Gut-Brain Axis and Metabolism in Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder, often accompanied and complicated by insulin resistance, glucose intolerance and obesity. Gut, brain and metabolism are highly related with each other in obesity and diabetes as well as in PCOS. Central nervous system regulates food intake through complex interactions of homeostatic and hedonic systems while gastrointestinal system contributes to food intake and metabolism via orexigenic and anorexigenic gastrointestinal hormones. Ghrelin is the only circulating orexigenic hormone whereas anorexigenic peptides include glucagon like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY) and cholecystokinin (CCK). Compared to healthy women, patients with PCOS show decreased or unaltered fasting ghrelin levels, along with decreased or unaltered postprandial suppression of this hormone. GLP-1, PYY and CCK show unaltered or decreased levels both in fasting and postprandial states in PCOS whereas fasting levels of another gut hormone, GIP is either unaltered or increased. Dietary interventions associated with weight loss or short term oral contraceptive use in PCOS do not alter fasting or postprandial levels of these hormones. However use of metformin is associated with an increase in ghrelin, PYY, GLP-1 and GIP in women with PCOS. GLP-1 agonists and bariatric surgery, both having a significant impact on gut-brain axis, appear to be effective therapeutic options in obese women with PCOS. Finally, alterations in gut microbiota and possible interactions with gut-brain axis in PCOS is a topic of interest. Understanding the relationship between PCOS and homeostatic and hedonic systems, gastrointestinal hormones, and gut microbiota as well as potential effects of different therapeutic interventions on these systems will provide further understanding and novel treatment opportunities for this syndrome.


Generation of animal form by the Chordin/Tolloid/BMP gradient: 100 years after D'Arcy Thompson.
The classic book "On Growth and Form" by naturalist D'Arcy Thompson was published 100 years ago. To celebrate this landmark, we present experiments in the Xenopus embryo that provide a framework for understanding how simple, quantitative transformations of a morphogen gradient might have affected evolution and morphological diversity of organisms. D'Arcy Thompson proposed that different morphologies might be generated by modifying physical parameters in an underlying system of Cartesian coordinates that pre-existed in Nature and arose during evolutionary history. Chordin is a BMP antagonist secreted by the Spemann organizer located on the dorsal side of the gastrula. Chordin generates a morphogen gradient as first proposed by mathematician Alan Turing. The rate-limiting step of this dorsal-ventral (D-V) morphogen is the degradation of Chordin by the Tolloid metalloproteinase in the ventral side. Chordin is expressed at gastrula on the dorsal side where BMP signaling is low, while at the opposite side peak levels of BMP signaling are reached. In fishes, amphibians, reptiles and birds, high BMP signaling in the ventral region induces transcription of a secreted inhibitor of Tolloid called Sizzled. By depleting Sizzled exclusively in the ventral half of the embryo we were able to expand the ventro-posterior region in an otherwise normal embryo. Conversely, ventral depletion of Tolloid, which stabilizes Chordin, decreased ventral and tail structures, phenocopying the tolloid zebrafish mutation. We explain how historical constraints recorded in the language of DNA become subject to the universal laws of physics when an ancestral reaction-diffusion morphogen gradient dictates form.


Ultrasonography in screening for developmental dysplasia of the hip in newborns: systematic review.
To assess the accuracy and effectiveness of the screening of all newborn infants for developmental dysplasia of the hip (DDH) using ultrasound imaging, as is standard practice in some European countries but not in the United Kingdom, the United States, or Scandinavia. Systematic review. Twenty three medical, economic, and grey literature databases (to March 2004), with no limitations of design or language; some references were provided by experts. Only diagnostic accuracy studies and comparative studies conducted in an unselected newborn population were eligible for the review. Two reviewers independently selected the studies and performed the quality assessment. The review identified one diagnostic accuracy study, and this was of limited quality. In this study the reference standard was treatment up to age of 8 months or an abnormal ultrasound finding at age 8 months. Ultrasound screening had a sensitivity of 88.5% (95% confidence interval 84.1% to 92.1%), specificity of 96.7% (96.4% to 97.4%), a positive predictive value of 61.6% and a negative predictive value of 99.4%. Ten studies evaluated the impact of ultrasound in screening, but these too had various methodological weaknesses, limiting the reliability of their findings. Compared with clinical screening, general ultrasound screening in newborns may increase overall treatment rates, but ultrasound screening seems to be associated with shorter and less intrusive treatment. Clear evidence is lacking either for or against general ultrasound screening of newborn infants for DDH. Studies that investigate the natural course of the disorder, the optimal treatment for DDH, and the best strategy for ultrasound screening are needed.


Role of IL-12 and 4-1BB ligand in cytokine production by CD28+ and CD28- T cells.
The costimulatory receptor CD28 is important in the development of both Th1 and Th2 responses. To further assess the requirement for CD28 in the development of Th1 and Th2 responses, we analyzed the ability of T cells from wild-type or CD28- mice to secrete cytokines in MLRs with B lymphomas. We find that in the absence of added IL-12, B lymphomas expressing the alternate costimulatory ligand 4-1BBL can support the production of IL-2 and IL-4 but little detectable IFN-gamma by allogeneic CD28+ and CD28- T cells. IL-4 production by CD28+ or CD28- T cells responding to B7(low) B lymphomas was abrogated by blocking 4-1BB ligand-4-1BB interaction. When APC express high levels of B7 family molecules as well as 4-1BBL, soluble 4-1BB inhibits IL-4 production by CD28- but not by CD28+ cells. Addition of IL-12 to the CD28- MLRs results in increased production of IFN-gamma and decreased amounts of IL-2 and IL-4. Thus, both Th1 and Th2 responses can develop in the complete absence of a signal through the CD28 molecule. CD28+ and CD28- T cells differed, however, with respect to the effect of IL-12 on IL-4 production. IL-12 severely curtailed the amount of IL-4 produced in the CD28- T cell cultures but had a less profound effect on the level of IL-4 produced in the CD28+ cultures, suggesting that a strong signal through the CD28 molecule prevents down-regulation of IL-4 production by IL-12.


NUCLEAR FACTOR Y transcription factors have both opposing and additive roles in ABA-mediated seed germination.
In the model organism Arabidopsis thaliana the heterotrimeric transcription factor NUCLEAR FACTOR Y (NF-Y) has been shown to play multiple roles in facilitating plant growth and development. Although NF-Y itself represents a multi-protein transcriptional complex, recent studies have shown important interactions with other transcription factors, especially those in the bZIP family. Here we add to the growing evidence that NF-Y and bZIP form common complexes to affect many processes. We carried out transcriptional profiling on nf-yc mutants and through subsequent analyses found an enrichment of bZIP binding sites in the promoter elements of misregulated genes. Using NF-Y as bait, yeast two hybrid assays yielded interactions with bZIP proteins that are known to control ABA signaling. Accordingly, we find that plants mutant for several NF-Y subunits show characteristic phenotypes associated with the disruption of ABA signaling. While previous reports have shown additive roles for NF-YC family members in photoperiodic flowering, we found that they can have opposing roles in ABA signaling. Collectively, these results demonstrated the importance and complexity of NF-Y in the integration of environmental and hormone signals.


Trends in socioeconomic inequalities in oral health among 15-year-old Danish adolescents during 1995-2013: A nationwide, register-based, repeated cross-sectional study.
Scandinavian welfare states, despite having better population oral health than less egalitarian societies, are characterized by ubiquitous social gradients and large relative socioeconomic inequalities in oral health. However, trends in these inequalities among Scandinavian children and adolescents have not been studied in detail. To describe the associations between socioeconomic position (SEP) and oral health in adolescents and to investigate the trends in these associations between 1995 and 2013. Nationwide repeated cross-sectional studies (using individual-level data) were conducted on 15-year-olds in Denmark from 1995, 2003, and 2013 (N=154,750). Dental data were obtained from the national dental register of the Danish Health Authority (Sundhedsstyrelsens Centrale Odontologiske Register [SCOR]) and data on social variables from administrative registers at Statistics Denmark. SEP measures included previous year's parental education (highest attained educational level by either of the parents), income (equivalized household disposable income), and occupational social class (highest recorded occupational class between the parents). Covariates were immigration status, country of origin, number of children and persons in the family, and household type. The outcome was dental caries experience, represented by the decayed, missing, and filled surfaces (DMFS) index. Negative binomial regression models were used to examine the association between DMFS count and each of the explanatory variables separately while accounting for cluster-correlated family data. Furthermore, hierarchical multiple regressions of DMFS on SEP indicators-using the zero-inflated negative binomial (ZINB) distribution as the outcome distribution-were estimated while successively adjusting for the potential effects of the included covariates. Caries prevalence declined from 71% in 1995 to 63% in 2003 and 45% in 2013. Separate assessment of each covariate showed statistically significant graded associations between each covariate and DMFS count at all time points. Similarly, in the ZINB models, in all 3 years, clear gradients were observed in terms of caries differentials in all three SEP categories, with statistically significant associations (Type 3 P values, <.0001) even after adjustment for all other covariates. For instance, in 2013, even among adolescents with positive caries experience, being of lower occupational social class was associated with up to 2.4-fold (95% confidence interval [CI]: 2.2-2.6) higher caries experience. Between 1995 and 2013, relative inequalities increased in all SEP categories, while absolute inequalities decreased in the education and occupation categories. Considerable progress has been made in reducing dental caries rates among Danish adolescents; however, this progress has benefited the disadvantaged social groups less than the better-off groups.


