment. The first noticeable signs of excessive exposure to fluoride in contaminated water, air, and food products include discolorations of the enamel. Dental fluorosis during tooth growth and loss of dentition in adulthood are two consequences of chronic intoxication with fluorine compounds. Abnormalities in mineralization processes affect by and large the osteoarticular system and are associated with changes in the density and structure of the bone presenting as irregular mineralization of the osteoid. Fluorine compounds also act on the organic part of supporting tissues, including collagen and other proteins, and on cells of the connective tissue. These interactions reduce the content of collagen proteins, modify the structure and regularity of collagen fibers, and induce mineralization of collagen. Interactions with cells produce transient activation of osteoblasts, stimulate fibroblasts to produce collagenase, and trigger toxic reactions in osteocytes and chondrocytes of trabecular bone. Growing deformations of the skeleton reduce mobility and result in permanent crippling of the patient. Fluoride increases the mass of non-collagen proteins such as proteoglycans and glucosaminoglycans, accelerating skin aging even though protein biosynthesis is generally suppressed. The final outcome includes progressive vascular lesions and disorders of energy metabolism in muscles. In conclusions, the use of fluoride, particularly by dentists and pediatricians, must be controlled and adapted to individual needs. It is worth remembering that fluoride: is the cause of disability due to bone deformations and abnormalities in the musculoskeletal system; reduces the incidence of caries but do not protect against tooth loss; exerts an adverse effect of metabolic processes in the skin; accelerates calcification of vessels and thus reduces their elasticity; inhibits bioenergetic reactions, in particular oxidative phosphorylation, reducing physical activity of muscles. These findings suggest that fluorine may be yet another factor in accelerated aging and revive the dispute started more than two and half thousand years ago whether aging is a physiologic or pathologic process. The understanding of factors modifying the process of aging is the basis for preventive measures aimed at extending life and maintaining full psychosocial activity.


Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation.
EBV, an oncogenic human herpesvirus, can transform primary B lymphocytes into immortalized lymphoblastoid cell lines (LCLs) through multiple regulatory mechanisms. However, the involvement of protein tyrosine kinases in the infinite proliferation of B cells is not clear. In this study, we performed kinase display assays to investigate this subject and identified a specific cellular target, Recepteur d'Origine Nantais (RON) tyrosine kinase, expressed in LCLs but not in primary B cells. Furthermore, we found that latent membrane protein 1 (LMP1), an important EBV oncogenic protein, enhanced RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-κB binding to the RON promoter. RON knockdown decreased the proliferation of LCLs, and transfection with RON compensated for the growth inhibition caused by knockdown of LMP1. Immunohistochemical analysis revealed a correlation between LMP1 and RON expression in biopsies from posttransplantation lymphoproliferative disorder (PTLD), suggesting that LMP1-induced RON expression not only is essential for the growth of LCLs but also may contribute to the pathogenesis of EBV-associated PTLD. Our study is the first to reveal the impact of RON on the proliferation of transformed B cells and to suggest that RON may be a novel therapeutic target for EBV-associated lymphoproliferative diseases.


Gender differences in barriers to alcohol and other drug treatment in Cape Town, South Africa.
The study aimed to identify gender differences in barriers to alcohol and other drug (AOD) treatment use among disadvantaged communities in Cape Town, South Africa. The Behavioral Model of Health Services Utilization was used as an analytic framework. A case-control design was used to compare 434 individuals with AOD problems from disadvantaged communities who had accessed treatment with 555 controls who had not accessed treatment on a range of variables. Logistic regression procedures were employed to examine the unique profile of variables associated with treatment utilization for male and female participants. Few gender differences emerged in terms of the pattern of variables associated with AOD treatment use. Greater awareness of treatment options and fewer geographic access and affordability barriers were strongly associated with an increased likelihood of AOD treatment use for both men and women from disadvantaged communities. However, while similar types of barriers to treatment were reported by men and women, these barriers had a greater impact on treatment utilization for women compared to men. Compared to men, women from disadvantaged communities in South Africa do not have equal access to AOD treatment. Recommendations on how to reduce these barriers and ways to improve AOD treatment use among women from disadvantaged communities in South Africa are provided.


