A Case of Beare-Stevenson Syndrome with Unusual Manifestations.
Beare-Stevenson syndrome (BSS) is an extremely rare genetic disorder, with fewer than 25 cases reported worldwide. This autosomal dominant syndrome has been linked to two mutations in the fibroblast growth factor receptor 2 gene (FGFR2), Tyr375Cys and Ser372Cys, both causing amino acid changes. BSS is characterized by a range of morphological features, some more classically associated than others, of which craniosynostosis has been almost uniformly present. Other common features include cutis gyrata, acanthosis nigricans, ear and eye defects, skin/mucosal tissue tags, prominent umbilical stump, and anogenital anomalies. This account reports what we believe to be the 25th case of BSS, and exhibits a constellation of the characteristic features similar to those previously described, including the presence of cutis gyrata, proptosis, a bifid scrotum, and hypospadias. However, craniosynostosis was not detected prenatally by ultrasound or at birth. Prenatal ultrasound may detect some dysmorphic features of BSS. Many of these features have also been associated with other genetic disorders with overlapping phenotypes. Our case presented with the unusual features of a natal tooth and absence of craniosynostosis at birth. At birth, a diagnosis of BSS was suspected based on clinical features despite the absence of craniosynostosis. This was later confirmed with the use of molecular analysis, revealing a Tyr375Cys mutation of exon 9 of the FGFR2 gene. We suggest that a normal antenatal ultrasound scan and the absence of craniosynostosis at birth should not preclude further workup for BSS if this possibility is clinically suspected.


The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production.
Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glia cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may influence neuronal cell survival. Recent studies have demonstrated that glia cell-mediated neuroinflammation is also related to the pathophysiology of schizophrenia. In the present study, anti-inflammatory and neuroprotective effects of antipsychotics were investigated using cultured brain cells as a model. The results showed that spiperone significantly decreased the production of nitric oxide in lipopolysaccharide-stimulated BV-2 microglia cells, primary microglia and primary astrocyte cultures. Spiperone also significantly inhibited nitric oxide production in adenosine 5'-triphosphate (ATP)-stimulated primary microglia cultures. Spiperone markedly decreased the production of tumor necrosis factor-alpha in BV-2 microglia cells. Spiperone attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha at mRNA levels in BV-2 microglia cells. Spiperone inhibited nuclear translocation and DNA binding of the p65 subunit of nuclear factor kappa B (NF-kappaB), inhibitor of kappa B (IkappaB) degradation, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated BV-2 microglia cells. Moreover, spiperone was neuroprotective, as the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture. These results imply that the antipsychotic spiperone has anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation.


Differences in photochemistry between seawater and freshwater for two natural organic matter samples.
We report changes in the excitation and resolved fluorescence spectra, inferred triplet formation and singlet oxygen formation abilities of two different Natural Organic Matter samples (NOM) in seawater vs. freshwater or NaCl solution. In artificial seawater solution (but not in NaCl solution), the natural water-derived NOM samples Suwannee River Natural Organic Matter (SRNOM) and Nordic Reservoir Natural Organic Matter (NRNOM) display large enhancements in fluorescence intensity. Nearly identical spectra are seen when seawater is replaced by solutions of Mg2+ at its seawater concentration, consistent with magnesium binding to ligand sites of the natural organic matter giving rise to different photophysics. Fluorescence anisotropy measurements show a decrease in anisotropy of SRNOM and NRNOM in seawater, also consistent with Mg2+ binding. Different effects of Mg2+ are seen when the different NOM samples are illuminated: NRNOM exhibits increased formation of its triplet state and also quenching of its triplet by oxygen, compared to its photochemistry in the absence of Mg2+, while SRNOM exhibits a reduction in triplet formation in the presence of Mg2+. These observations imply that the photochemistry of NOM in seawater may be very different from what is expected based on freshwater or NaCl solution measurements.


Dietary squid ink polysaccharide induces goblet cells to protect small intestine from chemotherapy induced injury.
Gastrointestinal mucositis induced by chemotherapy is associated with alterations of intestinal barrier function due to the potential damage induced by anti-cancer drugs on the epithelial cells. Goblet cells, an important epithelial lining in the intestine, contribute to innate immunity by secreting mucin glycoproteins. Employing a mouse model of chemotherapy induced intestinal mucosal immunity injury by cyclophosphamide, we demonstrated for the first time that polysaccharide from the ink of Ommastrephes bartramii (OBP) enhanced Cyto18, which is a mucin expression in goblet cells. The up-regulation of mucins by OBP relied on the augmented quantity of goblet cells, but not on the changes in the ultrastructure of endoplasmic reticulum (ER). Our results may have important implications for enhanced immunopotentiation function of functional OBP on intestinal mucosal immunity against intestinal disorders involving inflammation and infection.


The effect of technology assisted therapy for intellectually and visually impaired adults suffering from separation anxiety: Conquering the fear.
Persons with an intellectual disability (ID) are at risk of developing separation anxiety (SA) and, if left untreated, this can be a risk factor for the development of psychopathology. The effects of an intervention, namely technology assisted therapy for SA (TTSA), were examined on the SA, challenging behavior, psychosocial functioning, and quality of life (QOL) experienced by moderate to mild intellectually and visually disabled adults. This study aimed to determine whether TTSA reduces SA and challenging behavior in persons with ID and visual impairment, and if this results in increased psychosocial functioning and QOL. A pre-experimental within-group design with randomized multiple baselines and staggered intervention start-points was used (n = 6). The variables were monitored with standardized instruments. The frequencies of each participant's use of the technology and the frequency and intensity of their behavior were recorded over time. Results indicate that the SA and challenging behavior experienced by the participants decreased significantly and their psychosocial functioning and QOL increased significantly. The conclusions are that TTSA has the potential to be a valid intervention to address SA in adults with visual and moderate to mild IDs.


Muscle-related traits in cattle: The role of the myostatin gene in the South Devon breed.
In this paper, we examined the effects of an 11-bp mutation within the GDF-8 gene, originally identified in Belgian Blue cattle, in the South Devon breed. The mutation was found at moderate frequency (0.37) in the South Devon population. We quantified the effects of this mutation on growth, body composition and calving traits in South Devon cattle. We found that the mutation significantly increased muscle score and calving difficulty and decreased fat depth. The mutation did not significantly affect weight at 200 and 400 days or muscle depth. Its effect on muscle score and fat depth was additive while its effect on calving difficulty was recessive. The mutation accounted for a significant proportion of the phenotypic variance in muscle score and calving difficulty. There was an economic benefit of the mutation for this data set, however, calculations were sensitive to changes in the parameter values. Additional data would be required to refine these calculations.


Adaptation of clinical practice guidelines.
A rigorous development process of clinical practice guidelines through a systematic appraisal of available evidence is costly and time consuming. One way to reduce the costs and time, and avoid unnecessary duplication of effort of guideline development is by relying on a local adaptation approach of guidelines developed at the (inter)national level by expert groups. In this chapter we survey the work on guideline adaptation, which includes methodologies, case studies, assessment of effectiveness, and related work on guideline adaptation in the Artificial Intelligence community.


Simultaneous characterization of somatic events and HPV-18 integration in a metastatic cervical carcinoma patient using DNA and RNA sequencing.
Integration of carcinogenic human papillomaviruses (HPVs) into the host genome is a significant tumorigenic factor in specific cancers including cervical carcinoma. Although major strides have been made with respect to HPV diagnosis and prevention, identification and development of efficacious treatments for cervical cancer patients remains a goal and thus requires additional detailed characterization of both somatic events and HPV integration. Given this need, the goal of this study was to use the next generation sequencing to simultaneously evaluate somatic alterations and expression changes in a patient's cervical squamous carcinoma lesion metastatic to the lung and to detect and analyze HPV infection in the same sample. We performed tumor and normal exome, tumor and normal shallow whole-genome sequencing, and RNA sequencing of the patient's lung metastasis. We generated over 1.2 billion mapped reads and identified 130 somatic point mutations and indels, 21 genic translocations, 16 coding regions demonstrating copy number changes, and over 36 genes demonstrating altered expression in the tumor (corrected P < 0.05). Sequencing also revealed the HPV type 18 (HPV-18) integration in the metastasis. Using both DNA and RNA reads, we pinpointed 3 major events indicating HPV-18 integration into an intronic region of chromosome 6p25.1 in the patient's tumor and validated these events with Sanger sequencing. This integration site has not been reported for HPV-18. We demonstrate that DNA and RNA sequencing can be used to concurrently characterize somatic alterations and expression changes in a biopsy and delineate HPV integration at base resolution in cervical cancer. Further sequencing will allow us to better understand the molecular basis of cervical cancer pathogenesis.