The pathophysiology and clinical presentation of cerebral amyloid angiopathy.
Cerebral amyloid angiopathy (CAA) is defined as the deposition of amyloid ß peptide within leptomeningial and cortical vessels, likely reflecting an imbalance between Aβ production and clearance. Amyloid buildup triggers a series of destructive alterations in the cerebral vascular architecture, leading to a spectrum of neurological events including lobar intracerebral hemorrhage, brain ischemia and cognitive decline. Although traditionally diagnosed pathologically, neuroimaging has taken a central role in defining CAA. This review will discuss the pathological, clinical and radiological aspects of CAA.


Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma.
Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma. Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics. Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide. Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.


Notochord signals control the transcriptional cascade of myogenic bHLH genes in somites of quail embryos.
Microsurgical, tissue grafting and in situ hybridization techniques have been used to investigate the role of the neural tube and notochord in the control of the myogenic bHLH genes, QmyoD, Qmyf5, Qmyogenin and the cardiac alpha-actin gene, during somite formation in stage 12 quail embryos. Our results reveal that signals from the axial neural tube/notochord complex control both the activation and the maintenance of expression of QmyoD and Qmyf5 in myotomal progenitor cells during the period immediately following somite formation and prior to myotome differentiation. QmyoD and Qmyf5 expression becomes independent of axial signals during myotome differentiation when somites activate expression of Qmyogenin and alpha-actin. Ablation studies reveal that the notochord controls QmyoD activation and the initiation of the transcriptional cascade of myogenic bHLH genes as epithelial somites condense from segmental plate mesoderm. The dorsal medial neural tube then contributes to the maintenance of myogenic bHLH gene expression in newly formed somites. Notochord grafts can activate ectopic QmyoD expression during somite formation, establishing that the notochord is a necessary and sufficient source of diffusible signals to initiate QmyoD expression. Myogenic bHLH gene expression is localized to dorsal medial cells of the somite by inhibitory signals produced by the lateral plate and ventral neural tube. Signaling models for the activation and maintenance of myogenic gene expression and the determination of myotomal muscle in somites are discussed.


Development of a simplified model for the fixed biofilm reactor.
A simplified fixed biofilm model was developed to formulate the relationship between the substrate concentrations at both the entry and exit, at the biofilm-liquid interface and at the biofilm attached surface along with average substrate flux in the biofilm, substrate flux at the biofilm-liquid interface and effective biofilm thickness. The model considered the substrate mass transport external to the biofilm and into the biofilm as per Fick's law and the steady state substrate as well as biomass balance for attached growth microorganisms. Monod's growth kinetics has been adopted in substrate utilization, incorporating relevant boundary conditions. The numerical solution of model equations was accomplished for calculating average flux and exit substrate concentration and thereafter the Runge-Kutta method was employed for determining effective biofilm thickness. Consequently, two computer programs were developed for the purpose of rapid solution. The model was satisfactorily applied to data available from the literature for checking its accuracy and was validated with the experimental results. The model was found to be an easy, accurate and fast method that can be used for process design of a fixed biofilm reactor.


Value-Added Activities in Medical Education: A Multisite Survey of First- and Second-Year Medical Students' Perceptions and Factors Influencing Their Potential Engagement.
To describe attitudes of first- and second-year U.S. medical students toward value-added medical education, assess their self-reported desire to participate in value-added activities, and identify potentially modifiable factors influencing their engagement. The authors conducted a cross-sectional survey of first- and second-year students at nine U.S. medical schools in 2017. Survey items measured students' attitudes toward value-added medical education (n = 7), desire to participate in value-added activities (n = 20), and factors influencing potential engagement (n = 18). Of 2,670 students invited to participate, 1,372 (51%) responded. Seventy-six percent (1,043/1,368) moderately or strongly agreed they should make meaningful contributions to patient care. Students' desire to participate was highest for patient care activities approximating those traditionally performed by physicians, followed by systems improvement activities and lowest for activities not typically performed by physicians. Factors increasing desire to participate included opportunities to interact with practicing physicians (1,182/1,244; 95%), patients (1,177/1,246; 95%), and residents or fellows (1,166/1,246; 94%). Factors decreasing desire to participate included making changes to the health care system (365/1,227; 30%), interacting with patients via phone or electronic communication (410/1,243; 33%), and lack of curricular time (634/1,233; 51%). First- and second-year medical students agree they should add value to patient care, but their desire to participate in value-added activities varies depending on the nature of the tasks. Medical schools may be able to increase students' desire to participate by enabling face-to-face interactions with patients, embedding students in health care teams, and providing dedicated curricular time.


Impact of DAT-SPECT on Management of Patients Suspected of Parkinsonism.
To evaluate the value of I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) to change management strategies of patients suspected of parkinsonism. This was an institutional review board-approved, retrospective study. DAT-SPECT scans ordered by movement disorder specialist and neurologists from 2011-2014 were reviewed. Clinical data and radiological reports of 173 patients suspected of parkinsonism were reviewed. The DAT-SPECT scan results were correlated with clinical assessment and treatment changes. A total of 173 patients (104 male and 69 female subjects; age, 64.4 ± 12.6 years) suspected of parkinsonism were included. Median duration of symptoms was 36 months (range, 1-480 months). Scans were most often requested when there was diagnostic uncertainty in clinical features (59.6%, 103/173) or to differentiate one other disease from parkinsonism such as Parkinson disease (PD) versus essential tremor (23.7%, 41/173), PD versus drug-induced parkinsonism (8.7%, 15/173), or PD versus psychogenic (6.4%, 11/173) or vascular (1.7%, 3/173) disorders. Patients were classified, according to the DAT-SPECT scanning results, as those with abnormal DAT-SPECT findings (59%, 102/173) and those with normal DAT-SPECT findings (41%, 71/173). In patients with normal DAT-SPECT findings, follow-up management data were available in 76.1% (54/71). The management changed in 39.4% (28/54) after DAT scan with starting a new appropriate medications or supportive therapy in 4.2% (3/28), withholding inappropriate dopaminergic treatment in 11.3% (8/28), or continuing observation in 23.9% (17/28). In patients with abnormal DAT-SPECT findings, follow-up management data were available in 78.4% (80/102). There was change in management of 37.3% (38/80), a new PD treatment was started in 89.5% (34/38). The dose of medication was adjusted in 5.3% (2/38), although the original treatment was not changed. Parkinson disease treatment was stopped in 2.6% (1/38) and discontinued in 2.6% (1/38) based on clinical decision of neurologists despite abnormal DAT-SPECT findings. DAT-SPECT findings impacted treatment decisions in 44.7% of patients suspected of Parkinsonism.


Role of ITAM signaling module in signal integration.
Diverse cell types use a small number of evolutionarily conserved signaling modules to integrate external cues and elicit distinct functions. A question thus arises as to how does a receptor, which contains a single signaling module, produce distinct outcomes to diverse signals, particularly if such module is shared amongst a family of receptors? Emerging data suggest that many immunoreceptors, all of which use a conserved ITAM-module for their signaling, can couple with members of additional classes of membrane receptors to deliver unique signal(s) to the cell. We discuss the possible biological purposes and mechanisms behind these interactions at the plasma membrane. We offer a conceptual framework to understand information processing within the immune system and discuss the new biology of old receptors involving their structural and functional collaborations that evolved to deliver unique signal(s) to the cell using a limited set of conserved signaling modules.


Developmental changes in the scanning of faces by young infants.
6 1-month-old infants and 6 2-month-old infants each viewed 3 faces (his mother's, a strange woman's, and a strange man's) while his eye movements were recorded by corneal photography. The 1-month-olds fixated away from the faces most of the time, and they looked at their mothers even less often than at the strangers. When they did fixate a face, they usually chose a limited portion of the perimeter. By constrast, 2-month-olds fixated the faces most of the time, looked at more features, and were more likely to look at internal features, especially the eyes. This scanning resembles that reported previously for 2-dimensional shapes, although in some respects it appears unique to faces.