Assessing the Effectiveness of an Extender Model Partnership in Implementing a Multicomponent, School-Based Nutrition Intervention.
Childhood obesity continues to be a problem of national concern; school-based obesity prevention programs that incorporate nutrition education are among the efforts to address this issue. Implementation of these programs is often conducted through partner agencies like the Supplemental Nutrition Assistance Program Education (SNAP-Ed). As educators within these agencies have limited time and many schools qualify for programming, developing programs that extend reach by partnering with classroom teachers to deliver nutrition education is critical. The purpose of this article is to evaluate the effectiveness of a teacher extender model compared with direct nutrition education from trained staff using the research-tested, evidence-based Shaping Healthy Choices Program. Data collected as part of this evaluation in intervention and control groups included nutrition knowledge, body mass index percentile, and vegetable identification in youth; lesson fidelity observations and feasibility from teachers; and demographics from parents. Overall, unequal within variances did not allow for the statistical power to detect change. Generally, teachers enjoyed the program but found it too time-consuming to implement. While results were unclear, important lessons were learned regarding the implementation of extender programs warranting further research. Overall, this study aligns with others in the literature that indicate time is a major barrier to implementing nutrition education in the classroom. This study underscores the need for policy mandating nutrition education in schools.


The rate of rise of alveolar carbon dioxide pressure during expiration in man.
1. The purpose of the study was to see whether the rate of rise of alveolar PCO2 (PA, CO2) in expiration was directly proportional to the rate of pulmonary elimination of CO2 (VCO2) in man in the steady state. 2. Alveolar ventilation at rest and during exercise in man was calculated from the difference between total ventilation and dead space ventilation, and from the ratio of the rate of pulmonary CO2 elimination to the mean expired alveolar CO2 (total) fraction. The results were indistinguishable. In agreement with other workers' findings alveolar ventilation changed in direct proportion to the rate of carbon dioxide elimination, confirming the isocapnia of exercise ventilation in man. 3. The rate of rise of expiratory alveolar PCO2 in individual breaths has been obtained by two methods. In the first, a pattern of respiration with constant expiratory flow in each breath brought expiratory alveolar profiles to the outermost end of the airway. In the second method, the early part of the alveolar PCO2 during normal expiration was calculated from airway PCO2 and expired volume. 4. The data obtained with both methods show that, in the steady state, expiratory alveolar PCO2 rises at a rate which is directly proportional to the rate of CO2 production.


Emergency contraception in Senegal: challenges and opportunities.
This paper highlights lessons from introductory efforts and presents new data on community, provider and key opinion leader perspectives to support expanded use of emergency contraception (EC) in Senegal. The paper draws on four data sources: (i) a literature review; (ii) a secondary analysis of a household survey conducted by the Urban Reproductive Health Initiative; (iii) in-depth interviews with key opinion leaders; and (iv) a quantitative survey of healthcare providers from a range of service delivery points. ANALYSIS OF DATA: Knowledge of EC among women is low in urban areas, with only 20% of women having heard of the method and 4% having ever used it. There were serious gaps in providers' technical knowledge about EC; only 57% knew its mode of action and 34% were aware of the need for timely use (within 120 h). Moreover, nearly half reported reluctance to provide EC to married women and even fewer were willing to provide it to youths, particularly to adolescent girls. Responses from key opinion leaders were mixed, demonstrating ambivalence about EC and how it could be offered. In Senegal, the current positive political climate for family planning provides a good opportunity for strengthening EC programming to address knowledge and attitudinal barriers among providers, key opinion leaders and communities.