A pro-apoptotic function of iASPP by stabilizing p300 and CBP through inhibition of BRMS1 E3 ubiquitin ligase activity.
The p53 family and its cofactors are potent inducers of apoptosis and form a barrier to cancer. Here, we investigated the impact of the supposedly inhibitory member of the apoptosis-stimulating protein of p53, iASPP, on the activity of the p53 homolog TAp73, and its cofactors p300 and CBP. We found that iASPP interacted with and stabilized the histone acetyltransferase p300 and its homolog CBP upon cisplatin treatment. Vice versa, iASPP depletion by shRNA resulted in decreased amounts of p300 and CBP, impaired binding of p300 and TAp73 to target site promoters, reduced induction of pro-apoptotic TAp73 target genes, and impaired apoptosis. Mechanistically, we observed that the p300-regulatory E3 ubiquitin ligase BRMS1 could rescue the degradation of p300 and CBP in cisplatin-treated, iASPP-depleted cells. This argues that iASPP stabilizes p300 and CBP by interfering with their BRMS1-mediated ubiquitination, thereby contributing to apoptotic susceptibility. In line, iASPP overexpression partially abolished the interaction of BRMS1 and CBP upon DNA damage. Reduced levels of iASPP mRNA and protein as well as CBP protein were observed in human melanoma compared with normal skin tissue and benign melanocytic nevi. In line with our findings, iASPP overexpression or knockdown of BRMS1 each augmented p300/CBP levels in melanoma cell lines, thereby enhancing apoptosis upon DNA damage. Taken together, destabilization of p300/CBP by downregulation of iASPP expression levels appears to represent a molecular mechanism that contributes to chemoresistance in melanoma cells.


Effects of insulin-like growth factors I and II and insulin on the immortalized hypothalamic GTI-7 cell line.
Insulin and insulin-like growth factor I (IGF-I) participate in energy metabolism, regulate cellular growth and differentiation, and are thought to act locally in a paracrine manner through specific receptors. Systemic levels of these peptides in humans and primates are directly associated with levels of activity of the reproductive axis. To date, it is unclear whether these peptides participate in reproductive function by acting at the level of the GnRH neuron. In this study we examined the effects of IGF-I, IGF-II and insulin on immortalized GnRH-secreting neurons, the GTI-7 cell line. The GTI-7 cells expressed all three members of the insulin receptor family as determined by analysis of 125I-IGF-I, 125I-IGF-II and 125I-insulin binding sites. Insulin receptors bound insulin, IGF-II and IGF-I with a ratio of potency of 1:5:20. IGF-I and IGF-II receptors bound both IGF-I and IGF-II. The ratio of potency of IGF-I/IGF-II was 1:5 for the IGF-I receptor and 100:1 for the IGF-II receptor. The binding characteristics of the growth factors at 22 degrees C suggested the possibility that these cells may secrete IGF binding proteins. To ensure that changes in GnRH levels in the media were due to secretion and not to changes in cell number, the mitogenic effect of these peptides on GTI cells was evaluated. Both insulin and IGF-I were strong mitogens (48-hour incubation), restoring cell number to that of serum-replete cultures at a dose of 0.1 ng/ml. A 100-fold higher dose of IGF-II was required to produce a similar level of mitogenicity, implicating an action through the IGF-I and/or insulin receptor. Due to these mitogenic effects, the effect of insulin, IGF-I and IGF-II on GnRH secretion was studied after short-term exposure. Insulin and IGF-I did not affect GnRH secretion, but IGF-II had a biphasic effect on GnRH release after 2 h of incubation (a maximum stimulatory effect occurred with a 0.1 ng/ml dose). In order to examine the signal transduction mechanism, the role of cytoplasmic calcium mobilization in IGF-II-induced GnRH secretion was examined in single cells using calcium imaging. The effect of IGF-II on GnRH secretion appeared to operate via a calcium-independent mechanism. The studies document an insulin/IGF system in the GTI-7 neuronal cell line and show that insulin and IGFs can exert direct effects on the immortalized GnRH neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Influence of physical exercise on coronary collateral blood flow in chronic experimental two-vessel occlusion.
In 45 approximately 1-year-old purebred German shepherd dogs, the left circumflex and the right coronary arteries were chronically occluded by implantation of slowly swelling ameroid constrictors. Before the operation, 27 dogs were trained on a treadmill until they could run 8 mph on a 22% incline for 1 hour, 5 days per week. Two weeks after the operation, exercise was gradually resumed and continued for 4 weeks, until the preoperative fitness level had been regained. Preoperative exercise training lasted 1-3 months; postoperative training lasted 100 +/- 22 days (mean +/- SD). After the dogs had trained with two chronically occluded coronary arteries, collateral and coronary blood flows were measured with tracer microspheres at maximal coronary vasodilation (adenosine infusion) in an isolated, blood-perfused Langendorff preparation at perfusion pressures of 40, 60, 80, 100, 120 and 140 mm Hg. Eighteen nonexercising dogs that also had two-vessel coronary occlusion served as controls. Nine controls and nine exercising dogs were paired littermates. Exercise of relatively high intensity (heart rates greater than 200 beats/min) before and after occlusion had no effect on coronary collaterals. Collateral conductance in trained and untrained dogs reached only slightly less than 40% of that of the replaced coronary artery. This result agrees well with earlier results in a group of nonexercising dogs with chronic two-vessel occlusion studied in an identical way. Two-vessel occlusion was associated with a 25% mortality rate. All dogs died instantaneously without warning symptoms of ventricular fibrillation. Exercise had no influence on mortality.


Pilot study to investigate the possibility of cytogenetic and physiological changes in bio-electrosprayed human lymphocyte cells.
We recently pioneered the ability to directly electrospray and electrospin living cells without compromising their viability. These protocols, now referred to as 'bio-electrosprays' and 'cell electrospinning', are rapidly emerging bio-techniques with a plethora of promising applications within the life sciences, in particular to regenerative and therapeutic medicine. Our studies to date, with both bio-electrosprays and cell electrospinning, have demonstrated that a large population of viable cells exist post-treatment, in comparison to controls over both short and long periods as assessed by flow cytometry. Post-treated mammalian cells are investigated in comparison to controls (culture and needle controls) at a cytogenetic and physiological level. In particular, the study addresses chromosome integrity following these protocols to assess any protocol-inflicted aberrations. The procedures explored failed to inflict any process-driven gross chromosomal aberrations post-treatment. Our preliminary investigations demonstrate no significant compromising affects on the cell's structure at a cytogenetic or physiological level, post-treatment. Thus, further establishing these protocols as unique direct cell-engineering approaches with a host of biological and medical applications, from the development of tissues to perhaps even organs in the future.


Alcohol Rehabilitation Within 30 Days of Hospital Discharge Is Associated With Reduced Readmission, Relapse, and Death in Patients With Alcoholic Hepatitis.
Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and mortality. We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge. Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios [AOR] 0.16; 95% CI, 0.04-0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02-0.53; P < .001), and death (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.05-0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09-0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01-0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01-0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73. In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment.


Variation in the estrogen receptor alpha gene and risk of stroke: the Rotterdam Study.
Variations in the -397T>C (rs2234693) and -351A>G (rs9340799) single nucleotide polymorphisms of the estrogen alpha receptor (ESR1) gene were found to be strongly associated with risk of ischemic heart disease, although not all studies could replicate this finding. One study also reported an association with stroke. We assessed whether variations in the ESR1 gene are associated with the risk of stroke in the general population. This prospective population-based study was based on 6229 Rotterdam Study participants who at baseline (1990-1993) were aged 55 years or older, free from stroke, and had assessment of the ESR1 rs2234693 and rs9340799 single nucleotide polymorphisms. Follow-up for incident stroke was complete until January 1, 2005. Data were analyzed with Cox proportional hazards models for men and women separately with adjustment for age. During an average follow-up time of 10.1 years, 659 strokes occurred, of which 386 were ischemic. Three common haplotypes were identified: -397T/-351A (carried by 78% of all participants), -397C/-351G (carried by 57%), and -397C/-351A (carried by 22%). Although we had at least 89% power to detect a relative risk of 1.5 (alpha=0.05) in all subgroups, we did not find any association between ESR1 haplotype carriership and risk of stroke and ischemic stroke. We have not been able to replicate the previously reported association between variations in the ESR1 gene and risk of stroke.