Dietary management of childhood diarrhea in low- and middle-income countries: a systematic review.
Current WHO guidelines on the management and treatment of diarrhea in children strongly recommend continued feeding alongside the administration of oral rehydration solution and zinc therapy, but there remains some debate regarding the optimal diet or dietary ingredients for feeding children with diarrhea. We conducted a systematic search for all published randomized controlled trials evaluating food-based interventions among children under five years old with diarrhea in low- and middle-income countries. We classified 29 eligible studies into one or more comparisons: reduced versus regular lactose liquid feeds, lactose-free versus lactose-containing liquid feeds, lactose-free liquid feeds versus lactose-containing mixed diets, and commercial/specialized ingredients versus home-available ingredients. We used all available outcome data to conduct random-effects meta-analyses to estimate the average effect of each intervention on diarrhea duration, stool output, weight gain and treatment failure risk for studies on acute and persistent diarrhea separately. Evidence of low-to-moderate quality suggests that among children with acute diarrhea, diluting or fermenting lactose-containing liquid feeds does not affect any outcome when compared with an ordinary lactose-containing liquid feeds. In contrast, moderate quality evidence suggests that lactose-free liquid feeds reduce duration and the risk of treatment failure compared to lactose-containing liquid feeds in acute diarrhea. Only limited evidence of low quality was available to assess either of these two approaches in persistent diarrhea, or to assess lactose-free liquid feeds compared to lactose-containing mixed diets in either acute or persistent diarrhea. For commercially prepared or specialized ingredients compared to home-available ingredients, we found low-to-moderate quality evidence of no effect on any outcome in either acute or persistent diarrhea, though when we restricted these analyses to studies where both intervention and control diets were lactose-free, weight gain in children with acute diarrhea was shown to be greater among those fed with a home-available diet. Among children in low- and middle-income countries, where the dual burden of diarrhea and malnutrition is greatest and where access to proprietary formulas and specialized ingredients is limited, the use of locally available age-appropriate foods should be promoted for the majority of acute diarrhea cases. Lactose intolerance is an important complication in some cases, but even among those children for whom lactose avoidance may be necessary, nutritionally complete diets comprised of locally available ingredients can be used at least as effectively as commercial preparations or specialized ingredients. These same conclusions may also apply to the dietary management of children with persistent diarrhea, but the evidence remains limited.


Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study.
The safety and the effectiveness of the surgical treatment of spontaneous intracerebral hemorrhage (ICH) remain controversial. To investigate the feasibility of urgent surgical evacuation of ICH, we conducted a small, randomized feasibility study of early surgical treatment versus current nonoperative management in patients with spontaneous supratentorial ICH. Patients with spontaneous supratentorial ICH who presented to 1 university and 2 community hospitals were randomized to surgical treatment or best medical treatment. Principal eligibility criteria were ICH volume >10 cm(3) on baseline CT scan with a focal neurological deficit, Glasgow Coma Scale score >4 at the time of enrollment, randomization and therapy within 24 hours of symptom onset, surgery within 3 hours of randomization, and no evidence for ruptured aneurysm or arteriovenous malformation. The primary end point was the 3-month Glasgow Outcome Scale (GOS). A good outcome was defined as a 3-month GOS score >3. Twenty patients were randomized over 24 months, 9 to surgical intervention and 11 to medical treatment. The median time from onset of symptoms to presentation at the treating hospitals was 3 hours and 17 minutes, the time from randomization to surgery was 1 hour and 20 minutes, and the time from onset of symptoms to surgery was 8 hours and 35 minutes. The likelihood of a good outcome (primary outcome measure: GOS score >3) for the surgical treatment group (56%) did not differ significantly from the medical treatment group (36%). There was no significant difference in mortality at 3 months. Analysis of the secondary 3-month outcome measures showed a nonsignificant trend toward a better outcome in the surgical treatment group versus the medical treatment group for the median GOS, Barthel Index, and Rankin Scale and a significant difference in the National Institutes of Health Stroke Scale score (4 versus 14; P=0.04). Very early surgical treatment for acute ICH is difficult to achieve but feasible at academic medical centers and community hospitals. The trend toward less 3-month morbidity with surgical intervention in patients with spontaneous supratentorial ICH warrants further investigation of very early clot removal in larger randomized clinical trials.


Associations of Early Socio-familial Stress with Maladaptive and Adaptive Functioning in Middle Childhood: Roles of Executive Control and Foundational Cognitive Abilities.
This study examined whether cognitive processes in preschool, conceptualized as a unitary construct of executive control (EC) as well as foundational cognitive abilities (FCA), predict both maladaptive and adaptive functioning in middle childhood and mediate associations between early childhood socio-familial stress and those functional outcomes. Performance-based, multidimensional, and age-appropriate measures of EC and FCA were collected in a laboratory setting from 313 preschool-age children at age 5, along with questionnaire data from children and their parents on three dimensions of early socio-familial stress and parent smoking. Parent, teacher, and child self-report data on 285 of these children were obtained when they were in grade 3 or 4. Middle childhood data were used to create indices of maladaptive and adaptive functioning. A bi-factor structural equation modeling analysis captured distinct dimensions of preschool EC and FCA and was used to test the hypothesized pathways. EC had a statistically significant negative association with later maladaptive functioning. FCA, but not EC, served as a mediator in links between each type of family stressor and both maladaptive and adaptive functioning in middle childhood. Results suggest that EC may play a role in predicting maladaptation, whereas early childhood FCA may operate as an intervening variable in pathways from early family stressors to subsequent maladaptation as well as adaptation. Findings point to the need to address FCA by reducing early family stressors. Early interventions that enhance cognitive abilities may help reduce maladaptive and promote adaptive functioning later in childhood, thereby potentially preventing, in turn, later behavioral problems.


Age-dependent specification of the corticocortical connections of cerebral grafts.
To investigate further the factors involved in the development of cerebral cortical circuitry, we examined the organization of corticocortical connections of heterotopic grafts of fetal cortex placed into neonatal rat cortices. Presumptive perirhinal or sensorimotor areas of the cerebral wall were removed as slabs from embryonic day 12 (E12), E13, or E14 rats and transplanted heterotopically into either rostral perirhinal or sensorimotor cortical areas of neonatal rats. Two weeks later, the afferent cortical connections of the grafts were labeled by placing DilC18(-3) (Dil) into each transplant site. Both the E12 and E13 heterotopic transplants of presumptive perirhinal cortex contain mostly precursor cells. When these grafts are placed into sensorimotor cortex, callosal connections are formed primarily with the contralateral sensorimotor (Sml) area, the normal projection of Sml cortex. In contrast, the E14 heterotopic transplants of the perirhinal cortical wall, containing many more postmitotic neurons, developed contralateral connections with both sensorimotor and rostral perirhinal cortices. Thus, when precursor cells are transplanted heterotopically, by using E12/E13 donor tissue, the grafts receive projections that are similar to those of the host cortical area. When older cortical neurons, together with precursors, are transplanted into a heterotopic cortical area, by using E14 donor tissue, their cortical connections exhibit both host and original donor phenotypes. The data are consistent with our previous analysis of thalamocortical connections of grafts (Barbe and Levitt, 1992b) and suggest the existence of a cell-cell recognition system for thalamocortical and corticocortical circuit formation, whose mechanisms of action may be linked to the timing of neurogenesis.


Assessment of atherosclerotic plaque activity in patients with sleep apnea using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI): a feasibility study.
Evidence suggests that the inflammatory state of an atherosclerotic plaque is important in predicting future risk of plaque rupture. This study aims to investigate the feasibility of measuring plaque inflammation in patients with obstructive sleep apnea (OSA) utilizing advanced vascular imaging - hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) with fluorodeoxyglucose (FDG) tracer-before and after continuous positive airway pressure (CPAP). Patients with newly diagnosed moderate to severe OSA underwent baseline PET/MRI for assessment of vascular inflammation of the carotid arteries and thoracic aorta prior to initiation of CPAP. Those adherent to CPAP returned for repeat imaging after 3-6 months of CPAP use. Atherosclerotic plaque activity, as measured by arterial wall FDG uptake, was calculated using target-to-background ratios (TBR) before and after CPAP. Five patients were recruited as part of a focused project. Mean age was 52 years (80% male), and mean apnea-hypopnea index (AHI) was 33. Three patients were objectively adherent with CPAP. In the pre-CPAP phase, all patients had focal FDG uptake in the carotid arteries and aorta. After CPAP, there was an average reduction in TBR of 5.5% (TBRmean) and 6.2% (TBRmax) in carotid and aortic plaque inflammation, similar in magnitude to the reduction observed with statin therapy alone in non-OSA patients (previously reported by others). We demonstrate the feasibility of using hybrid PET/MRI to assess atherosclerotic plaque inflammation in patients with OSA before and after CPAP. Use of the vascular PET/MRI platform in patients with OSA may provide better insight into the role of OSA and its treatment in reducing atherosclerotic inflammation.