Random migration of induced pluripotent stem cell-derived human gastrulation-stage mesendoderm.
Gastrulation is the initial systematic deformation of the embryo to form germ layers, which is characterized by the placement of appropriate cells in their destined locations. Thus, gastrulation, which occurs at the beginning of the second month of pregnancy, is a critical stage in human body formation. Although histological analyses indicate that human gastrulation is similar to that of other amniotes (birds and mammals), much of human gastrulation dynamics remain unresolved due to ethical and technical limitations. We used human induced pluripotent stem cells (hiPSCs) to study the migration of mesendodermal cells through the primitive streak to form discoidal germ layers during gastrulation. Immunostaining results showed that hiPSCs differentiated into mesendodermal cells and that epithelial-mesenchymal transition occurred through the activation of the Activin/Nodal and Wnt/beta-catenin pathways. Single-cell time-lapse imaging of cells adhered to cover glass showed that mesendodermal differentiation resulted in the dissociation of cells and an increase in their migration speed, thus confirming the occurrence of epithelial-mesenchymal transition. These results suggest that mesendodermal cells derived from hiPSCs may be used as a model system for studying migration during human gastrulation in vitro. Using random walk analysis, we found that random migration occurred for both undifferentiated hiPSCs and differentiated mesendodermal cells. Two-dimensional random walk simulation showed that homogeneous dissociation of particles may form a discoidal layer, suggesting that random migration might be suitable to effectively disperse cells homogeneously from the primitive streak to form discoidal germ layers during human gastrulation.


Is there a pulse wave encephalopathy component to multiple sclerosis?
The dominant hypothesis in multiple sclerosis is that it is an autoimmune disease; however, there is considerable evidence that the immune attack on myelin may be secondary to a cytodegenerative event. Furthermore, the immune modulating therapies longest in clinical use, although modulating the frequency and severity of exacerbation, do not affect long-term progression towards disability. Clearly alternative perspectives on the etiology of multiple sclerosis are warranted. In this paper I outline the commonalities between idiopathic normal pressure hydrocephalus and multiple sclerosis. These include decreased intracranial compliance as evidenced by increased cerebrospinal fluid volume and velocity of cerebrospinal fluid flow through the cerebral aqueduct; increased ventricular volume; periventricular demyelination lesions; increase in size of Virchow-Robin spaces; presence of Hakim's triad comprised of locomotory disabilities, cognitive problems and bladder control problems. Furthermore, multiple sclerosis is associated with decreased arterial compliance. These are all suggestive that there is a pulse wave encephalopathy component to multiple sclerosis. There are enough resemblances between normal pressure hydrocephalus and multiple sclerosis to warrant further investigation. Whether decreases in intracranial compliance is a consequence of multiple sclerosis or is a causal factor is unknown. Effective therapies can only be developed when the etiology of the disease is understood.


Analysis of stress in the active site of myosin accompanied by conformational changes in transient state intermediate complexes using photoaffinity labeling and 19F-NMR spectroscopy.
Myosin forms stable ternary complexes with ADP and the phosphate analogues, fluoroaluminate (Al F4-), fluoroberyllate (BeFn) or orthovanadate (Vi); these ternary complexes mimic transient intermediates in the myosin ATPase cycle. Moreover, we previously demonstrated that these complexes may mimic different myosin ATPase reaction intermediates corresponding to separate steps in the cross-bridge cycle [Maruta, S., Henry, G. D., Sykes, B. D. & Ikebe, M. (1993) J. Biol. Chem. 268, 7093-7100]. Park et al. suggested that the changing conformation of ATP during hydrolysis stresses the active site of myosin subfragment-1 (S-1) through protein-nucleotide contacts at the gamma-phosphate and nucleotide base, and the stress-induced strain in the cross-bridge may be the mechanism by which energy in ATP is transferred to the myosin structure [Park, S., Ajtai, K. & Burghardt, T. P. (1997) Biochemistry 36, 3368-3372]. In the present study, the photoactive ADP analogue, 3'-O-(N-methylanthraniloyl)-2-azido-ADP (Mant-2-N3-ADP), and the 19F-labeled ADP analogue, 2-[(trifluoromethylnitrophenyl)aminoethyl]diphosphate, were employed to examine conformational differences in protein-nucleotide contact in the ATP-binding site that may correlate with energy transduction. Mant-2-N3-ADP was trapped within the active site of skeletal and smooth muscle myosin in the presence of AlF4-, BeFn or Vi. For both skeletal and smooth muscle myosins, trapped Mant-2-N3-ADP was covalently linked to the 25-kDa N-terminal fragment of S-1 of both myosin/Mant-2-N3-ADP/AlF4- and BeFn complexes, presumably at Trp130. However, the efficiency of the incorporation was much higher for skeletal than for smooth muscle myosin suggesting that the conformations of the adenine-binding pockets of the two myosins are somewhat different. Although the amount of Mant-2-N3-ADP trapped in the presence of AlF4- and BeFn was the same for both myosins, the efficiency of photolabeling skeletal muscle myosin was approximately two times higher for BeFn complex than for AlF4- complex. The 19F-NMR spectra of the bound 2-[(trifluoromethylnitrophenyl)aminoethyl]diphosphate in the ternary complexes formed in the presence of AlF4-, BeFn or Vi showed small but distinguishable differences. Taken together, these results indicate that there is some variation in the protein-nucleotide contacts at the nucleotide base among the ternary complexes studied, and these differences mimic separate steps occurring transiently during the contractile cycle.


Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs.
Argonaute proteins associate with small RNAs that guide mRNA degradation, translational repression, or a combination of both. The human Argonaute family has eight members, four of which (Ago1 through Ago4) are closely related and coexpressed in many cell types. To understand the biological function of the different Ago proteins, we set out to determine if Ago1 through Ago4 are associated with miRNAs as well as RISC activity in human cell lines. Our results suggest that miRNAs are incorporated indiscriminately of their sequence into Ago1 through Ago4 containing microRNPs (miRNPs). Purification of the FLAG/HA-epitope-tagged Ago containing complexes from different human cell lines revealed that endonuclease activity is exclusively associated with Ago2. Exogenously introduced siRNAs also associate with Ago2 for guiding target RNA cleavage. The specific role of Ago2 in guiding target RNA cleavage was confirmed independently by siRNA-based depletion of individual Ago members in combination with a sensitive positive-readout reporter assay.


Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts.
Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors are implanted directly into mice. Increased understanding of the application and limitations of PDXs will facilitate their rational use. Studies to date have not reported protein profiles of PDXs. Therefore, we developed a large cohort of HNSCC PDXs and found that tumor take rate was not influenced by the clinical, pathologic, or processing features. Protein expression profiles, from a subset of the PDXs, were characterized by reverse-phase protein array and the data was compared with The Cancer Genome Atlas HNSCC data. Cluster analysis revealed that HNSCC PDXs were more similar to primary HNSCC than to any other tumor type. Interestingly, while a significant fraction of proteins were expressed similarly in both primary HNSCC and PDXs, a subset of proteins/phosphoproteins were expressed at higher (or lower) levels in PDXs compared with primary HNSCC. These findings indicate that the proteome is generally conserved in PDXs, but mechanisms for both positive and negative model selection and/or differences in the stromal components exist. Proteomic characterization of HNSCC PDXs demonstrates potential drivers for model selection and provides a framework for improved utilization of this expanding model system.


Hyperbaric oxygen therapy protects against mitochondrial dysfunction and delays onset of motor neuron disease in Wobbler mice.
The Wobbler mouse is a model of human motor neuron disease. Recently we reported the impairment of mitochondrial complex IV in Wobbler mouse CNS, including motor cortex and spinal cord. The present study was designed to test the effect of hyperbaric oxygen therapy (HBOT) on (1) mitochondrial functions in young Wobbler mice, and (2) the onset and progression of the disease with aging. HBOT was carried out at 2 atmospheres absolute (2 ATA) oxygen for 1 h/day for 30 days. Control groups consisted of both untreated Wobbler mice and non-diseased Wobbler mice. The rate of respiration for complex IV in mitochondria isolated from motor cortex was improved by 40% (P<0.05) after HBOT. The onset and progression of the disease in the Wobbler mice was studied using litters of pups from proven heterozygous breeding pairs, which were treated from birth with 2 ATA HBOT for 1 h/day 6 days a week for the animals' lifetime. A "blinded" observer examined the onset and progression of the Wobbler phenotype, including walking capabilities ranging from normal walking to jaw walking (unable to use forepaws), and the paw condition (from normal to curled wrists and forelimb fixed to the chest). These data indicate that the onset of disease in untreated Wobbler mice averaged 36+/-4.3 days in terms of walking and 40+/-5.7 days in terms of paw condition. HBOT significantly delayed (P<0.001 for both paw condition and walking) the onset of disease to 59+/-8.2 days (in terms of walking) and 63+/-7.6 days (in terms of paw condition). Our data suggest that HBOT significantly ameliorates mitochondrial dysfunction in the motor cortex and spinal cord and greatly delays the onset of the disease in an animal model of motor neuron disease.


Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial.
Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged >/=70 y with mild vitamin B-12 deficiency. In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 microg vitamin B-12, 1000 microg vitamin B-12 + 400 microg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function.


Sites of neocortical reorganization critical for remote spatial memory.
The hippocampus is crucial for spatial memory formation, yet it does not store long-lasting memories. By combining functional brain imaging and region-specific neuronal inactivation in mice, we identified prefrontal and anterior cingulate cortices as critical for storage and retrieval of remote spatial memories [correction]. Imaging of activity-dependent genes also revealed an involvement of parietal and retrosplenial cortices during consolidation of remote memory. Long-term memory storage within some of these neocortical regions was accompanied by structural changes including synaptogenesis and laminar reorganization, concomitant with a functional disengagement of the hippocampus and posterior cingulate cortex [correction]. Thus, consolidation of spatial memory requires a time-dependent hippocampal-cortical dialogue, ultimately enabling widespread cortical networks to mediate effortful recall and use of cortically stored remote memories independently.


Magnetic scattering effects in two-band superconductor: the ferromagnetic dopants in MgB₂.
This paper demonstrates the magnetic scattering effects on the electron-phonon interaction in two-band superconductors based on the transition-metal-doped MgB₂ to clarify the effects of magnetic dopants on multi-band superconductivity. The phonon properties of polycrystalline Mg(1-x)M(x)B₂ (M = Fe, Ni and Co), with x up to 0.05, were studied, with the investigation based on the normal state Raman spectra, especially the variation of the E(2g) mode. The magnetic scattering effect of Fe is much weaker than that of Mn in MgB₂, while it is stronger than that of Ni. The weak magnetic scattering effects are responsible for the superconducting behaviors of Mg(1 - x)Fe(x)B₂ and Mg(1 - x)Ni(x)B₂. Co shows almost no magnetic scattering effects on the superconductivity, while the depression of the critical temperature, T(c), in Mg(1 - x)Co(x)B₂ is attributed to the phonon behavior and is independent of the ferromagnetic nature of cobalt.


Polygermanes: bandgap engineering via tensile strain and side-chain substitution.
Successful synthesis of the phenylisopropyl hexagermane (Chem. Commun. 2013, 49, 8380) offers an exciting opportunity to synthesize a new class of low-dimensional germanium compounds with novel optical and electronic properties. Using the phenylisopropyl hexagermane as a model template, we have performed an ab initio study of electronic properties of polygermanes. Our density functional theory calculations show that the polygermane is a quasi-one-dimensional semiconductor with a direct bandgap, and its valence and conduction bands are mainly contributed by the skeletal Ge atoms. We have also explored effects of tensile and compressive strains and various side-chain substituents on the bandgap. The bandgap of polygermanes can be reduced upon attaching larger-sized substituents to the side chains. More importantly, applying a tensile/compressive strain can modify the bandgap of polygermanes over a wide range. For poly(diphenlygermane), the tensile strain can result in significant bandgap reduction due to the increasingly delocalized charge density in the conduction band. Moreover, a strong compressive strain can induce a direct-to-indirect semiconductor transition owing to the change made in the band-edge states. A similar strain effect is seen in polystannanes as well.


Contribution of Mass Spectrometry-Based Proteomics to Discoveries in Developmental Biology.
Understanding multicellular organism development from a molecular perspective is no small feat, yet this level of comprehension affords clinician-scientists the ability to identify root causes and mechanisms of congenital diseases. Inarguably, the maturation of molecular biology tools has significantly contributed to the identification of genetic loci that underlie normal and aberrant developmental programs. In combination with cell biology approaches, these tools have begun to elucidate the spatiotemporal expression and function of developmentally-regulated proteins. The emergence of quantitative mass spectrometry (MS) for biological applications has accelerated the pace at which these proteins can be functionally characterized, driving the construction of an increasingly detailed systems biology picture of developmental processes. Here, we review the quantitative MS-based proteomic technologies that have contributed significantly to understanding the role of proteome regulation in developmental processes. We provide a brief overview of these methodologies, focusing on their ability to provide precise and accurate proteome measurements. We then highlight the use of discovery-based and targeted mass spectrometry approaches in model systems to study cellular differentiation states, tissue phenotypes, and spatiotemporal subcellular organization. We also discuss the current application and future perspectives of MS proteomics to study PTM coordination and the role of protein complexes during development.


Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.
The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.


Proton Control of the Lanthanoid Single-Ion Magnet Behavior of a Double-Decker Complex with an Indolenine-Substituted Annulene Ligand.
Two double-decker complexes with annulene ligands functionalized with indolenine groups were synthesized and characterized. The position of the proton acting as a counterion on one of the four indolenine nitrogen atoms was determined by using DFT calculations. Deprotonation and protonation of the complex induced by adding a base and an acid, respectively, were monitored by using NMR spectroscopy. Moreover, a correlation among the degree of protonation of the complex, the opening of the hysteresis, and the slow relaxation time is discussed.


Associations of polyunsaturated fatty acids with residual depression or anxiety in older people with major depression.
Depression in late life often follows a chronic course with residual depressive and anxiety symptoms. Levels of omega-3 polyunsaturated fatty acids (PUFAs) have been found to be depleted in people with major depression in the acute stage. Additionally, lower omega-3 PUFA levels have been suggested to be associated with anxiety. The aim of this study was to investigate whether PUFAs levels (omega-3 or omega-6) are correlated with residual depressive or anxiety symptoms in older people with previous depression. Participants aged 60 years or over with previous major depression in remission were enrolled from outpatient psychiatric services of four hospitals. Participants with residual depressive symptoms were defined as the Hamilton Depression Rating Scale (HDRS) scores>5, and those with anxiety were defined as sum of scores for the two anxiety subscale of HDRS≧2. The levels of fatty acids in erythrocyte membranes and in plasma were measured separately by gas chromatography. One hundred and thirty two older people with previous major depression (mean age of 68 years, range 60-86 years) were analyzed. Erythrocyte membrane linoleic acid levels had a curvilinear association with depressive symptoms and anxiety symptoms. Plasma linoleic acid levels were found to have a negative linear relationship with depressive symptoms. No significant associations were found between any omega-3 fatty acid level and depressive or anxiety symptoms. Linoleic acid levels may be a possible biomarker for residual depression and anxiety in older people with previous depression. Possible clinical applications need further investigation.


Correlation of Aqueous, Vitreous, and Plasma Cytokine Levels in Patients With Proliferative Diabetic Retinopathy.
To investigate the relationship between proangiogenic and inflammatory cytokines in concurrent vitreous, aqueous, and plasma samples from patients with proliferative diabetic retinopathy (PDR). Vitreous, aqueous, and plasma samples were analyzed using multiplex immunoassay for 10 PDR-related cytokines (IL-6, IL-8, TNF-α, monocyte chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β], VEGF receptor 1 [Flt-1], placental growth factor [PlGF], VEGF-A, VEGF-C, VEGF-D). A total of 17 patients with PDR and 7 controls were included. The primary outcome was correlation of cytokines in vitreous, aqueous, and plasma. The secondary outcome was the comparison of cytokine levels in controls and diabetics with and without recent anti-VEGF injection. The following factors were elevated in diabetics compared with controls: vitreous IL-6, IL-8, TNF-α, MCP-1, MIP-1β, PlGF, and VEGF-A; and aqueous IL-6, IL-8, PlGF, and VEGF-C (all P < 0.05). Vitreous and aqueous IL-8, PlGF, and VEGF-A were significantly correlated in patients with PDR (all P < 0.05). Plasma cytokines were not correlated with those in vitreous and aqueous (all P > 0.05). Vitreous and aqueous IL-6, IL-8, TNF-α, PlGF, and VEGF-A differed among controls and diabetics with and without recent anti-VEGF injection (all P < 0.05). In one-to-one comparisons, aqueous VEGF-A levels were lower in diabetic patients who had recent anti-VEGF injection compared with those who did not (P = 0.01). In this proof-of-concept study, IL-8, VEGF-A, and PlGF demonstrated a strong correlation in vitreous and aqueous of patients with PDR. The aqueous may serve as a proxy for vitreous for some cytokines involved in PDR. Recent anti-VEGF injections decreased VEGF-A levels in aqueous, but did not significantly affect other cytokines, suggesting a role for other targeted therapies in PDR management.