The brain and communication are basic for clinical human sciences.
This article focuses on basic concepts modelled on medical science for the human sciences. This reformulates problems experienced by people who consult counsellors, psychologists, psychiatrists, social workers and other human science clinicians as located in the brain. These troubles can be described as difficulties in social life and human communication, on the one hand, and as varied brain physiology, on the other. These problems and their solutions are not traditionally biological but restrictive views of biology need modification as the brain is obviously the central organ for not only the medical specialities of neurology and psychiatry but for all professionals concerned with social interactions. The human genome determines the brain of each person: each such brain constitutes the latest iteration of ancestral genomes that include species precursor to humans and primates, extending back to unicellular life forms. The genome that determines the human brain confers remarkable flexibility or learning potential. Yet many factors influence what is learned and experienced. Understanding this entails comparing and contrasting humans and non-humans. The genomes of chimpanzees and gorillas differ little from that of humans so most basic plans determining behaviour must be shared. Yet contrasted to these animals, the human brain is three times greater in mass and the human cerebral cortex has four times more area. This increased brain correlated with more social interaction; humans are the story-telling animal, producing, consuming and otherwise using small and large tales intensely and incessantly. But do communicational features resemble each other across species? Commnunicational propensity states in humans compare to those of non-humans. So do those of normal people and psychiatric patients. Psychiatry's efforts at systematic description and nosology provided guidelines to the ethology of ancient but still active communicational propensity states called PSALICs (Gardner, 1988). This double acronym refers to their normal function and prehuman origins; they are defined from a three-legged base in that each exists in psychiatric patients, normal people and non-human animals. This article describes the following psalics: alpha, audience, in-group omega, mating, nurturant, nurturance-eliciting, out-group omega and spacing-avoidant. The article describes psalics' varied expression in people. This basic science formulation and an across-species comparisons approach has implications for treating patients and clients.


Incidence and Associations of Chronic Kidney Disease in Community Participants With Diabetes: A 5-Year Prospective Analysis of the EXTEND45 Study.
To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in people with diabetes. We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006-2014) that linked the Sax Institute's 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m2 recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m2 at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m2 and multivariable Cox regression to examine factors associated with the study outcome. Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m2 over a median follow-up time of 5.7 years (interquartile range, 3.0-5.9 years). The eGFR <60 mL/min/1.73 m2 incidence rate per 100 person-years was 6.0 (95% CI 5.7-6.3) overall, 1.5 (1.3-1.9) in participants aged 45-54 years, 3.7 (3.4-4.0) for 55-64 year olds, 7.6 (7.1-8.1) for 65-74 year olds, 15.0 (13.0-16.0) for 75-84 year olds, and 26.0 (22.0-32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19-1.26), geography (outer regional and remote versus major city: 1.36; 1.17-1.58), obesity (obese class III versus normal: 1.44; 1.16-1.80), and the presence of hypertension (1.52; 1.33-1.73), coronary heart disease (1.13; 1.02-1.24), cancer (1.30; 1.14-1.50), and depression/anxiety (1.14; 1.01-1.27). In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m2 was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.


Cannabis or alcohol first? Differences by ethnicity and in risk for rapid progression to cannabis-related problems in women.
Initiation of cannabis use typically follows alcohol use, but the reverse order does occur and is more common for African-Americans (AAs) than European-Americans (EAs). The aim of this study was to test for differences in the order of initiation of cannabis and alcohol use between AA and EA women and to determine whether order and ethnicity contribute independently to risk for rapid progression to cannabis-related problems. Method Data were drawn from structured psychiatric interviews of 4102 women (mean age = 21.6 years), 3787 from an all-female twin study and 315 from a high-risk family study; 18.1% self-identified as AA, 81.9% as EA. Ethnicity and order of initiation of cannabis and alcohol use were modeled as predictors of transition time from first use to onset of cannabis use disorder symptom(s) using Cox proportional hazards regression analyses. AA women were nearly three times as likely as EA women to initiate cannabis use before alcohol use. Using cannabis before alcohol [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.08-1.93] and AA ethnicity (HR 1.59, 95% CI 1.13-2.24) were both associated with rapid progression from first use to cannabis symptom onset even after accounting for age at initiation and psychiatric risk factors. The findings indicate that AA women are at greater risk for rapid development of cannabis-related problems than EA women and that this risk is even higher when cannabis use is initiated before alcohol use. Prevention programs should be tailored to the various patterns of cannabis use and relative contributions of risk factors to the development of cannabis-related problems in different ethnic groups.


Changes in the inequality of mental health: suicide in Australia, 1907-2003.
Rising suicide rates have been identified as a social problem in several Western countries. The application of a Welfare Economics argument justifies a role for policy that reduces the welfare impact of suicide, whereas the measurement of that impact can inform policy making. Two dimensions of the concept can be measured: the social loss from suicide, and the inequality in the distribution of that loss. In this study, an alternative measure of suicide to the conventional suicide headcount, viz. the potential years of life lost (PYLL), is employed. The PYLL measure is a proxy measure of the social impact of suicide, and involves the concept of 'premature' loss of life. The PYLL also lends itself to inequality measurement. We apply the approach to inequality measurement of health phenomena that was pioneered in the 1980s by Jacques Silber and Julian Le Grand, in a literature now described as measuring health inequality per se. The empirical part of the paper statistically estimates equations on Australian suicide data for the period 1907-2003 and determines the trends in the social loss from suicide and the inequality of its age distribution. Some illustrative examples assist in interpreting the welfare impact of suicide measured both ways, by the headcount rate and the PYLL rate.


Electrochemical control of cell and tissue polarity.
Localized ion fluxes at the plasma membrane provide electrochemical gradients at the cell surface that contribute to cell polarization, migration, and division. Ion transporters, local pH gradients, membrane potential, and organization are emerging as important factors in cell polarization mechanisms. The power of electrochemical effects is illustrated by the ability of exogenous electric fields to redirect polarization in cells ranging from bacteria, fungi, and amoebas to keratocytes and neurons. Electric fields normally surround cells and tissues and thus have been proposed to guide cell polarity in development, cancer, and wound healing. Recent studies on electric field responses in model systems and development of new biosensors provide new avenues to dissect molecular mechanisms. Here, we review recent advances that bring molecular understanding of how electrochemistry contributes to cell polarity in various contexts.


[Protective effect of cresacin in D-galactosamine-induced acute experimental hepatitis].
Antioxidant properties of cresacin were studied on the model of galactosamine hepatitis and on the isolated liver cells of white male rats. It has been shown, that cresacin in a dose of 20 mg/kg effectively inhibits the processes of lipid peroxidation induced by hepatotoxin. Cresacin also normalized some components of fermentative and non-enzymatic antioxidant system. In particular the indexes of the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and the level of reduced glutathione, total phospholipids and ascorbic acid was increased for certain. In vitro, on the isolated hepatocytes, cresacin showed the dose-dependent antioxidant effect. This fact is confirmed by its property to inhibit the speed of formation of the malonic dialdehyde in the incubation medium.


Clinical predictors of malaria and other febrile illnesses in children under five on Pemba Island, Tanzania.
Under the current guidelines of presumptive treatment of all children with reported fever, the risk of over-prescribing antimalarial drugs and missing other important causes of fever, like acute respiratory tract infection (ARI), is substantial. Clinical algorithms have been shown to be useful in diagnosing malaria, but often with differing results, due to regional variations. We set out to explore the clinical features associated with malaria compared with other febrile illnesses and specifically severe malaria with ARI in children under five in Pemba. Two hundred and seven children aged six months to five years presenting to a hospital clinic with fever were studied in Pemba. Clinical findings were related to the presence of malaria parasitaemia. Malaria accounted for 67.7% of the febrile episodes investigated. Five symptoms and signs, including pallor, drowsiness, splenomegaly, fever duration and no chest crackles, could accurately predict a case of malaria with a sensitivity of 91.3% and specificity of 53% and positive predictive value of 80.3%. Several clinical features were found to differentiate severe malaria from ARI. These results confirm that clinical algorithms can increase the diagnostic accuracy of malaria, although not sufficiently to replace microscopy, and by promoting the use of clinical skills other treatable causes of febrile illnesses may be identified. These findings could have implications in optimizing treatment and malaria control in children on Pemba.


Effect of season and photoperiod on the time of first postpartum ovulation in Awassi ewes.
Seasonal differences in the resumption of postpartum ovarian activity, milk production and periparturient metabolic status were investigated in lactating non-suckling dairy Awassi sheep in two consecutive experiments. In Experiment 1, autumn-lambing (AL, n = 27) and spring-lambing (SL, n = 37) ewes were investigated. Ovarian activity was monitored by means of individual progesterone (P4) profiles from day 5 to day 100 post partum. Most of the AL dams (89%) ovulated till day 35 after parturition and became cyclic thereafter. Incidence of persistent corpus luteum (CLP) and short luteal phases (sCL) was frequent (18% and 29%, respectively) among non-conceiving dams. In contrast, only 24% of the SL ewes ovulated before day 35. P4 levels during the luteal phase were lower in cyclic animals, and the cycle was longer in SL than in AL animals. No CLP or sCL was detected in the spring-lambing group, and 61% of SL ewes remained acyclic till the end of the trial. Lactation length was significantly longer in SL dams than in AL ewes (P = 0.008). According to the plasma metabolites (BHB, NEFA) and metabolic hormones (insulin, IGF-I, thyroxine) examined, negative energy balance did not appear in any of the animals. However, seasonal differences were seen in IGF-I and thyroxine levels, which were higher in the SL dams. In Experiment 2, influence of additional lighting was studied in autumn-lambing ewes. The long-day photoperiod (LD, n = 23) group was exposed to artificial light from sunset till midnight (approx. 16 h light/8 h dark) from some weeks before the expected date of delivery in mid-September until the end of December. The control group (n = 25) experienced only natural daylength. The first postpartum ovulation tended to occur later in the LD animals than in the controls (P = 0.047). The lactation of the LD group tended to be longer (P = 0.061). NEFA, BHB, insulin, IGF-I and thyroxine levels did not differ between the groups. (i) The ovarian function of the Awassi population is seasonal under temperate continental climate conditions. (ii) The first postpartum ovulation of non-suckling, autumn-lambing dams may occur very early, even before the completion of uterine involution. (iii) Additional artificial lighting may delay the time of first postpartum ovulation in AL ewes. (iv) Postpartum negative energy balance is unlikely to occur in dairy Awassi ewes even in high-producing intensive systems.