Feasibility of ultrasound examination in posterior ligament complex injury of thoracolumbar spine fracture.
A prospective study of 12 patients with thoracolumbar spinal fractures was conducted. To assess the feasibility of ultrasound examination for posterior ligament complex injury in thoracolumbar spinal fractures. In posterior ligament complex injury of thoracolumbar spine fracture, the reliability of magnetic resonance imaging (MRI) for diagnosis has been reported. Nevertheless the usefulness of ultrasound for diagnosis has not been studied, whereas diagnostic ultrasound has been applied in the musculoskeletal system. Two healthy volunteers without a history of spinal trauma were recruited for pilot examination of the ultrasound procedure to access normal findings of the posterior ligament complex. This study investigated 12 thoracolumbar spine fractures. Four were flexion distraction injury; six were stable or unstable burst fractures; and two were simple compression fractures. Osteoporotic spine fractures were excluded from this study. Ultrasound was performed over the injured area by an experienced musculoskeletal radiologist in addition to radiography and MRI. Five patients underwent operative procedures to stabilize the fractured spine. Imaging data and operative findings were correlated with ultrasound examination. In the patients who did not undergo surgery, agreement in diagnosis between MRI and ultrasound was moderate (5 of 7). Difficulty evaluating ligament status was encountered when the region of interest was the lower thoracic level (T10, T11, T12) because of long overlapping spinous processes. In the patients who underwent surgery, correlation between MRI, ultrasound, and operative findings was excellent, especially in diagnosing the status of the supraspinous and interspinous ligaments. Nevertheless, it is impossible to visualize deep-seated structures (i.e., ligamentum flavum, deep muscles of the spine, and facet joint) with ultrasound. This study demonstrated the excellent diagnostic ability of ultrasound to detect the status of the supraspinous and interspinous ligaments, especially in patients who undergo surgery. Although ultrasound examination appears to be less sensitive than MRI in predicting ligament status, the cost effectiveness of ultrasound and its use as an alternative to MRI in special situations (i.e., patients with pacemaker, ferromagnetic implant, or severe claustrophobia) should be emphasized. More clinical data concerning the sensitivity, specificity, and accuracy of ultrasound examination should be addressed in future studies.


Unveiling White Light Emission of a One-Dimensional Cu(I)-Based Organometallic Halide toward Single-Phase Light-Emitting Diode Applications.
Luminescent organometallic halide crystals, especially with single-component white emission, are urgently needed for light-emitting diode (LED) applications. Barriers for the applications, however, lie in their lead toxicity, poor stability, and low photoluminescence quantum yield (PLQY). Here, a one-dimensional Cu(I)-based hybrid metal halide (C12H24O6)CsCu2Br3 is designed and prepared via a simple solution method. Upon 365 nm excitation, a broad-band white light emission centered at 535 nm with a full width at half maximum of 186 nm and a PLQY of 78.3% is monitored. The experimental results together with calculation data indicate that the existence of the split peaks at 486 and 570 nm at a low temperature is attributed to the decrease of energy level degeneracy by virtue of the lattice distortion. Moreover, the stability along with the good device performance of the as-fabricated white LED was also discussed. The results demonstrate that (C12H24O6)CsCu2Br3 is highly competitive in lighting application, and it can further enable breakthrough material design for new luminescent organometallic halides.


Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution.
Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.


I did NOT feel like this at all before the accident: do men and women report different health and life consequences of a road traffic injury?
Worldwide, injuries represent one of the leading causes of mortality, and nearly one-quarter of all injuries are road traffic related. In many high-income countries, the burden of road traffic injuries (RTIs) has shifted from premature death to injury and disability with long-term consequences; therefore, it is important to assess the full burden of an RTI on individual lives. To describe how men and women with minor and moderate injuries reported the consequences of an RTI on their health and lives. The study was designed as an explorative qualitative study, in which the answers to an open-ended question concerning the life and health consequences following injury were analysed using systematic text condensation. A total of 692 respondents with a minor or a moderate injury were included. The respondents reported the consequences of the crash on their health and lives according to four categories: physical consequences, psychological consequences, everyday life consequences and financial consequences. The results show that medically classified minor and moderate injuries have detrimental long-term health and life consequences. Although men and women report some similar consequences, there are substantial differences in their reported psychological and everyday life consequences following an injury. Women report travel anxiety and PTSD-like symptoms, being life altering for them compared with men, for whom these types of reports were missing. These differences emphasise the importance of considering gender-specific physical and psychological consequences following an RTI.


Evaluation of Aggressive Behavior and Invasive Features of Pituitary Adenomas Using Radiological, Surgical, Clinical and Histopathological Markers.
Total surgical resection of pituitary macroadenomas is difficult due to the location of the adenoma and the propensity to invade surrounding tissues. The purpose of this study was to evaluate the risk factors for invasive and aggressive pituitary macroadenomas using radiological, hormonal, clinical, and immunohistochemical markers. Seventy cases of pituitary macroadenoma were examined. Age, gender, symptoms, the presence of fibrosis within the adenoma, hormonal levels, radiological findings, pathological results and immunohistochemical staining of the patients were evaluated using statistical methods. We observed that the patients with macroadenomas in our study most frequently presented during their 5th decade. The most frequent pituitary adenomas were non-functional, GH-secreting and PRL-secreting macroadenomas. The most frequent complaint was vision loss, headache and acral growth. Based on Magnetic Resonance Imaging (MRI) results, it was observed that the degree of invasion into surrounding tissues increased as the size of the macroadenoma increased. Macroadenomas that had invaded into the cavernous sinus invasion or that had a fibrotic tumor structure had a low probability of being resectable. There were no significant relationships between invasive behavior and p53, telomerase, ghrelin and CD46. It is not possible to identify only one factor that affects the prognosis of patients with pituitary macroadenomas. The contribution of the experience of surgeon to the treatment is surely beyond dispute. Fibrotic tumor structure, the surgical technique, the type of hormone, and cavernous sinus invasion affect the ability to perform a total resection and the overall prognosis.


Child with RET proto-oncogene codon 634 mutation.
İnce D, Demirağ B, Ataseven E, Oymak Y, Tuhan H, Karakuş OZ, Hazan F, Abacı A, Özer E, Mutafoglu K, Olgun N. Child with RET proto-oncogene codon 634 mutation. Turk J Pediatr 2017; 59: 590-593. Herein we reported a 7-year-old child with RET proto-oncogene c634 mutation. Her mother had been diagnosed with medullary thyroid carcinoma (MTC), and treated six years ago. Heterozygous mutation of the RET proto-oncogene at c634 had been detected in her mother. Genetic analysis showed the presence of the same mutation in our patient. Thyroid functions were normal. Serum calcitonin level was found mildly elevated. Parathormone (PTH) and carcinoembrionic antigen (CEA) levels were normal. Prophylactic thyroidectomy and sampling of cervical lymph nodes were performed. Histopathologic examination revealed hyperplasia in thyroid C cells, and reactive lymphadenopathy. The risk of MTC has been reported 100% through the life of patients with RET proto-oncogene mutation. It has been reported that particularly patients with c634 mutation have more risk of occurence of metastatic and progressive/recurrent MTC. Prophylactic `thyroidectomy, cervical lymph node dissection` before 5-years-of-age should be considered for these patients.


Localization of an absorber in a turbid semi-infinite medium by spatially resolved continuous-wave diffuse reflectance measurements.
A method to locate an absorber embedded in a semi-infinite turbid medium by spatially-resolved continuous-wave (SRCW) diffuse reflectance measurements is introduced. The depth of the absorber is assessed by single wavelength SRCW diffuse reflectance measurements by two detectors in a radial row. The ratio of perturbations introduced by the defect at two detectors is used to be matched with the ratio-versus-depth curve, which are generated by approximate formulas of continuous wave diffuse reflectance. The error due to approximation and the error in depth assessment are studied for different cases revealing favorable source-detector placements with respect to planar position of the defect. The effect of lateral displacement of the source with respect to defect is studied. A strategy to overcome errors introduced by erroneous prediction of background medium optical properties is suggested. Theoretical results indicate that the depth of the absorber can be obtained with 0.1 mm precision independent of its absorption coefficient and its size for the values chosen in the study. The approach is tested experimentally and it is observed that theoretical results fit with experimental data.