Reframing clinical workplace learning using the theory of distributed cognition.
In medicine, knowledge is embodied and socially, temporally, spatially, and culturally distributed between actors and their environment. In addition, clinicians increasingly are using technology in their daily work to gain and share knowledge. Despite these characteristics, surprisingly few studies have incorporated the theory of distributed cognition (DCog), which emphasizes how cognition is distributed in a wider system in the form of multimodal representations (e.g., clinical images, speech, gazes, and gestures) between social actors (e.g., doctors and patients) in the physical environment (e.g., with technological instruments and computers). In this article, the authors provide an example of an interaction between medical actors. Using that example, they then introduce the important concepts of the DCog theory, identifying five characteristics of clinical representations-that they are interwoven, co-constructed, redundantly accessed, intersubjectively shared, and substantiated-and discuss their value for learning. By contrasting these DCog perspectives with studies from the field of medical education, the authors argue that researchers should focus future medical education scholarship on the ways in which medical actors use and connect speech, bodily movements (e.g., gestures), and the visual and haptic structures of their own bodies and of artifacts, such as technological instruments and computers, to construct complex, multimodal representations. They also argue that future scholarship should "zoom in" on detailed, moment-by-moment analysis and, at the same time, "zoom out" following the distribution of cognition through an overall system to develop a more integrated view of clinical workplace learning.


Neurohumoral control of esophageal epithelial electrolyte transport.
The neurohumoral control of epithelial esophageal electrolyte transport was investigated by studying the effect of various hormones and neuroeffector agents on the potential difference (PD) in vivo or on the electrical parameters of electrolyte transport in vitro. The rabbit esophagus, which has no submucosal esophageal glands, demonstrated no effect of pentagastrin, cholecystokinin octapeptide, or synthetic secretin in vivo, and no effect of these hormones or of vasopressin, aldosterone, carbachol, epinephrine, or cAMP in vitro. The rabbit esophagus did respond to metabolic substrates (glucose) in vitro by increasing sodium absorption. In contrast, the opossum esophagus, which contains extensive submucosal glands, had a lower electrical resistance, PD, short-circuit current, and sodium absorption with higher chloride secretion. This esophagus responded to carbachol and epinephrine by sodium and chloride secretion. We believe that only the submucosal glands of the esophagus are under significant neurohumoral control while the sodium transporting function of the stratified squamous epithelium of this organ is important in maintaining its barrier function.


Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study.
Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer's disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.


Perceptual Real-Time 2D-to-3D Conversion Using Cue Fusion.
We propose a system to infer binocular disparity from a monocular video stream in real-time. Different from classic reconstruction of physical depth in computer vision, we compute perceptually plausible disparity, that is numerically inaccurate, but results in a very similar overall depth impression with plausible overall layout, sharp edges, fine details and agreement between luminance and disparity. We use several simple monocular cues to estimate disparity maps and confidence maps of low spatial and temporal resolution in real-time. These are complemented by spatially-varying, appearance-dependent and class-specific disparity prior maps, learned from example stereo images. Scene classification selects this prior at runtime. Fusion of prior and cues is done by means of robust MAP inference on a dense spatio-temporal conditional random field with high spatial and temporal resolution. Using normal distributions allows this in constant-time, parallel per-pixel work. We compare our approach to previous 2D-to-3D conversion systems in terms of different metrics, as well as a user study and validate our notion of perceptually plausible disparity.


Post-infectious olfactory dysfunction exhibits a seasonal pattern.
We investigated whether olfactory dysfunction following infections of the upper respiratory tract (post-URTI) has an incidence matching the seasonality of URTIs. Retrospective study. In total, 457 patients (126 male, 331 female) with post-URTI olfactory loss were examined during a 6-year-period (1999-2004). Their records were assessed for age, sex, and time of onset of the disease. The severity of olfactory dysfunction was assessed using the "Sniffin' Sticks" (odour threshold, odour discrimination, and odour identification). Incidence of post-URTI olfactory dysfunction exhibited seasonal fluctuations with deviations from the winter seasonality of URTIs. The overall incidence of the disease differed significantly between months. March (12.7%) and May (12.6%) were the months with the highest incidence of the disease throughout the year. The lowest incidence was observed in September (5.6%). Significant differences were found between these months and months with a high incidence of URTIs. The peak incidence of post-URTI olfactory loss in March may be explained by the high incidence of influenza at this time. However, it is unclear why the incidence of the disease presents a second peak in May, when the incidence of respiratory viruses is relatively low. Climate conditions at this time might play a role in the susceptibility of the nasal epithelia towards certain viral infections, e.g. parainfluenza type III. Post-URTI olfactory dysfunction exhibits spring seasonality with peaks in March and May and possible causative factors being influenza and parainfluenza viruses (type III), respectively.