New anticoagulants for the prevention and treatment of venous thromboembolism.
Anticoagulant therapy is effective at preventing the development of venous thromboembolism in high-risk patients, and reduces morbidity and mortality in individuals with established thromboembolic disease. Vitamin K antagonists and heparins are currently the most commonly used anticoagulant drugs, but they have practical limitations. Therefore, new antithrombotic agents with predictable dose-responses (thereby decreasing the need for monitoring without compromising efficacy or safety), ideally available in an oral formulation and with a rapidly reversible anticoagulant effect, are needed. New drugs fulfilling some of the above criteria have been developed and have proven to be effective agents for the treatment and prevention of venous thromboembolism.


Intraspecific variation in leaf growth of wheat (Triticum aestivum) under Australian Grain Free Air CO2 Enrichment (AGFACE): is it regulated through carbon and/or nitrogen supply?
Underlying physiological mechanisms of intraspecific variation in growth response to elevated CO2 concentration [CO2] were investigated using two spring wheat (Triticum aestivum L.) cultivars: Yitpi and H45. Leaf blade elongation rate (LER), leaf carbon (C), nitrogen (N) in the expanding leaf blade (ELB, sink) and photosynthesis (A) and C and N status in the last fully expanded leaf blade (LFELB, source) were measured. Plants were grown at ambient [CO2] (~384µmolmol-1) and elevated [CO2] (~550µmolmol-1) in the Australian Grains Free Air CO2 Enrichment facility. Elevated [CO2] increased leaf area and total dry mass production, respectively, by 42 and 53% for Yitpi compared with 2 and 13% for H45. Elevated [CO2] also stimulated the LER by 36% for Yitpi compared with 5% for H45. Yitpi showed a 99% increase in A at elevated [CO2] but no A stimulation was found for H45. There was a strong correlation (r2=0.807) between LER of the ELB and soluble carbohydrate concentration in LFELB. In ELB, the highest spatial N concentration was observed in the cell division zone, where N concentrations were 67.3 and 60.6mg g-1 for Yitpi compared with 51.1 and 39.2mg g-1 for H45 at ambient and elevated [CO2]. In contrast, C concentration increased only in the cell division and cell expansion zone of the ELB of Yitpi. These findings suggest that C supply from the source (LFELB) is cultivar dependent and well correlated with LER, leaf area expansion and whole-plant growth response to elevated [CO2].


Recent Advances in Nanotechnology for the Treatment of Melanoma.
Melanoma is one of the most aggressive forms of skin cancer, with few possibilities for therapeutic approaches, due to its multi-drug resistance and, consequently, low survival rate for patients. Conventional therapies for treatment melanoma include radiotherapy, chemotherapy, targeted therapy, and immunotherapy, which have various side effects. For this reason, in recent years, pharmaceutical and biomedical research has focused on new sito-specific alternative therapeutic strategies. In this regard, nanotechnology offers numerous benefits which could improve the life expectancy of melanoma patients with very low adverse effects. This review aims to examine the latest advances in nanotechnology as an innovative strategy for treating melanoma. In particular, the use of different types of nanoparticles, such as vesicles, polymers, metal-based, carbon nanotubes, dendrimers, solid lipid, microneedles, and their combination with immunotherapies and vaccines will be discussed.


The role of melanin-concentrating hormone in conditioned reward learning.
The orexigenic neuropeptide melanin-concentrating hormone (MCH) is well positioned to play a key role in connecting brain reward and homeostatic systems due to its synthesis in hypothalamic circuitry and receptor expression throughout the cortico-striatal reward circuit. Here we examined whether targeted-deletion of the MCH receptor (MCH-1R) in gene-targeted heterozygote and knockout mice (KO), or systemic treatment with pharmacological agents designed to antagonise MCH-1R in C57BL/6J mice would disrupt two putative consequences of reward learning that rely on different neural circuitries: conditioned reinforcement (CRf) and Pavlovian-instrumental transfer (PIT). Mice were trained to discriminate between presentations of a reward-paired cue (CS+) and an unpaired CS-. Following normal acquisition of the Pavlovian discrimination in all mice, we assessed the capacity for the CS+ to act as a reinforcer for new nose-poke learning (CRf). Pharmacological disruption in control mice and genetic deletion in KO mice impaired CRf test performance, suggesting MCH-1R is necessary for initiating and maintaining behaviors that are under the control of conditioned reinforcers. To examine a dissociable form of reward learning (PIT), a naïve group of mice were trained in separate Pavlovian and instrumental lever training sessions followed by the PIT test. For all mice the CS+ was capable of augmenting ongoing lever responding relative to CS- periods. These results suggest a role for MCH in guiding behavior based on the conditioned reinforcing value of a cue, but not on its incentive motivational value.


Molecular cloning of a bovine cathepsin.
A cDNA clone for a thiol endoproteinase has been isolated from a bovine heart cDNA library by using a mixture of 32 synthetic oligonucleotides as a hybridization probe. The inserted region is 672 base pairs in length. It contains a sequence encoding the C-terminal region of a protein that is homologous to rat liver cathepsins B and H and to plant thiol proteinases. In addition, it contains the sequence of 442 bases corresponding to the 3' untranslated region of the mRNA. The inserted region was used as a specific probe in RNA transfer analysis; the size of the mRNA encoding the thiol endoproteinase is estimated to be approx. 1.7 kilobases. Thus, the maximum size of the encoded protein is about 350-400 amino acids.


Alopecia areata with lymphocytic mural folliculitis affecting the isthmus in a thoroughbred mare.
A 13-year-old, thoroughbred mare was presented with an 8-year history of multifocal, generalized, noninflammatory alopecia and a 3-month history of alopecia, erythema and scaling of the white star on the forehead and muzzle. Histopathological examination of biopsy samples from multiple sites on the body (mane, neck, shoulder, flank and gluteal region) showed a subtle lymphocytic inflammatory infiltrate affecting and surrounding the anagen hair bulbs, consistent with a diagnosis of alopecia areata. The biopsy sample from the star on the forehead showed atrophic hair follicles with perifollicular and mural mononuclear folliculitis affecting the isthmus. Immunohistochemical staining with a CD3 marker confirmed the T-lymphocytic origin of the inflammatory infiltrate in all the samples. The concurrent presence of lymphocytic infiltration at the bulbar and isthmic level of the hair follicles in the same horse is unusual. This finding may represent a variation of the histological appearance of alopecia areata.


Colistin dry powder inhalation with the Twincer™: An effective and more patient friendly alternative to nebulization.
Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates.


Differential antigen requirements for protection against systemic and intranasal vaccinia virus challenges in mice.
The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.


Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review.
The optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown. To perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported. Medline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4-5 [Gleason score {GS} 8-10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3-4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed. Overall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems. Based on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment. We reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.


Neuropsychological long-term outcome of rolandic EEG traits.
Long-term outcome of rolandic epilepsy (RE) is associated with a diversity of neuropsychological deficits in childhood, although RE is historically considered as a benign epileptic disorder. Dyslexia and other developmental disorders are associated with rolandic EEG traits. To investigate if there is an association between the manifestation of a specific EEG trait of RE and dyslexia. If the EEG traits are causing dyslexia, the cognitive deficits are supposed to be normalised after the EEG trait have resolved. Thirty adolescents and young adults, who had previously received a diagnosis of dyslexia by standard criteria, were included. Fifteen probands (mean age = 15.9) with dyslexia and rolandic EEG traits were compared with 15 age- and sex-matched controls (mean age = 16.0) with normal EEG. There were no statistical differences between the groups according to intelligence (Verbal IQ, Performance IQ and Arithmetical IQ) or spelling ability. However, there was a significant difference between the groups in reading ability of non-related words with the group without RE performing better than the group with RE (p < 0.01). Attentional shifts in dichotic listening with forced or directed attention are generally found in 50-60% in normative samples. However, the present date suggest an impaired attentional shift in dichotic listening test for both groups. Only one third was able to modulate their ear-preference. There were no group differences. In general, both dyslectic groups did not show significant neuropsychological deficits as compared to standard controls. However, there were more reading errors and a tendency to attention impairments in the group with rolandic EEG trait as compared to the dyslectic group with normal EEG. Possible pathogenic factors are discussed.