Isolation of peripheral blood mononuclear cells and the expression of toll-like receptors in Betong chickens.
Toll-like receptors (TLRs) comprise microbial sensing receptors present on cell surfaces that are capable of detecting pathogens. The present study aims to examine the expression of TLRs within the peripheral blood mononuclear cell (PBMC) of the Betong chickens. Blood samples were harvested from 12 Betong (KU line) chickens. Hematological values were calculated. PBMC was isolated from the blood utilizing a Histopaque solution and stored in a RPMI1640 culture medium. Cell viability was investigated using a Trypan Blue dye exclusion test. DNA was extracted from PBMC and the expression of the DNA's TLRs was examined using a polymerase chain reaction. Hematological values were determined from the blood samples collected in this study obtained from healthy Betong chickens. PBMC that was isolated from the Betong chickens possessed cell viability higher than 95% (95.37±1.06). From the examination of TLRs gene expression, results revealed instances of TLR1.1, TLR1.2, TLR2.1, TLR2.2, TLR3, TLR4, TLR5, TLR 7, TLR15, and TLR21 that were present in the PBMC of Betong chickens. PBMC isolated from the blood of healthy Betong chickens possessed excellent cell quality. All chicken TLRs were discovered within the PBMC of Betong chickens. Hence, PBMC stands out as one of the premier sources for in vitro studies of chicken immune response.


Modeling the influence of intermittent rain events on long-term fate and transport of organic air pollutants.
The deposition of particles and substances in air is under strong influence of the precipitation patterns of the atmosphere. Most multimedia models, like type III Mackay models, treat rain as a continuous phenomenon. This may cause severe overestimation of the substance removal from the atmosphere through wet deposition and an underestimation of travel distances, leading to the following questions: How strong is the influence of the intermittent character of rain on concentrations, residence times, deposited fractions, and characteristic transport distances of different substances in air? Is there an expression that can provide an accurate approximation to be used in steady-state multimedia models? Assuming a periodically intermittent rain, the mass of an emitted substance that is present in the air compartment is calculated as a function of the deposition rate constants during dry and wet periods and the durations of these periods. In this paper, results for 300 different organic chemicals are presented and illustrated in more detail for four typical substances, showing the following: (i) Deposition velocities can be up to 4 orders of magnitude higher during rain events than during dry periods, especially for persistent substances with low Henry constant. (ii) For substances with a short reaction time (residence time as determined by atmospheric degradation alone) (e.g., propoxur), the assumption of continuous rain may lead to an underestimation of the atmospheric residence time and travel distance by up to 3 orders of magnitude. For this group of substances, the residence time during dry period provides a good estimate of the overall atmospheric residence time. (iii) For substances with reaction times close to the duration of the dry period, the behavior is driven by the length of the time interval between two rain events, as for example, for methomyl. (iv) For very persistent substances such as pentachloronitrobenzene or carbon tetrachloride, the continuous rain approximation provides a good estimate. On the basis of these findings, an accurate but simple approximation is provided by eq 17 for the incorporation of intermittent rain behavior in steady-state multimedia models.


Bistable molecular materials with dynamic structures.
The development of molecular materials whose physical properties can be switched between different states has attracted significant attention for their potential application in sensing, information processing, spintronics, and smart actuators. Generally speaking, such functional bistability can be induced by the motion of electrons or constituted molecules in response to external stimuli. In this Feature Article, we will introduce how to manipulate the structural variations, including spin crossover, molecular reorientation, and molecular displacement, to tune the magnetic properties, optical properties, dielectric properties, and mechanical response of single-crystal materials, with a highlight of our contributions to this booming field.


Expert consensus document: Semantics in active surveillance for men with localized prostate cancer - results of a modified Delphi consensus procedure.
Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if ≥70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.


Improved ethical guidance for the return of results from psychiatric genomics research.
There is an emerging consensus that genomic researchers should, at a minimum, offer to return to individual participants clinically valid, medically important and medically actionable genomic findings (for example, pathogenic variants in BRCA1) identified in the course of research. However, this is not a common practice in psychiatric genetics research. Furthermore, psychiatry researchers often generate findings that do not meet all of these criteria, yet there may be ethically compelling arguments to offer selected results. Here, we review the return of results debate in genomics research and propose that, as for genomic studies of other medical conditions, psychiatric genomics researchers should offer findings that meet the minimum criteria stated above. Additionally, if resources allow, psychiatry researchers could consider offering to return pre-specified 'clinically valuable' findings even if not medically actionable-for instance, findings that help corroborate a psychiatric diagnosis, and findings that indicate important health risks. Similarly, we propose offering 'likely clinically valuable' findings, specifically, variants of uncertain significance potentially related to a participant's symptoms. The goal of this Perspective is to initiate a discussion that can help identify optimal ways of managing the return of results from psychiatric genomics research.


Prevalence of autism according to maternal immigrant status and ethnic origin.
To examine the rates of autism separately according to maternal immigrant status and ethnic origin in respect to the vitamin D insufficiency hypothesis. Articles were identified by electronic searches. Studies were selected when they analysed autism rates according to maternal immigrant status and/or ethnic origin using multivariate techniques. This review gave further support to the association between maternal immigrant status and an increased risk of autism. The relationship with ethnic origin was more complex. Although the crude rates did not differ, multivariate analyses taking into account confounding factors found that black ethnicity was associated with an increased risk for autism. The risk was highly significant when considering the strict definition of autistic disorders as opposed to the large definition of other pervasive developmental disorders. The risk was also very significant for autism associated with mental retardation. These results are consistent with the maternal vitamin D insufficiency hypothesis. Neurobiological studies are warranted to document the effect of maternal vitamin D insufficiency during pregnancy on the foetal brain and the window of vulnerability. This review stresses the importance of monitoring vitamin D levels in pregnant women, especially those who are immigrant, dark-skinned or veiled, and the urgency of randomized controlled trials.


Post-traumatic osteomyelitis in Middle East war-wounded civilians: resistance to first-line antibiotics in selected bacteria over the decade 2006-2016.
War-wounded civilians in Middle East countries are at risk of post-traumatic osteomyelitis (PTO). We aimed to describe and compare the bacterial etiology and proportion of first-line antibiotics resistant bacteria (FLAR) among PTO cases in civilians from Syria, Iraq and Yemen admitted to the reconstructive surgical program of Médecins Sans Frontières (MSF) in Amman, Jordan, and to identify risk factors for developing PTO with FLAR bacteria. We retrospectively analyzed the laboratory database of the MSF program. Inclusion criteria were: patients from Iraq, Yemen or Syria, admitted to the Amman MSF program between October 2006 and December 2016, with at least one bone biopsy sample culture result. Only bone samples taken during first orthopedic surgery were included in the analysis. To assess factors associated with FLAR infection, logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CI). 558 (76.7%) among 727 patients included had ≥1 positive culture results. 318 were from Iraq, 140 from Syria and 100 from Yemen. Median time since injury was 19 months [IQR 8-40]. Among the 732 different bacterial isolates, we identified 228 Enterobacteriaceae (31.5%), 193 Staphylococcus aureus (26.3%), 99 Pseudomonas aeruginosa (13.5%), and 21 Acinetobacter baumanii (2.8%). Three hundred and sixty four isolates were FLAR: 86.2% of Enterobacteriaceae, 53.4% of Pseudomonas aeruginosa, 60.5% of S. aureus and 45% of Acinetobacter baumannii. There was no difference in bacterial etiology or proportion of FLAR according to the country of origin. In multivariate analysis, a FLAR infection was associated with an infection of the lower extremity, with a time since the injury ≤12 months compared with time > 30 months and with more than 3 previous surgeries. Enterobacteriaceae were frequently involved in PTO in war wounded civilians from Iraq, Yemen and Syria between 2006 and 2016. Proportion of FLAR was high, particularly among Enterobacteriaceae, regardless of country of origin.


Peripheral venous catheter fracture with embolism into the pulmonary artery.
Peripheral vein catheterization is generally considered a harmless procedure. Venous catheter rupture associated with pulmonary embolism is an unlikely but potentially serious complication. We report a case of a peripheral venous catheter (PVC) fracture with pulmonary artery embolization in the left lower lobe treated successfully by a surgical approach. The positioning of a PVC is not always a harmless procedure. Every time there are difficulties in positioning or in removal of a catheter device, it should be carefully inspected to verify integrity. The advisability of removal of these small foreign bodies is debated; percutaneous retrieval is preferred, while surgery should be discussed case by case.