Dynamic range extension for photon counting arrays.
Confocal microscopes use photomultiplier tubes and hybrid detectors due to their large dynamic range, which typically exceeds the one of single-photon avalanche diodes (SPADs). The latter, due to their photon counting operation, are usually limited to an output count rate to 1/Tdead. In this paper, we present a thorough analysis, which can actually be applied to any photon counting detector, on how to extend the SPAD dynamic range by exploiting the nonlinear photon response at high count rates and for different recharge mechanisms. We applied passive, active event-driven and clock-driven (i.e. clocked, following quanta image sensor response) recharge directly to the SPADs. The photon response, photon count standard deviation, signal-to-noise ratio and dynamic range were measured and compared to models. Measurements were performed with a CMOS SPAD array targeted for image scanning microscopy, featuring best-in-class 11 V excess bias, 55% peak photon detection probability at 520 nm and >40% from 440 to 640 nm. The array features an extremely low median dark count rate below 0.05 cps/μm2 at 9 V of excess bias and 0°C. We show that active event-driven recharge provides ×75 dynamic range extension and offers novel ways for high dynamic range imaging. When compared to the clock-driven recharge and the quanta image sensor approach, the dynamic range is extended by a factor of ×12.7-26.4. Additionally, for the first time, we evaluate the influence of clock-driven recharge on the SPAD afterpulsing.


Why Test study protocol: a UK-wide audit using the Primary Care Academic CollaboraTive (PACT) to explore the reasons for primary care testing.
The number of blood tests done in primary care has been increasing over the past 20 years. Some estimates suggest that up to one-quarter of these tests may not have been needed. This could lead to a cascade effect of further investigations, appointments, or referrals, as well as anxiety for patients, increased workload, and costs to the health service. To better understand the impact and sequelae of blood tests on patients, it is necessary to know why blood tests are requested and what is done with the results. To explore who orders blood tests and why, and how test results are actioned in primary care. Retrospective audit of electronic health records in general practices across the UK. The Primary care Academic CollaboraTive (PACT), a UK-wide network of primary care health professionals, will be utilised to collect data from individual practices. PACT members will be asked to review the electronic health records of 50 patients who had recent blood tests in their practice, and manually extract anonymised data on who requested the test, the indication, the result, and subsequent actions. Data will also be collected from PACT members to assess the feasibility of the collaborative model. PACT offers a unique opportunity to extract clinical data which cannot otherwise be obtained. Understanding the indications for tests will help identify priority areas for research to optimise testing and patient safety in primary care.


Multilevel assessment of immunisation uptake as a performance measure in general practice.
To provide a measure of general practitioners' performance regarding uptake of immunisation against pertussis, taking account of the impact of patient characteristics on levels of uptake. Multilevel model of immunisation status against six measures of patient characteristics (level 1 predictor variables) with practice constraints as level 2 variables. 126 practices in southern England. 2048 infants identified from infant surveillance and immunisation records. Top 10 practices with respect to uptake of pertussis immunisation according to a "null" model (model A) and according to a model that included six level 1 variables (model B); differences in ranking between the two models. Practices with low numbers of infants' requiring immunisation had imprecise and unstable uptake rates (range 0%-100%). With the multilevel procedure, after controlling for patient characteristics, practices in suburban catchment areas comprised largely of mature or young professionals performed best. Most improved performances when patient characteristics were taken into account were in practices in areas with a stable population and local authority housing--one such practice improved its ranking by 47 places. Crude uptake rates are inadequate performance indicators. Alternative approaches suggest that praiseworthy efforts to raise immunisation rates in unpromising areas are unrewarded by simple target based assessments.