ANCA-small vessel vasculitides: what have we (not yet) learned from animal models?
Anti-neutrophil cytoplasmic autoantibodies (ANCA) with a specificity for myeloperoxidase or proteinase 3 are closely associated with small vessel vasculitides (SVV). In vitro, ANCA activate primed neutrophils to release toxic substances that destroy endothelial cells, suggesting a pathogenic role for these autoantibodies in disease development. However, to study the complex interplay between ANCA, neutrophils, and the local environment in vivo, animal models are required. Here, we will review the animal models developed for ANCA-SVV and discuss how these models have been applied to study ANCA-SVV pathogenesis. In addition, some directions for future research pertaining to unresolved issues relevant for the pathogenesis and immunogenesis of ANCA-SVV are proposed.


Dual suction Headway27 microcatheter thrombectomy for the treatment of distal intracranial arterial occlusion strokes: initial experience with the micro-ADAPT technique.
Recent studies suggest that the proven benefits of endovascular thrombectomy (EVT) for the treatment of large vessel occlusion (LVO) strokes are transferable to more peripheral distal vessel occlusion (DVO) strokes under certain circumstances. Safely accessing and extracting these thrombi however remains challenging, particularly in more tortuous peripheral arteries. For such cases we have utilized the dual suction Headway27 microcatheter thrombectomy, or micro-ADAPT, technique with the aim of reducing potential trauma associated with negotiating stent retrievers or large bore aspiration catheters into the peripheral intracranial vasculature. We present our experience utilizing the micro-ADAPT in the treatment of DVO strokes. We describe our technique as well as present angiographic and clinical outcomes. A retrospective review of our institution's prospectively collected EVT registry for the 12 months spanning July 2017 to June 2018 was undertaken. Data on all cases of micro-ADAPT EVT were collected and analyzed. Micro-ADAPT EVT was performed 14 times over the study period, with a recanalization rate of 79%. DVO strokes in multiple locations were treated, including the A3, M3, P3, and superior cerebellar artery. In cases where an LVO stroke was also present, the mean duration between primary LVO recanalization and secondary DVO micro-ADAPT recanalization was 15.5 min. No complications relating to the micro-ADAPT technique were recorded. No infarcts were present in the territory of the recanalized DVO stroke on day 1 CT in successful micro-ADAPT cases CONCLUSIONS: In the setting of challenging peripheral DVO strokes, the micro-ADAPT technique appears to be a fast and effective technique with a low complication rate.


Proximity of Cytomegalovirus-Specific CD8+ T Cells to Replicative Senescence in Human Immunodeficiency Virus-Infected Individuals.
Antiretroviral therapy (ART) effectively extends the life expectancy of human immunodeficiency virus (HIV)-infected individuals; however, age-related morbidities have emerged as major clinical concerns. In this context, coinfection with cytomegalovirus (CMV) accelerates immune senescence and elevates risk for other age-related morbidities, possibly through increased inflammation. We investigated potential relationships between CMV memory inflation, immune senescence, and inflammation by measuring markers of inflammation and telomere lengths of different lymphocyte subsets in HIV-infected individuals seropositive for anti-CMV antibodies. Our study cohort consists mainly of middle aged men who have sex with men (MSM) and heterosexuals who are stable under long-term ART. Median levels of IL-6, TNF-α, and CRP were significantly higher in those coinfected with CMV. Lymphocyte telomere length in general correlated with age, but for 32/32 subjects tested, there was a consistent hierarchy of telomere lengths with CD8+ T cells' shorter than the general lymphocyte population, CD57+CD8+ T cells' shorter than CD8+ T cells' and CMV-specific CD57+CD8+ T cells' the shortest of all. Telomeres of HIV-specific CD8+ T cells were longer than those of CMV-specific CD8+ T cells in all cases tested and over 10 years, CMV-specific CD8+ T cell telomeres of two HIV-infected individuals eroded faster than those of HIV-specific CD8+ T cells. These data indicate that CMV-specific CD8+ T cells of HIV-infected individuals are the lymphocytes closest to telomere-imposed replicative senescence. Exhaustive proliferation of CMV-specific CD8+ T cells in HIV-infected individuals is a potential source of senescent lymphocytes affecting systemic immune function and inflammation.


Participation and yield of a population-based colorectal cancer screening programme in China.
Colorectal cancer (CRC) screening has been widely implemented in many countries. However, evidence on participation and diagnostic yield of population-based CRC screening in China is sparse. The analyses were conducted in the context of the Cancer Screening Program in Urban China, which recruited 1 381 561 eligible participants aged 40-69 years from 16 provinces in China from 2012 to 2015. 182 927 participants were evaluated to be high risk for CRC by an established risk score system and were subsequently recommended for colonoscopy. Participation rates and detection of colorectal neoplasms in this programme were reported and their associated factors were explored. 25 593 participants undertook colonoscopy as recommended, with participation rate of 14.0%. High level of education, history of faecal occult blood test, family history of CRC and history of colonic polyp were found to be associated with the participation in colonoscopy screening. Overall, 65 CRC (0.25%), 785 advanced adenomas (3.07%), 2091 non-advanced adenomas (8.17%) and 1107 hyperplastic polyps (4.33%) were detected. Detection rates of colorectal neoplasms increased with age and were higher for men. More advanced neoplasms were diagnosed in the distal colon/rectum (65.2%). Several factors including age, sex, family history of CRC, dietary intake of processed meat and smoking were identified to be associated with the presence of colorectal neoplasms. The diagnostic yield was not optimal using colonoscopy screening in high-risk populations given the relatively low participation rate. Our findings will provide important references for designing effective population-based CRC screening strategies in the future.


Childhood sexual abuse and dating experiences of undergraduate women.
Child sexual abuse is a prevalent social problem with a variety of negative consequences for adult survivors. Whereas most studies have focused on intrapersonal effects including depressive symptomatology and post-traumatic stress disorder, recent work has begun to call attention to interpersonal results as well. The current study examined the relationship between the experience of childhood sexual abuse and being a victim of psychological aggression, physical violence, or sexual coercion in a dating relationship in the past year. Participants were 219 female college undergraduates. Child sexual abuse was significantly related to having experienced both physical and psychological dating aggression even after controlling for the presence of conflict in the family of origin. Child sexual abuse was not significantly related to sexual coercion or reports of silencing oneself in relationships.


Eteplirsen for the treatment of Duchenne muscular dystrophy.
In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT). DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n = 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT. At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p≤0.001). Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.


[Pregnancy and cystic fibrosis. A case history].
The authors report a case of pregnancy in a patient suffering from moderately severe cystic fibrosis (the syndrome consisted of diffused obstruction in respiratory function with a vital capacity of 79% and the lowered blood oxygen level with arterial blood gas estimations; oxygen saturation was 94%). The condition was marked by temporary worsening during the pregnancy in which infective bronchitis supervened). She also threatened to go into early labour and did in fact deliver at 36 1/2 weeks of an infant which was normal for the duration of the maturity. The authors review previous known facts about cystic fibrosis. A study of the literature has made it possible to be more accurate in describing methods of ante natal diagnosis of the condition and ways of following the pregnancy and the illness as well as the woman's fertility and her ability to breast feed.


One-step, zero-background ligation-independent cloning intron-containing hairpin RNA constructs for RNAi in plants.
*The hairpin-based RNA interference (RNAi) technique plays an important role in exploring gene function in plants. Although there are several methods for making hairpin RNA (hpRNA) constructs, these methods usually need multiple relatively laborious, time-consuming or high-cost cloning steps. Here we describe a one-step, zero-background ligation-independent cloning (OZ-LIC) method for making intron-containing hpRNA (ihpRNA) constructs by our vector pRNAi-LIC. *To generate the ihpRNA constructs with zero-background, this method only requires treating two PCR products of target gene flanked with different LIC sequences and SmaI-linearized pRNAi-LIC vector by T4 DNA polymerase respectively, and then transforming these treated DNA mixture into Escherichia coli. *The ihpRNA constructs generated with our OZ-LIC RNAi vector can efficiently induce not only transient silencing of the exogenous marker genes and the endogenous resistance-related Nicotiana benthamiana SGT1 gene, but also stable transgenic suppression of Arabidopsis SGT1b gene. *Our new OZ-LIC method and RNAi vector will represent a powerful tool for gene knockdown in plants and may facilitate high-throughput determination of plant gene function.


