The anti-microbial activity of electrolysed oxidizing water against microorganisms relevant in veterinary medicine.
Standards of the German Association of Veterinary Medicine (DVG) for the evaluation of chemical disinfectants were used to assess the anti-microbial efficacy of electrolysed oxidizing water (EOW). Enterococcus faecium, Mycobacterium avium subspecies avium, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans were exposed to anode EOW (pH, 3.0+/-0.1; oxidation-reduction potential (ORP), +1100+/-50 mV; free chlorine, 400+/-20 mg/l Cl2) and combined EOW (7:3 anode:cathode, v/v; pH, 8.3+/-0.1; ORP, 930-950 mV; free chlorine, 271+/-20 mg/l Cl2). In water of standardized hardness (WSH), all bacterial strains were completely inactivated by a 30 min exposure to maximum 10.0% anode EOW (approximately 40.0 mg/l Cl2) or 50.0% combined EOW (approximately 135.5 mg/l Cl2). The sensitivity ranking order for anode EOW to the bacterial test strains was P. mirabilis>S. aureus>M. avium ssp. avium>E. faecium>P. aeruginosa. P. mirabilis and S. aureus decreased to undetectable levels after 5 min of exposure to 7.5% anode EOW (approximately 30.0 mg/l Cl2). Candida albicans was completely inactivated by a 5-min exposure to 5.0% anode EOW. Both, anode and combined EOW exhibited no anti-microbial activities in standardized nutrient broth or after addition of 20.0% bovine serum to the WSH. Further research is necessary to evaluate the efficacy of EOW as a disinfectant under operating conditions in animal production facilities.


COVID-19 Risk Appears to Vary Across Different Alcoholic Beverages.
Objectives: To evaluate the associations of status, amount, and frequency of alcohol consumption across different alcoholic beverages with coronavirus disease 2019 (COVID-19) risk and associated mortality. Methods: This study included 473,957 subjects, 16,559 of whom tested positive for COVID-19. Multivariate logistic regression analyses were used to evaluate the associations of alcohol consumption with COVID-19 risk and associated mortality. The non-linearity association between the amount of alcohol consumption and COVID-19 risk was evaluated by a generalized additive model. Results: Subjects who consumed alcohol double above the guidelines had a higher risk of COVID-19 (1.12 [1.00, 1.25]). Consumption of red wine above or double above the guidelines played protective effects against the COVID-19. Consumption of beer and cider increased the COVID-19 risk, regardless of the frequency and amount of alcohol intake. Low-frequency of consumption of fortified wine (1-2 glasses/week) within guidelines had a protective effect against the COVID-19. High frequency of consumption of spirits (≥5 glasses/week) within guidelines increased the COVID-19 risk, whereas the high frequency of consumption of white wine and champagne above the guidelines decreased the COVID-19 risk. The generalized additive model showed an increased risk of COVID-19 with a greater number of alcohol consumption. Alcohol drinker status, frequency, amount, and subtypes of alcoholic beverages were not associated with COVID-19 associated mortality. Conclusions: The COVID-19 risk appears to vary across different alcoholic beverage subtypes, frequency, and amount. Red wine, white wine, and champagne have chances to reduce the risk of COVID-19. Consumption of beer and cider and spirits and heavy drinking are not recommended during the epidemics. Public health guidance should focus on reducing the risk of COVID-19 by advocating healthy lifestyle habits and preferential policies among consumers of beer and cider and spirits.


Global Radiative Impacts of Black Carbon Acting as Ice Nucleating Particles.
Black carbon (BC) aerosols from incomplete combustion generally warm the climate, but the magnitudes of their various interactions with climate are still uncertain. A key knowledge gap is their role as ice nucleating particles (INPs), enabling ice formation in clouds. Here we assess the global radiative impacts of BC acting as INPs, using simulations with the Community Earth System Model 2 climate model updated to include new laboratory-based ice nucleation parameterizations. Overall, we find a moderate cooling through changes to stratiform cirrus clouds, counteracting the well-known net warming from BC's direct scattering and absorption of radiation. Our best estimates indicate that BC INPs generally thin cirrus by indirectly inhibiting the freezing of solution aerosol, with a global net radiative impact of -0.13 ± 0.07 W/m2. Sensitivity tests of BC amounts and ice nucleating efficiencies, and uncertainties in the environment where ice crystals form, show a potential range of impacts from -0.30 to +0.02 W/m2.