Δ9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB2 receptors.
Despite pharmacological treatment, bronchial hyperresponsiveness continues to deteriorate as airway remodelling persists in airway inflammation. Previous studies have demonstrated that the phytocannabinoid Δ9-tetrahydrocannabinol (THC) reverses bronchoconstriction with an anti-inflammatory action. The aim of this study was to investigate the effects of THC on bronchial epithelial cell permeability after exposure to the pro-inflammatory cytokine, TNFα. Calu-3 bronchial epithelial cells were cultured at air-liquid interface. Changes in epithelial permeability were measured using Transepithelial Electrical Resistance (TEER), then confirmed with a paracellular permeability assay and expression of tight junction proteins by Western blotting. Treatment with THC prevented the TNFα-induced decrease in TEER and increase in paracellular permeability. Cannabinoid CB1 and CB2 receptor-like immunoreactivity was found in Calu-3 cells. Subsequent experiments revealed that pharmacological blockade of CB2, but not CB1 receptor inhibited the THC effect. Selective stimulation of CB2 receptors displayed a similar effect to that of THC. TNFα decreased expression of the tight junction proteins occludin and ZO-1, which was prevented by pre-incubation with THC. These data indicate that THC prevents cytokine-induced increase in airway epithelial permeability through CB2 receptor activation. This highlights that THC, or other cannabinoid receptor ligands, could be beneficial in the prevention of inflammation-induced changes in airway epithelial cell permeability, an important feature of airways diseases.


Metabolic engineering as therapy for inborn errors of metabolism--development of mice with phenylalanine hydroxylase expression in muscle.
Treatment of many inherited liver enzyme deficiencies requires the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver. Phenylalanine hydroxylase (PAH) activity was constitutively expressed in skeletal and cardiac muscle of transgenic mice which carried the PAH cDNA under the transcriptional control of the mouse muscle creatine kinase promoter. Muscle PAH-expressing mice were bred to liver PAH-deficient, hyperphenylalaninemic mice to yield progeny that lack PAH activity in liver but express PAH in muscle. These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH. This is the first demonstration that a liver-specific enzyme, when expressed in a heterologous tissue and supplied with necessary cofactors, can effectively clear toxic metabolites from the circulation of individuals with inherited enzyme deficiency. This result suggests that gene therapy targeted to heterologous tissues, such as muscle, will be effective in the treatment of selected inborn errors of metabolism.


Rho-kinase and RGS-containing RhoGEFs as molecular targets for the treatment of erectile dysfunction.
Erectile dysfunction (ED) is a highly prevalent and often under-treated condition. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between contractile and relaxant factors, which control the degree of contraction of penile corporal cavernosal smooth muscles and, thus, determine the erectile state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of ED. Recent studies have revealed important roles for the small GTPase RhoA and its effector, Rho-kinase in regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca(2+)-sensitization in smooth muscle contraction. Changes in this pathway may contribute to ED in various patient subgroups (e.g. hypertension, diabetes, hypogonadism). This review summarizes the importance of Rho-kinase signaling in the erectile response and introduces the evidence pointing to RGS-containing Rho-guanine nucleotide exchange factors (GEFs) as critical mediators of RhoA-GTPase activation in cavernosal smooth muscle and its possible compartmentalization in the caveolae. In addition, we suggest that the design of selective inhibitors of these GEFs might represent a novel class of pharmacological agents to treat ED.


An ATP-gated cation channel with some P2Z-like characteristics in gastric smooth muscle cells of toad.
1. Whole-cell and single-channel currents elicited by extracellular ATP were studied in freshly dissociated smooth muscle cells from the stomach of the toad Bufo marinus using standard patch clamp and microfluorimetric techniques. 2. This ATP-gated cation channel shares a number of pharmacological and functional properties with native rat myometrium receptors, certain native P2Z purinoceptors and the recently cloned P2X7 purinoceptor. But, unlike the last two, the ATP-gated channel does not mediate the formation of large non-specific pores. Thus, it may represent a novel member of the P2X or P2Z class. 3. Extracellular application of ATP (> or = 150 microM) elicited an inward whole-cell current at negative holding potentials that was inwardly rectifying and showed no sign of desensitization. Na+, Cs+ and, to a lesser degree, the organic cation choline served as charge carriers, but Cl- did not. Ratiometric fura-2 measurements indicated that the current is carried in part by Ca2+. The EC50 for ATP was 700 microM in solutions with a low divalent cation concentration. 4. ATP (> or = 100 microM) at the extracellular surface of cell-attached or excised patches elicited inwardly rectifying single-channel currents with a 22 pS conductance. Cl- did not serve as a charge carrier but both Na+ and Cs+ did, as did choline to a lesser extent. The mean open time of the channel was quite long, with a range in hundreds of milliseconds at a holding potential of -70 mV. 5. Mg2+ and Ca2+ decreased the magnitude of the ATP-induced whole-cell currents. Mg2+ decreased both the amplitude and the activity of ATP-activated single-channel currents. 6. ADP, UTP, P1, P5-di-adenosine pentaphosphate (AP5A), adenosine and alpha, beta-methylene ATP (alpha, beta-Me-ATP) did not induce significant whole-cell current. ATP-gamma-S and 2-methylthio ATP (2-Me-S-ATP) were significantly less effective than ATP in inducing whole-cell currents, whereas benzoylbenzoyl ATP (BzATP) was more effective. BzATP, alpha, beta-Me-ATP, ATP-gamma-S and 2-Me-S-ATP induced single-channel currents, but a higher concentration of alpha, beta-Me-ATP was required. 7. BzATP did not induce the formation of large non-specific pores, as assayed using mag-fura-2 as a high molecular mass probe.


Diarrhoea case management in low- and middle-income countries--an unfinished agenda.
To ascertain whether diarrhoea management improved during 1986-2003, a period when significant efforts were made to promote effective case management in children. We analysed household data from 107 Demographic and Health Surveys in 40 low- and middle-income countries from 1986 to 2003 and assessed trends in indicators of rehydration, fluid quantity and food intake in children with diarrhoea. A statistical analysis was made of the overall trend for each indicator. Modest progress was made with regard to the use of oral rehydration therapy (ORT) (0.39% per year) and increased fluid intake (1.02% per year), and use rates remained low in 2003, when compared with desired full coverage. Although use rates improved in the majority of countries, no progress was made in several countries. We estimate that, annually, 307 million children in low- and middle-income countries did not receive ORT, 356 million did not get increased amounts of fluids, and at the beginning of the 21st century, 227 million children got neither ORT nor increased amounts of fluids. The finding that many children in low- and middle-income countries do not receive proper treatment for diarrhoea points to the urgency in addressing this unfinished agenda in child survival. The effectiveness of diarrhoea control needs to be improved after critical review of established approaches and activities to reach caregivers of children at risk of dying from diarrhoeal diseases. Significant efforts must be made to scale up activities to improve case management and reduce childhood deaths from diarrhoea.


Spatial working memory deficit in unilateral neglect.
Based on the similarity of brain areas lesioned in neglect and those activated by spatial working memory (WM) tasks in normals, we hypothesized that neglect may involve spatial WM impairments. A left neglect patient with right inferior frontal and basal ganglia damage performed cancellation tasks, making either highly visible marks (to provide a reminder of visited items), or invisible marks (so only spatial WM could represent cancelled items). Invisible marks led to repeated cancellations for targets that differed only in location, but not for targets with memorable unique identities, suggesting a deficit of spatial WM, with non-spatial WM spared. Neglect was greater for cancellation with invisible marks, consistent with a role for deficient spatial WM in cancellation deficits, but contrary to account solely in terms of attention capture by salient visible marks made in ipsilesional space.


Dissipation and maintenance of stable states in an enzymatic system: analysis and simulation.
The constraint-based analysis has emerged as a useful tool for analysis of biochemical networks. An essential assumption for constraint-based analysis is the formation of a stable steady state. This work investigates dissipation and maintenance of stable states in a simple reversible enzymatic reaction with substrate inhibition. Under mass-action kinetics, the conditions under which the reaction maintains a stable steady state are analytically derived and numerically confirmed. It is shown that, in order to maintain a steady state in the regulated reaction, maximal enzyme activity must be much higher than input rate. Moreover, it is revealed that requirements for large enzyme activity are due to substrate inhibition. It is suggested that high activities of enzymes may play a vital role in protecting a stable state from its catastrophic collapse, giving an additional explanation to an intriguing problem--why the activities of some enzymes greatly exceed the flux capacity of a pathway. In addition, dissipation of the enzymatic reaction is analysed. It is shown that the collapse of stable states is always associated with a point at which dissipation is the highest. Therefore, in order to maintain a stable state, dissipation of the reaction must be less than a critical value. Moreover, although external forcing may not change net mass flow, it may lead to collapse of stable states. Furthermore, when stable states collapse at a critical forcing amplitude and period, dissipation also reaches a highest value. It is concluded that collapse of stable steady state in the enzyme system with substrate inhibition always corresponds to critical points at which dissipation is highest, regardless if the reaction is forced or not. Therefore, for the substrate inhibited reaction, maintenance of stable states is intrinsically related to level of dissipation.