Phylogenomics Reveals an Ancient Hybrid Origin of the Persian Walnut.
Persian walnut (Juglans regia) is cultivated worldwide for its high-quality wood and nuts, but its origin has remained mysterious because in phylogenies it occupies an unresolved position between American black walnuts and Asian butternuts. Equally unclear is the origin of the only American butternut, J. cinerea. We resequenced the whole genome of 80 individuals from 19 of the 22 species of Juglans and assembled the genome of its relatives Pterocarya stenoptera and Platycarya strobilacea. Using phylogenetic-network analysis of single-copy nuclear genes, genome-wide site pattern probabilities, and Approximate Bayesian Computation, we discovered that J. regia (and its landrace J. sigillata) arose as a hybrid between the American and the Asian lineages and that J. cinerea resulted from massive introgression from an immigrating Asian butternut into the genome of an American black walnut. Approximate Bayesian Computation modeling placed the hybrid origin in the late Pliocene, ∼3.45 My, with both parental lineages since having gone extinct in Europe.


Microbiological problems and biofilms associated with Mycobacterium chimaera in heater-cooler units used for cardiopulmonary bypass.
The role of heater-cooler units (HCUs) in the transmission of Mycobacterium chimaera during open heart surgery has been recognized since 2013. Subsequent investigations uncovered a remarkable global outbreak reflecting the wide distribution of implicated devices. HCUs are an essential component of cardiopulmonary bypass operations and their withdrawal would severely affect capacity for life-saving cardiac surgery. However, studies have demonstrated that many HCUs are contaminated with a wide range of micro-organisms, including M. chimaera and complex biofilms. Whole genome sequencing of M. chimaera isolates recovered from one manufacturer's HCUs, worldwide, has demonstrated a high level of genetic similarity, for which the most plausible hypothesis is a point source contamination of the devices. Dissemination of bioaerosols through breaches in the HCU water tanks is the most likely route of transmission and airborne bacteria have been shown to have reached the surgical field even with the use of ultraclean theatre ventilation. Controlling the microbiological quality of the water circulating in HCUs and reducing biofilm formation has been a major challenge for many hospitals. However, enhanced decontamination strategies have been recommended by manufacturers, and, although they are not always effective in eradicating M. chimaera from HCUs, UK hospitals have not reported any new cases of M. chimaera infection since implementing these mitigation strategies. Water safety groups in hospitals should be aware that water in medical devices such as HCUs may act as a vector in the transmission of potentially fatal water-borne infections.


Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1.
We previously reported that insulin-like growth factor 1 (IGF1) was involved in coregulating female sexual maturation and longevity. To understand the underlying genetic mechanisms, based on the strain survey assays of development and aging traits, we crossed two mouse strains, KK/HIJ and PL/J, and produced 307 female F2 mice. We observed the age of vaginal patency (AVP) and the life span of these females. We also measured circulating IGF1 level at 7, 16, 24, 52, and 76 weeks. IGF1 level at 7 weeks significantly correlated with AVP. IGF1 levels at ages of 52 and 76 weeks negatively correlated with longevity (p ≤ .05). A gene mapping study found 22, 4 ,and 3 quantitative trait loci for IGF1, AVP, and life span, respectively. Importantly, the colocalization of IGF1, AVP, and life span quantitative trait loci in the distal region of chromosome 2 suggests this locus carries gene(s) that could regulate IGF1, AVP, and life span. In this region, proprotein convertase subtilisin/kexin type 2 has been found to be associated with female sexual maturation in a human genome-wide association study. We verified the roles of proprotein convertase subtilisin/kexin type 2 in regulating IGF1 and AVP by showing that depletion of proprotein convertase subtilisin/kexin type 2 significantly reduced IGF1 and delayed AVP in mice, suggesting that it also might be involved in the regulation of aging.


Helicobacter pylori: beyond peptic ulcer disease.
Beyond peptic ulcer disease, Helicobacter pylori infection is associated with intestinal-type gastric cancer and low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. It is also currently implicated as a possible cause of dyspepsia and extraintestinal disorders such as coronary artery disease, rosacea, chronic urticaria, and delayed growth in children. There are strong epidemiological data from large cohort studies linking H. pylori to gastric adenocarcinoma. Several cofactors, including early childhood acquisition of infection, strain-specific differences, genetic predisposition of the host, and the environment, appear to play a role in the progression of chronic gastritis to gastric cancer. H. pylori infection is seen in over 90% of MALT lymphomas, and about 70% of localized nonbulky tumors will undergo complete histological regression after eradication of the bacterium. Because follow-up data are limited to less than 2 years, those undergoing H. pylori eradication as primary therapy for MALT lymphoma require frequent histological surveillance for tumor recurrence. There are conflicting data from short-term studies regarding the effect of H. pylori eradication on dyspeptic symptoms. The decision to test or not for H. pylori in the dyspeptic patient may become easier when well-controlled studies with longer periods of follow-up become available. Because H. pylori induces a systemic inflammatory response, investigators are beginning to explore possible extraintestinal disease associations with the infection. The global prevalence of both peptic ulcer disease and gastric cancer has led to studies focusing on noninvasive screening for H. pylori in high-risk populations and prevention of primary infection by means of vaccination.


Essential roles for the products of the napABCD genes, but not napFGH, in periplasmic nitrate reduction by Escherichia coli K-12.
The seven nap genes at minute 47 on the Escherichia coli K-12 chromosome encode a functional nitrate reductase located in the periplasm. The molybdoprotein, NapA, is known to be essential for nitrate reduction. We now demonstrate that the two c-type cytochromes, the periplasmic NapB and the membrane-associated NapC, as well as a fourth polypeptide, NapD, are also essential for nitrate reduction in the periplasm by physiological substrates such as glycerol, formate and glucose. None of the three iron-sulphur proteins, NapF, NapG or NapH, are essential, irrespective of whether the bacteria are grown anaerobically in the presence of nitrate or fumarate as a terminal electron acceptor, or by glucose fermentation. Mutation of napD resulted in the total loss of Methyl Viologen-dependent nitrate reductase activity of the molybdoprotein, NapA, consistent with an earlier suggestion by others that NapD might be required for post-translational modification of NapA.


Zeeman- and Orbital-Driven Phase Shifts in Planar Josephson Junctions.
We perform supercurrent and tunneling spectroscopy measurements on gate-tunable InAs/Al Josephson junctions (JJs) in an in-plane magnetic field and report on phase shifts in the current-phase relation measured with respect to an absolute phase reference. The impact of orbital effects is investigated by studying multiple devices with different superconducting lead sizes. At low fields, we observe gate-dependent phase shifts of up to φ0 = 0.5π, which are consistent with a Zeeman field coupling to highly transmissive Andreev bound states via Rashba spin-orbit interaction. A distinct phase shift emerges at larger fields, concomitant with a switching current minimum and the closing and reopening of the superconducting gap. These signatures of an induced phase transition, which might resemble a topological transition, scale with the superconducting lead size, demonstrating the crucial role of orbital effects. Our results elucidate the interplay of Zeeman, spin-orbit, and orbital effects in InAs/Al JJs, giving improved understanding of phase transitions in hybrid JJs and their applications in quantum computing and superconducting electronics.


Transdermal contraceptive patch delivering norelgestromin and ethinyl estradiol. Effects on the lipid profile.
To evaluate the metabolic impact on lipids of a contraceptive patch that delivers norelgestromin (primary active metabolite of norgestimate) and ethinyl estradiol to the systemic circulation as compared with a placebo patch. In this randomized, double-blind trial, healthy women received the contraceptive patch (n = 99) or placebo patch (n = 47) for up to 9 cycles. Fasting blood samples were obtained at baseline and cycles 3, 6 and 9 for determining the serum lipid profile. At cycles 3, 6 and 9, mean increases from baseline in high-density lipoprotein (HDL) cholesterol, HDL3 cholesterol, total cholesterol and total triglycerides, and mean decreases in calculated (Friedewald) low-density lipoprotein (LDL)/HDL were observed in the contraceptive patch group (all P < .05 vs. placebo except for total cholesterol at cycle 6). Mean changes in HDL2 and calculated LDL cholesterol were minimal and comparable between treatments. Mean body weight increased from baseline to the end of treatment by 0.8 and 0.6 kg in the 2 groups, respectively; this difference was not significant. The lipid changes seen with the contraceptive patch are consistent with those of oral contraceptives containing norgestimate and ethinyl estradiol.