Surgical extraction of an intraocular infection of Parelaphostrongylus tenuis in a horse.
A 4-year-old Hanoverian gelding was evaluated because of a mobile worm-like structure in the right eye. Ophthalmologic examination of the right eye revealed a white, thin, coiled, mobile parasite, which was presumed to be a nematode, located in the ventral portion of the anterior chamber of the eye; there also were vitreal strands located temporally and inferiorly near the margin of the pupil. Results of ophthalmologic examination of the left eye were unremarkable. The horse was treated with a neomycin-polymyxin B-dexamethasone ophthalmic solution applied topically (1 drop, q 8 h) to the right eye and penicillin V potassium (22,000 U/kg [10,000 U/lb], IV, q 6 h). The horse was anesthetized. A stab incision was made in the cornea, and a viscoelastic agent was infused around the parasite. The parasite was extracted via the incision by use of an iris hook and tying forceps. The horse had an uncomplicated recovery from the procedure and retained vision in the right eye. Gross and microscopic examination was used to identify the parasite as an adult metastrongyloid nematode consistent with a fully developed male Parelaphostrongylus tenuis. To the authors' knowledge, this is the first report of intraocular parelaphostrongylosis in a horse. This report provided evidence that vision could be retained after treatment for intraocular P tenuis infection in a horse.


Perceptions of prenatal and obstetric care in Sub-Saharan Africa.
The maternal mortality ratio in Sub-Saharan Africa remains high, despite progress in reducing maternal mortality in other parts of the world. To explore the perceptions of women and communities to identify barriers to the uptake of obstetric services. A systematic review of qualitative studies exploring perceptions of pregnancy and obstetric services, with thematic synthesis of the included studies. Qualitative studies reporting findings from focus group discussions and in-depth interviews between 1996 and 2009 were included. Thematic synthesis involved collating and reviewing quotations taken directly from included studies. Themes were generated and clustered for analysis. Twenty-seven studies were included and 6 major themes identified: perceptions of healthcare workers; perceptions of the hospital environment; cultural perceptions of women; cultural perceptions of pregnancy; perceptions of traditional birth attendants and traditional healers; and role of the community in pregnancy and birth. Community attitudes regarding cultural beliefs and interactions with healthcare providers were identified as barriers to the utilization of healthcare services during pregnancy in Sub-Saharan Africa. These prevent engagement with prenatal care and timely use of medical services. Addressing the barriers will be seminal to the success of any healthcare intervention.


Aneurysmal bone cyst as a rare cause of spinal cord compression in a young child.
Case report. To report: 1) one of the youngest cases of aneurysmal bone cysts presenting with cord compression at the cervicothoracic junction with 7-year follow-up; and 2) the technique we used to stabilize such a small spine. Aneurysmal bone cyst is an uncommon but well-recognized tumor affecting the spine of children. The mean age of presentation is 16 years. It has hardly been reported below the age of 4 years. All data are in the form of case reports or series. Surgical or nonoperative management can be used. Spinal implant systems are not designed for use in very small children. Clinical data analysis. A girl presented at age 2 years and 3 months with cord compression at the cervicothoracic junction. After an inconclusive biopsy, a formal excision and reconstruction of the C7 and T1 were performed anteriorly and posteriorly. We used a fibular graft, internal fixation with crossed plates from the maxillofacial implant tray and a Cervifix rod contoured into a rectangle with sublaminar titanium cables. Postsurgery, she had a left Horner syndrome that has never recovered and motor weakness of the right arm that improved but did not fully recover. She developed a staphylococcal infection 6 months postsurgery that was managed by removal of the rectangle. She developed a posterior recurrence 10 months postsurgery, which was managed surgically. Follow-up has been for 7 years without further evidence of recurrence. Both surgical and nonsurgical management has been advocated for these tumors. The cord compression at presentation forced us toward surgical management. It is likely that observational data are the only evidence available for clinical decision-making. In this case, we were able to obtain good access to the front of the upper thoracic spine by a supraclavicular approach. Tiny plates are available to maxillofacial surgeons that can be adapted for use in the spines of small children.


The role of estrogen receptor in Xenopus laevis vitellogenin gene expression.
Administration of estradiol 17 beta [estra-1,3,5(10)-triene-3,17-beta-diol] to male Xenopus laevis induces the massive synthesis by the liver of the egg yolk precursor phospholipoglycoprotein, vitellogenin, and its cognate mRNAs. Restimulation of male X. laevis that have been previously induced to synthesize vitellogenin mRNA but are inactive in vitellogenin mRNA synthesis at the time of restimulation with estrogen results in more rapid accumulation of vitellogenin mRNA and more efficient transcription of the vitellogenin genes than occurs following primary estrogen stimulation. The estrogen receptor system that mediates estrogen action in this organism exhibits several unusual properties. The cytoplasm of unstimulated liver cells contains high levels of a middle-affinity estrogen-specific binding protein and little if any estrogen receptor. The properties of the estrogen binding protein are consistent with a role in protecting estradiol 17 beta against metabolism, as a fraction of cytoplasmic estradiol 17 beta is not subject to rapid metabolism. In addition, similar binding activities are found in all Xenopus tissues surveyed that respond to steroid hormones. The induction of nuclear estrogen receptor is coincident with the onset of vitellogenin mRNA accumulation. However, an increased level of estrogen receptor is not responsible for the elevated rate of vitellogenin gene transcription observed following restimulation with estrogen.