Predicting maximal oxygen uptake from a 3-minute progressive knee-ups and step test.
Cardiorespiratory fitness assessment is crucial for diagnosing health risks and assessing interventions. Direct measurement of maximum oxygen uptake (V̇O2 max) yields more objective and accurate results, but it is practical only in a laboratory setting. We therefore investigated whether a 3-min progressive knee-up and step (3MPKS) test can be used to estimate peak oxygen uptake in these settings. The data of 166 healthy adult participants were analyzed. We conducted a V̇O2 max test and a subsequent 3MPKS exercise test, in a balanced order, a week later. In a multivariate regression model, sex; age; relative V̇O2 max; body mass index (BMI); body fat percentage (BF); resting heart rate (HR0); and heart rates at the beginning as well as at the first, second, third, and fourth minutes (denoted by HR0, HR1, HR2, HR3, and HR4, respectively) during a step test were used as predictors. Moreover, R2 and standard error of estimate (SEE) were used to evaluate the accuracy of various body composition models in predicting V̇O2max. The predicted and actual V̇O2 max values were significantly correlated (BF% model: R2 = 0.624, SEE = 4.982; BMI model: R2 = 0.567, SEE = 5.153). The BF% model yielded more accurate predictions, and the model predictors were sex, age, BF%, HR0, ΔHR3-HR0, and ΔHR3-HR4. In our study, involving Taiwanese adults, we constructed and verified a model to predict V̇O2 max, which indicates cardiorespiratory fitness. This model had the predictors sex, age, body composition, and heart rate changes during a step test. Our 3MPKS test has the potential to be widely used in epidemiological research to measure V̇O2 max and other health-related parameters.


The assistant medical officer in Sri Lanka: mid-level health worker in decline.
The history of Assistant Medical Officers (AMOs) in Sri Lanka can be traced back to the 1860s. Their training from the beginning followed an allopathic, 'evidence based' model. AMOs have played a key role in rural and peripheral health care, through staffing of government central dispensaries and maternity homes and may have contributed to Sri Lanka's favorable health outcomes. While there are currently approximately 2000 AMOs, their training course was discontinued in 1995. It was argued that the quality of care provided by the AMOs is substandard relative to that of physicians. The success, rapid expansion and integration of physician assistant programs into the US health care system have recently spurred other countries to introduce similar programs. This paper reviews Sri Lanka's move in the opposite direction, phasing out the AMO profession, without any research into their contributions to access to interprofessional primary health care and positive health outcomes.


A developmental origins perspective on the emergence of violent behavior in males with prenatal substance exposure.
Children with prenatal substance exposure are at increased risk for externalizing behavior problems and violence. However, the contribution of early life experiences for placing these individuals at risk is not well understood. Utilizing a sample of 1,388 children with prenatal substance exposure from the Maternal Lifestyle Study, we attempt to shed light on these contributing factors by examining the impact of infant temperament, maternal sensitivity, and early life stress on the expression of violent behavior at ages 12 through 14 years. Males may be more at risk for increases in violent behavior in early adolescence through a number of early life experiences, such as variability in responses to maternal flexibility and engagement related to individual differences in temperament, as well as exposure to early adversity. Comparing two prevailing developmental theoretical frameworks, deficit models and differential susceptibility, we aim to understand the developmental origins of violent behavior in males by identifying children who may be most susceptible to early caregiving experiences.


Neuropeptide induction of cyclic GMP increases in the insect CNS: resolution at the level of single identifiable neurons.
In insects, the neuropeptide eclosion hormone (EH) acts on the CNS to evoke the stereotyped behaviors that cause ecdysis, the shedding of the cuticle at the end of each molt. Concomitantly, EH induces an increase in cyclic GMP (cGMP). Using antibodies against this second messenger, we show that this increase is confined to a network of 50 peptidergic neurons distributed throughout the CNS. Increases appeared 30 min after EH treatment, spread rapidly throughout these neurons, and were extremely long lived. We show that this response is synaptically driven, and does not involve the soluble, nitric oxide (NO)-activated, guanylate cyclase. Stereotyped variations in the duration of the cGMP response among neurons suggest a role in coordinating responses having different latencies and durations.


[Metabolic acidosis].
Metabolic acidosis is frequently observed in clinical practice, especially among critically ill patients and/or in the course of renal failure. Complex mechanisms are involved, in most cases identifiable by medical history, pathophysiology-based diagnostic reasoning and measure of some key acid-base parameters that are easily available or calculable. On this basis the bedside differential diagnosis of metabolic acidosis should be started from the identification of the two main subtypes of metabolic acidosis: the high anion gap metabolic acidosis and the normal anion gap (or hyperchloremic) metabolic acidosis. Metabolic acidosis, especially in its acute forms with elevated anion gap such as is the case of lactic acidosis, diabetic and acute intoxications, may significantly affect metabolic body homeostasis and patients hemodynamic status, setting the stage for true medical emergencies. The therapeutic approach should be first aimed at early correction of concurrent clinical problems (e.g. fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, hemodialysis for acute intoxications etc.), in parallel to the formulation of a diagnosis. In case of severe acidosis, the administration of alkalizing agents should be carefully evaluated, taking into account the risk of side effects, as well as the potential need of renal replacement therapy.


Levels of change in adolescent sexual behavior in three Asian cities.
Considerable change in the romantic and sexual behaviors of Asian young people may be occurring as traditionally Confucian societies modernize and increase outside contacts. This study explores the dimensions and context of this change in three sites at different stages in the process of modernization: Hanoi (early), Shanghai (intermediate), and Taipei (later stage). A survey was conducted of 17,016 males and females aged 15-24 in urban and rural settings in three large metropolitan areas. Survival analysis and Cox regressions were performed to explore ages of respondents at key transitions and the significance of differences between two age cohorts: 15-19 and 20-24. Significant differences are found in levels of sexual and other transitions, even within the narrow time span reflected by the age cohorts. The findings highlight the differential impact of modernization on adolescent sexual behavior as traditional societies undergo social change, and they underline the importance of context in exploring youthful transitions.


Shigella phagocytic vacuolar membrane remnants participate in the cellular response to pathogen invasion and are regulated by autophagy.
Intracellular pathogens like Shigella flexneri enter host cells by phagocytosis. Once inside, the pathogen breaks the vacuolar membrane for cytosolic access. The fate and function of the vacuolar membrane remnants are not clear. Examining Shigella-infected nonmyeloid cells, we observed that proteins associated with vacuolar membrane remnants are polyubiquinated, recruit the autophagy marker LC3 and adaptor p62, and are targeted to autophagic degradation. Further, inflammasome components and caspase-1 were localized to these membranes and correlated with dampened inflammatory response and necrotic cell death. In Atg4B mutant cells in which autophagosome maturation is blocked, polyubiquitinated proteins and P62 accumulated on membrane remnants, and as in autophagy-deficient Atg5(-/-) cells, the early inflammatory and cytokine response was exacerbated. Our results suggest that host membranes, after rupture by an invading cytoplasm-targeted bacterium, contribute to the cellular responses to infection by acting as a signaling node, with autophagy playing a central role in regulating these responses.


The effect of the vaginal diaphragm and lubricant gel on acquisition of HSV-2.
In the context of a multisite HIV prevention trial in Southern African women, we examined the effectiveness of the Ortho All-Flex Diaphragm, lubricant gel (Replens) and condoms compared to condoms alone on the incidence of herpes simplex virus type 2 (HSV-2) infections. We analysed data from 2016 sexually active women in Zimbabwe and South Africa. Women were followed quarterly, and specimens obtained at the closing visit from previously HSV-2 seronegative women were retested for HSV-2 antibodies using Focus HerpeSelect Elisa. The first visit at which the participant tested positive for HSV-2 was defined by back-testing. We compared the incidence of HSV-2 after randomisation between study arms in both intent-to-treat (ITT) and per-protocol populations. 210 women acquired HSV-2 during study participation (HSV incidence: 6.8 cases/100 women years). Allocation to the intervention arm was found to offer no benefit in reduction of HSV-2 by modified ITT (HR 1.03, 95% CI 0.78 to 1.35; p=0.85) or per protocol analysis (HR 0.87, 95% CI 0.61 to 1.24; p=0.45). HSV-2 infection was common in the study population as detected by type-specific Elisa testing. Provision of diaphragm and lubricant gel offered no additional protection against HSV-2 acquisition over male condoms alone.