Synaptology of trigemino- and spinothalamic lamina I terminations in the posterior ventral medial nucleus of the macaque.
We used the electron microscope to examine lamina I trigemino- and spinothalamic (TSTT) terminations in the posterior part of the ventral medial nucleus (VMpo) of the macaque thalamus. Lamina I terminations were identified by anterograde labeling with biotinylated dextran, and 109 boutons on 38 terminal fibers were closely studied in series of ultrathin sections. Five unlabeled terminal boutons of similar appearance were also examined in detail. Three-dimensional, volume-rendered computer models were reconstructed from complete series of serial sections for 29 boutons on 10 labeled terminal fibers and one unlabeled terminal fiber. In addition, postembedding immunogold staining for GABA was obtained in alternate sections through 23 boutons. Lamina I TSTT terminations in VMpo generally have several large boutons (mean length = 2.16 microm, mean width = 1.29 microm) that are densely packed with vesicles and make asymmetric synaptic contacts on low-order dendrites of VMpo neurons (mean diameter 1.45 microm). They are closely associated with GABAergic presynaptic dendrites (PSDs), and nearly all form classic triadic arrangements (28 of 29 reconstructed boutons). Consecutive boutons on individual terminal fibers make multiple contacts with a single postsynaptic dendrite and can show evidence of progressive complexity. Dendritic appendages that enwrap and invaginate the terminal bouton constitute additional anatomic evidence for secure, high-fidelity synaptic transfer. These observations provide direct ultrastructural evidence supporting the hypothesis that VMpo is a lamina I TSTT thalamocortical relay nucleus in primates that subserves pain, temperature, itch, and other sensations related to the physiological condition of the body.


Assessment of a national monitoring and evaluation system for rapid expansion of antiretroviral treatment in Malawi.
Monitoring and evaluation of national antiretroviral therapy (ART) programs is vital, but routine, standardized assessment of national ART patient monitoring systems has not been established. Malawi has undertaken an ambitious ART scale-up effort, with over 57,000 patients initiated on ART by June 2006. We assessed the national ART monitoring and evaluation system in Malawi to ensure that the response to the epidemic was being monitored efficiently and effectively, and that data collected were useful. The evaluation, performed in August 2005, generally followed the Updated Guidelines for Evaluating Public Health Surveillance Systems (CDC) and Interim Patient Monitoring Guidelines for HIV Care and ART (WHO). Assessment was conducted with qualitative methods, including twelve ART site visits, with standardized key informant interviews with ART clinic coordinators, clinical staff, and data managers, at each site. Meetings were also held with key governmental stakeholders, including Ministry of Health and National AIDS Commission. The national monitoring and evaluation system devised by the Ministry of Health HIV/AIDS Unit is successful in achieving its objectives, and facilitates important aspects of the national response to HIV. Several basic changes in the data collection tools and system would facilitate more effective long-term assessment of the ART program and support improved patient care. As the number of ART sites and patients continues to expand, the current manual paper-based system may be overwhelmed. Identification and implementation of a feasible electronic data system that would maintain and improve data quality and the efficiency of data recording and reporting and enhance patient care is a priority. The assessment of ART monitoring and evaluation systems can optimize the effectiveness of national ART programs, and should be considered in other resource-constrained countries rapidly scaling up ART.


Preferences for long-term follow-up care in childhood cancer survivors.
Follow-up care is important for childhood cancer survivors to facilitate early detection and treatment of late effects. We aimed to describe preferences for different organisational aspects and models of follow-up care among Swiss childhood cancer survivors, and characteristics associated with preferences for different models. We contacted 720 survivors aged 18+ years, diagnosed with cancer after 1990 (age 0-16 years), registered in the Swiss Childhood Cancer Registry (SCCR), and Swiss resident, who previously participated in a baseline survey. They received questionnaires to assess attendance and preferences for follow-up (rated on 4-point scales, 0-3). Clinical information was available from the SCCR. Survivors (n = 314: response rate 43.6%; 47.8% still attended follow-up) rated clinical reasons for follow-up higher than supportive reasons (p < .001). They rated checking for cancer recurrence (mean = 2.78, SD = 0.53) and knowing about risks for my children most important (mean = 2.22, SD = 0.83). They preferred to attend a children's hospital (mean = 1.94, SD = 1.11), adult hospital (mean = 1.86, SD = 0.98) or general practitioner (mean = 1.86, SD = 1.01) rather than a central specialised late effects clinic (mean = 1.25, SD = 1.06, p < .001), and be seen by paediatric (mean = 2.24, SD = 0.72) or medical oncologist (mean = 2.17, SD = 0.69). Survivors preferred decentralised clinic-based follow-up, rather than one central specialised late effects clinic. Survivors' preferences should be considered to ensure future attendance.


Risk Factors for Post-Operative Multi-Drug-Resistant Organism Bacterial Infection in Patients With Stanford Acute Type A Aortic Dissection.
Background: To explore the risk factors for multi-drug-resistant organism (MDRO) infection in patients with Stanford acute type A aortic dissection (ATAAD). We conducted a retrospective cohort study using the data of post-operative patients with ATAAD in our hospital. Patients and Methods: This study included 82 post-operative patients with ATAAD in the past decade. They were divided into a MDRO group (n = 31) and a non-MDRO group (n = 51) according to whether they had acquired multi-drug-resistant (MDR) bacterial infection. Multivariable logistic regression was used to analyze the risk factors for MDR infections in patients with ATAAD. Results: The incidence of multi-drug-resistant bacterial infection was 37.80%. Seventeen factors, including hospital stay (p = 0.007), utilization of third-generation cephalosporins (p = 0.0068), antibiotic species of exposure (p = 0.0002), leukocyte-depleted red blood cell suspension dosage (p < 0.0001), fresh frozen plasma dosage (p < 0.0001), application of blood purification (p = 0.0493), and the total antibiotic days of exposure (p = 0.0001) diverged between the two groups (all p < 0.05). The logistic regression analysis revealed that the utilization of third-generation cephalosporins (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.01-5.33; p = 0.0478), antibiotic species of exposure (OR, 5.76; 95% CI, 1.45-22.83; p = 0.0128), leukocyte-depleted red blood cell suspension dosage (OR, 12.43; 95% CI, 2.71-57.07; p = 0.0012), and fresh frozen plasma dosage (OR, 5.05; 95% CI, 1.18-21.56; p = 0.0286) were independent variables for MDRO infections. Among the 23 drug-resistant bacteria detected, Acinetobacter baumannii was the main pathogen. Conclusions: Our study shows that the utilization of third-generation cephalosporins, antibiotic species of exposure, leukocyte-depleted red blood cell suspension dosage, and fresh frozen plasma dosage were independent risk factors for post-operative multi-drug-resistant infection in patients with ATAAD. Acinetobacter baumannii occupied the largest share of resistant bacteria that induce infection in post-operative patients with ATAAD.


A Neural Network Underlying Circadian Entrainment and Photoperiodic Adjustment of Sleep and Activity in Drosophila.
A sensitivity of the circadian clock to light/dark cycles ensures that biological rhythms maintain optimal phase relationships with the external day. In animals, the circadian clock neuron network (CCNN) driving sleep/activity rhythms receives light input from multiple photoreceptors, but how these photoreceptors modulate CCNN components is not well understood. Here we show that the Hofbauer-Buchner eyelets differentially modulate two classes of ventral lateral neurons (LNvs) within the Drosophila CCNN. The eyelets antagonize Cryptochrome (CRY)- and compound-eye-based photoreception in the large LNvs while synergizing CRY-mediated photoreception in the small LNvs. Furthermore, we show that the large LNvs interact with subsets of "evening cells" to adjust the timing of the evening peak of activity in a day length-dependent manner. Our work identifies a peptidergic connection between the large LNvs and a group of evening cells that is critical for the seasonal adjustment of circadian rhythms. In animals, circadian clocks have evolved to orchestrate the timing of behavior and metabolism. Consistent timing requires the entrainment these clocks to the solar day, a process that is critical for an organism's health. Light cycles are the most important external cue for the entrainment of circadian clocks, and the circadian system uses multiple photoreceptors to link timekeeping to the light/dark cycle. How light information from these photorecptors is integrated into the circadian clock neuron network to support entrainment is not understood. Our results establish that input from the HB eyelets differentially impacts the physiology of neuronal subgroups. This input pathway, together with input from the compound eyes, precisely times the activity of flies under long summer days. Our results provide a mechanistic model of light transduction and integration into the circadian system, identifying new and unexpected network motifs within the circadian clock neuron network.


A longitudinal study of lung impairment in patients with primary Sjögren's syndrome.
A longitudinal evaluation of lung involvement in primary Sjögren's syndrome (SS). Eighteen non-smoking women fulfilling the European criteria for primary SS were followed for 55 months (range 26-137 mos.). These were consecutive patients with exclusion for current smokers and patients with lung diseases. Every patient underwent clinical examination, chest radiographs and lung function tests (spirography, flow/volume loop and CO lung diffusing capacity measurements). No patient was given any immunosuppressive or mucolytic therapy. Cough, dyspnea on exertion and recurrent bronchitis were observed in 50, 40 and 20% of the patients respectively and their frequency did not change with time. Chest radiographs were and remained normal. At presentation, lung volumes and diffusing capacity were in the normal range, whereas expiratory flows in the small airways tended to be in the low range. With time, the peak expiratory flow (PEF) significantly increased (95.8 +/- 4.6 v 103.5 +/- 4.6, mean +/- SE, % of predicted, Wilcoxon, p < 0.05) whereas the lung transfer factor for CO (TLCO) and the transfer coefficient (KCO = TLCO/alveolar volume) decreased (92.9 +/- 4.0 v 87.0 +/- 4.0 and 89.7 +/- 2.4 v 84.2 +/- 2.6 respectively, p < 0.05 for both). The TLCO decrease, corrected for the duration of follow-up, correlated with the titers of IgA circulating immune complexes (CIC) at presentation and to a lesser extent with the occurrence of cough. During the follow-up of these primary SS patients, respiratory symptoms did not change, the recurrent respiratory infection rate was low, and no cases of pulmonary hypertension or lymphoma was observed. The diffusion capacity decrease was associated with IgA CIC titers at presentation. This impairment could contribute to dyspnea during its evolution over a lifetime but is too slight to explain the dyspnea on exertion seen in most of our patients.


Magnetic resonance imaging in experimental models of brain disorders.
This review gives an overview of the application of magnetic resonance imaging (MRI) in experimental models of brain disorders. MRI is a noninvasive and versatile imaging modality that allows longitudinal and three-dimensional assessment of tissue morphology, metabolism, physiology, and function. MRI can be sensitized to proton density, T1, T2, susceptibility contrast, magnetization transfer, diffusion, perfusion, and flow. The combination of different MRI approaches (e.g., diffusion-weighted MRI, perfusion MRI, functional MRI, cell-specific MRI, and molecular MRI) allows in vivo multiparametric assessment of the pathophysiology, recovery mechanisms, and treatment strategies in experimental models of stroke, brain tumors, multiple sclerosis, neurodegenerative diseases, traumatic brain injury, epilepsy, and other brain disorders. This report reviews established MRI methods as well as promising developments in MRI research that have advanced and continue to improve our understanding of neurologic diseases and that are believed to contribute to the development of recovery improving strategies.


Guide to the draft human genome.
There are a number of ways to investigate the structure, function and evolution of the human genome. These include examining the morphology of normal and abnormal chromosomes, constructing maps of genomic landmarks, following the genetic transmission of phenotypes and DNA sequence variations, and characterizing thousands of individual genes. To this list we can now add the elucidation of the genomic DNA sequence, albeit at 'working draft' accuracy. The current challenge is to weave together these disparate types of data to produce the information infrastructure needed to support the next generation of biomedical research. Here we provide an overview of the different sources of information about the human genome and how modern information technology, in particular the internet, allows us to link them together.


Does the use of a novel self-adhesive flowable composite reduce nanoleakage?
The aim of the study reported here was to evaluate the performance of a self-adhesive flowable composite and two self-etching adhesive systems, when subjected to cyclic loading, in preventing the nanoleakage of Class V restorations. Wedge-shape Class V cavities were prepared (4×2×2 mm [length × width × depth]) on the buccal surfaces of 90 sound human premolars. Cavities were divided randomly into three groups (n=30) according to the used adhesive (Xeno(®) V [self-etching adhesive system]) and BOND-1(®) SF (solvent-free self-etching adhesive system) in conjunction with Artiste(®) Nano Composite resin, and Fusio™ Liquid Dentin (self-adhesive flowable composite), consecutively. Each group was further divided into three subgroups (n=10): (A) control, (B) subjected to occlusal cyclic loading (90N for 5,000 cycles), and (C) subjected to occlusal cyclic loading (90N for 10,000 cycles). Teeth then were coated with nail polish up to 1 mm from the interface, immersed in 50% silver nitrate solution for 24 hours and tested for nanoleakage using the environmental scanning electron microscopy and energy dispersive analysis X-ray analysis. Data were statistically analyzed using two-way analysis of variance and Tukey's post hoc tests (P≤0.05). The Fusio Liquid Dentin group showed statistically significant lower percentages of silver penetration (0.55 μ) compared with the BOND-1 SF (3.45 μ) and Xeno V (3.82 μ) groups, which were not statistically different from each other, as they both showed higher silver penetration. Under the test conditions, the self-adhesive flowable composite provided better sealing ability. Aging of the two tested adhesive systems, as a function of cyclic loading, increased nanoleakage.


Chylothorax as a complication of anterior thoracic interbody fusion: a case report.
A case is reported of chylothorax following an uneventful anterior thoracic interbody spinal fusion. To present knowledge, this complication is reported to occur in 0.2% of intrathoracic operations, and may give rise to 50% mortality unless stress properly recognized and managed.


Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion.
Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury. C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2. The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01). Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.


Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children: Adequacy of Revised Dosages of TB Drugs for Children.
The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages. Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low. Bivariate and multivariate analyses were used to examine the factors associated with low Cmax of each drug. Of the 100 children, 58% were male, 50% HIV-infected and 49% younger than 5 years old. The median (interquartile range) Cmax was 5.9 (4.5-7.7) µg/mL for isoniazid, 6.5 (4.9-8.8) µg/mL for rifampin, 26.0 (21.2-33.4) µg/mL for pyrazinamide and 1.7 (0.9-2.7) µg/mL for ethambutol. There was a strong correlation between Cmax and AUC0-8h for all drugs. Low Cmax occurred in 9/100 (9.0%), 61/100 (61.0%), 17/97 (17.5%) and 60/97 (61.9%) for isoniazid, rifampin, pyrazinamide and ethambutol, respectively. In addition, 75/97 (77.3%) children had pyrazinamide Cmax < 35 µg/mL. Factors associated with low Cmax were NAT2 metabolizer phenotype status for isoniazid; height, dosage and HIV coinfection status for rifampin; height for pyrazinamide; and age, dosage and HIV coinfection status for ethambutol. The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children.


Role of hydrogen in the activation and regulation of hydrogen oxidation by the soluble hydrogenase from Alcaligenes eutrophus H16.
The activation kinetics of the H2-oxidizing activity of the soluble hydrogenase from Alcaligenes eutrophus H16 were investigated. Activation with Na2S2O4 plus 101 kPa H2 resulted in a rapid increase in activity over 1 h and constant activity after 3 h incubation. Less-stable activations were achieved if enzyme was incubated with Na2S2O4 under 1 kPa H2 or 101 kPa N2. The enzyme could also be partly activated either with NADH alone or with H2 alone. The level of activity obtained with both 101 kPa H2 and NADH present was greater than that obtained with either 101 kPa H2 or NADH alone. Activation with H2 plus NADH was virtually independent of NADH concentration but highly dependent on H2 concentration. The effects of various concentrations of H2 and constant concentration of NADH on the level of activation were the same whether H2 oxidation was assayed by H2-dependent Methylene Blue or NAD+ reduction. Diaphorase activity did not require activation and was little affected by the treatments that activated H2-oxidizing activity. The results suggest that H2 plays an important role in regulating the level of H2-oxidizing activity in this soluble hydrogenase.


A Three-Year Analysis of Ocular Infections in a Tertiary Care University Hospital in Turkey.
Ocular infections may result in severe vision and eye loss. Especially in keratitis and endophthalmitis, it is essential to identify the causative microorganism and treat it with appropriate antimicrobials. This study aims to investigate microorganisms isolated from various samples in ocular infections and their sensitivity to antibiotics. The samples, e.g., abscess, swab, were inoculated to suitable media and at appropriate ambient conditions at 35 - 37°C for 24 - 48 hours. Sterile liquid samples were cultivated in a blood culture bottle. The isolated microorganisms were identified by classical biochemical methods and by using an automatic identification system when necessary. Antibiotic susceptibility tests were performed by the disc diffusion method and interpreted according to CLSI criteria. From a total of 167 ocular samples from 69 patients, 78 (46.7%) microorganisms were isolated. Thirteen (19%) infections were found to be polymicrobial. Three bacteria were isolated from one of them and two bacteria from 12 of them. Twenty-one (30%) of the patients were newborns, and two were children. The average age of adult patients was 55.45 ± 19.7 years. Gram-positive bacteria (n = 46, 59%) were found to be more common than Gram-negative (n = 27, 35%) among all bacteria isolated over three years. Gram-positive bacteria included Staphylococcus aureus (n = 17, 22%), coagulase-negative staphylococci (CNS) (n = 13, 17%), and streptococci (n = 10, 13%). Pseudomonas aeruginosa (n = 8, 10%) was the most common bacterium of the Gram-negative bacteria. Besides, two anaerobic bacteria (2.6%), two fungi (2.6%), and one (1.3%) Nocardia spp. were isolated. It was determined that 35% of S. aureus strains and 46% of CNS strains were resistant to methicillin. Various and rare microorganisms can be isolated from ocular infections. However, it is still seen that Gram-positive bacteria are more common than Gram-negative. Multi-resistant Gram-negative rods and high rates of methicillin-resistance in staphylococci can affect treatment regimens.


[Isolation of eugenol from biological material].
The optimal conditions for isolation of eugenol from biological material by ethyl acetate were determined. Possible purification of the compound from coextractive substances of biomaterial on the colon with silica gel L 40/100 micro is demonstrated. Methods of thin-layer and high-yield liquid chromatography for identification and quantitative determination of eugenol are proposed.