Assessing coughing and wheezing in lung cancer: a pilot study.
To establish reliability and validity of two self-report questionnaires, the Lung Cancer Cough Questionnaire and the Lung Cancer Wheezing Questionnaire. Prospective, exploratory pilot study. Clinical oncology settings in the southern United States. 31 adult women with lung cancer. Content validity of both questionnaires was assessed through a comprehensive literature review and an expert judge panel. Concurrent validity was established by Spearman rank correlation coefficients and Wil-coxon Rank Sum tests with items from other valid tools. Test-retest reliability was assessed by percent agreement, kappa, paired t tests, and correlations. Internal consistency was determined by Cronbach's alpha. Cough, wheeze. Cronbach's alpha showed excellent internal consistency and percent agreement, and kappa showed similarity of item responses across test-retest administrations. Nonsignificant paired t tests indicated similar mean scores, and significant test-retest correlations supported test-retest reliability. Preliminary testing indicates good reliability and validity for both questionnaires. Both instruments can identify people with problems of coughing and wheezing and have the potential for monitoring these symptoms over time and determining effectiveness of interventions. Assessment of coughing and wheezing is an important component of monitoring respiratory symptoms of lung cancer. Both of these symptoms can be amenable to interventions. Further research is needed to confirm psychometrics and sensitivity of these tools.


Guidelines for the Content of Statistical Analysis Plans in Clinical Trials.
While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration-registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.


Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter trial assessing 2 switching techniques in Asia Pacific.
This open-label, multicenter, randomized study compared the efficacy and safety of switching moderately ill Asian patients with schizophrenia from their current regimen of antipsychotic medication to the atypical antipsychotic olanzapine using either a direct switch method or a start-taper switch method. Asian inpatients and outpatients with DSM-IV schizophrenia (N = 108) currently treated with predominantly typical antipsychotics were switched to olanzapine (initial dose of 10 mg/day) for 6 weeks. Patients were randomly assigned to 1 of 2 groups: the direct switch group (N = 54) received only olanzapine, while the start-taper switch group (N = 54) received olanzapine and their usual antipsychotic in decreasing doses for the first 2 weeks. A successful switch was defined as completing 6 weeks of therapy without worsening of symptoms (Clinical Global Impressions-Severity of Illness scale [CGI-S]) or extrapyramidal side effects (Simpson-Angus Scale). Overall efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and safety was assessed by recording adverse events and measuring vital signs. Statistically significant (p < .001) improvements from baseline to endpoint occurred in both switch groups in the CGI-S score and the PANSS total score and subscores. However, no significant differences were observed between the switch groups for any efficacy measure. Both techniques had comparable rates of successful switching (direct switch, 74.1% vs. start-taper switch, 67.9%). The frequency of treatment-emergent adverse events was similar between switch groups with no clinically significant differences in any laboratory value or vital sign. Weight gain occurred in both switch groups (p < .001), but the groups were not statistically different from each other. Both switch groups showed statistically significant (p < .01) improvements from baseline to endpoint on the Simpson-Angus Scale and Barnes Akathisia Scale. Moderately ill Asian patients with schizophrenia may experience a decrease in symptom severity and improvement in extrapyramidal symptoms when switched from their current medication to olanzapine therapy.


Building grass roots capacity to tackle childhood obesity.
In recognition of the increasing problem of child obesity in London and elsewhere, we were commissioned to build capacity to tackle this major public health concern. This paper describes one of the outputs of this work: to develop and deliver effective brief intervention training on the subject of childhood healthy/unhealthy weight and obesity to be used by anyone who works with children and families, regardless of their job title or level of educational achievement. A literature review informed the process. The slim evidence derived was combined with the expertise of an expert working group to develop clear learning objectives for training and then to develop a flexible one-day training programme suitable for delivery to mixed groups of participants, to meet the learning objectives. Evaluation was built into the programme by means of a questionnaire at the end of the training session and by the use of a structured reflective log to be returned by participants once they had put their training into practice. The training programme was delivered free of charge to over 560 people during the course of a Regional Public Health Group-sponsored project. Subsequently it has been delivered to several more audiences working in the NHS, local government and third sectors in London on a not-for-profit basis. The programme, based on best available evidence and clear evidence of needs, provides a low-cost evaluated intervention that permits people from diverse professional and occupational backgrounds to acquire the knowledge, skills and confidence needed to raise the subject of healthy and unhealthy weight with parents of primary school-aged children and signpost them to appropriate local facilities and services. Although developed in London, the programme may be used anywhere in the UK, with the substitution of local information about prevalence of overweight and obesity and about local services and facilities.


BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling.
For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.


Application of multivariate analyses of enzymic data to classification of members of the Actinobacillus-Haemophilus-Pasteurella group.
Outer membrane vesicles and fragments from Actinobacillus actinomycetemcomitans, Actinobacillus lignieresii, Actinobacillus ureae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Haemophilus influenzae, Haemophilus parainfluenzae, Pasteurella haemolytica, and Pasteurella multocida were isolated and examined semiquantitatively for 19 enzyme activities by using the API ZYM micromethod. The enzyme contents of vesicles and fragments were compared with the enzyme contents of whole cells of the same organisms. Enzymic data were analyzed by using principal-component analysis and soft independent modeling of class analogy. This technique allowed us to distinguish among the closely related organisms A. actinomycetemcomitans, H. aphrophilus, and H. paraphrophilus. A. actinomycetemcomitans was divided into two groups of strains. A. lignieresii fell outside or on the border of the A. actinobacillus class. A. ureae, H. influenzae, H. parainfluenzae, P. haemolytica, and P. multocida fell outside the A. actinomycetemcomitans, H. aphrophilus, and H. paraphrophilus classes.


Investigation of CMOS Multiplexer Jet Matrix Addressing and Micro-Droplets within a Printhead Chip.
In this study, we demonstrate and investigate a new droplet injection design. We create a thermal inkjet (TIJ) printhead using an application-specific integrated circuit system and bulk micromachining technology (microelectromechanical systems). We design inkjet printhead chips with a new structure and investigate their properties. For the new structure, the integration of complementary metal-oxide-semiconductors (MOSs) and enhancement-mode devices, as well as power switches and a TIJ heater transducer, enables logic functions to be executed on-chip. This capability is used in the proposed design to address individual jets with even fewer input lines than in matrix addressing. A high number of jets (at least 896) can be addressed with only 11 input lines. E1 (Enable 1) and E2 (Enable 2) are set up dependently, and they have the ability to reverse their signals in relation to each other (i.e., if E1 is disabled, E2 is enabled and vice versa). The E1 and E2 signals each service 448 jets. If one of the MOSs is turned on, then it corresponds to a power line with a similar function. If an addressing gate terminal of the other MOS has a discharge action, then we can control a different heater to generate heating bubbles in the jet inks. The operating frequency for addressing these measurements is 18 kHz in normal mode, 26 kHz in draft mode, and 16 kHz in best mode.


A global metagenomic map of urban microbiomes and antimicrobial resistance.
We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.


Obstetric ultrasound use in low and middle income countries: a narrative review.
Although growing, evidence on the impact, access, utility, effectiveness, and cost-benefit of obstetric ultrasound in resource-constrained settings is still somewhat limited. Hence, questions around the purpose and the intended benefit as well as potential challenges across various domains must be carefully reviewed prior to implementation and scale-up of obstetric ultrasound technology in low-and middle-income countries (LMICs). This narrative review discusses these issues for those trying to implement or scale-up ultrasound technology in LMICs. Issues addressed in this review include health personnel capacity, maintenance, cost, overuse and misuse of ultrasound, miscommunication between the providers and patients, patient diagnosis and care management, health outcomes, patient perceptions and concerns about fetal sex determination. As cost of obstetric ultrasound becomes more affordable in LMICs, it is essential to assess the benefits, trade-offs and potential drawbacks of large-scale implementation. Additionally, there is a need to more clearly identify the capabilities and the limitations of ultrasound, particularly within the context of limited training of providers, to ensure that the purpose for which an ultrasound is intended is actually feasible. We found evidence of obstetric uses of ultrasound improving patient management. However, there was evidence that ultrasound use is not associated with reducing maternal, perinatal or neonatal mortality. Patients in various studies reported to have both positive and negative perceptions and experiences related to ultrasound and lastly, illegal use of ultrasound for determining fetal sex was raised as a concern.