Interactions between Sec complex and prepro-alpha-factor during posttranslational protein transport into the endoplasmic reticulum.
Posttranslational translocation of prepro-alpha-factor (ppalphaF) across the yeast endoplasmic reticulum membrane begins with the binding of the signal sequence to the Sec complex, a membrane component consisting of the trimeric Sec61p complex and the tetrameric Sec62p/63p complex. We show by photo-cross-linking that the signal sequence is bound directly to a site where it contacts simultaneously Sec61p and Sec62p, suggesting that there is a single signal sequence recognition step. We found no evidence for the simultaneous contact of the signal sequence with two Sec61p molecules. To identify transmembrane segments of Sec61p that line the actual translocation pore, a late translocation intermediate of ppalphaF was generated with photoreactive probes incorporated into the mature portion of the polypeptide. Cross-linking to multiple regions of Sec61p was observed. In contrast to the signal sequence, neighboring positions of the mature portion of ppalphaF had similar interactions with Sec61p. These data suggest that the channel pore is lined by several transmembrane segments, which have no significant affinity for the translocating polypeptide chain.


'People say that we are already dead much as we can still walk': a qualitative investigation of community and couples' understanding of HIV serodiscordance in rural Uganda.
Stable, co-habiting HIV serodiscordant couples are a key population in terms of heterosexual transmission in sub-Saharan Africa. Despite the wide availability of antiretroviral treatment and HIV educational programs, heterosexual transmission continues to drive the HIV epidemic in Africa. To investigate some of the factors involved in transmission or maintenance of serodiscordant status, we designed a study to examine participants' understanding of HIV serodiscordance and the implications this posed for their HIV prevention practices. In-depth interviews were conducted with 28 serodiscordant couples enrolled in a treatment-as-prevention study in Jinja, Uganda. Participants were asked questions regarding sexual behaviour, beliefs in treatment and prevention, participants' and communities' understanding and context around HIV serodiscordance. Qualitative framework analysis capturing several main themes was carried out by a team of four members, and was cross-checked for consistency. It was found that most couples had difficulty explaining the phenomenon of serodiscordance and tended to be confused regarding prevention. Many individuals still held beliefs in pseudoscientific explanations for HIV susceptibility such as blood type and blood "strength". The participants' trust of treatment and medical services were well established. However, the communities' views of both serodiscordance and treatment were more pessimistic and wrought with mistrust. Stigmatization of serodiscordance and HIV-positive status were reported frequently. The results indicate that despite years of treatment and prevention methods being available, stigmatization and mistrust persist in the communities of HIV-affected individuals and may directly contribute to new cases and seroconversion. We suggest that to optimize the effects of HIV treatment and prevention, clear education and support of such methods are sorely needed in sub-Saharan African communities.


Effect of vascular burden as measured by vascular indexes upon vascular dementia: a matched case-control study.
Vascular dementia (VaD) is a challenging illness that affects the lives of older adults and caregivers. It is unclear how multiple vascular risk factor exposures (polyvascular disease) affect VaD. To determine the relationship between multiple vascular risk exposures, as counted on an index in cases with VaD, compared with healthy age-/gender-matched controls. This was a matched case-control study of subjects living in Olmsted County, MN with documented VaD. Controls were selected by gender and age within 3 years from those who did not have dementia. The exposures included a total index (eleven exposure factors) added together, along with indexes for cerebrovascular disease (two exposures), cardiovascular disease (four exposures), vascular disease (three exposures), and lifestyle (two exposures). Analysis used matched conditional univariable logistic regression for each index. A total of 1736 potential subjects were identified, and 205 subjects were diagnosed with VaD. There was a significant association of the total score index with an odds ratio of 1.45 (95% confidence interval 1.21-1.74). The cerebrovascular index was also associated with VaD with an odds ratio of 12.18 (95% confidence interval 6.29-23.61). The cardiovascular and vascular indexes were also associated with VaD status. The lifestyle index was not associated with VaD. The cumulative role of multiple vascular risk factors or diseases increased the risk of VaD, as noted by the total vascular index. The lifestyle index did not reveal any significant differences. Further work is required for evaluation of these indexes.


Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn's Disease Patients.
The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn's disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects' fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects' baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.


Basic-level visual similarity and category specificity.
The role of visual crowding in category deficits has been widely discussed (e.g.,;; ). Most studies have measured overlap at the superordinate level (compare different examples of 'animal') rather than at the basic level (compare different examples of 'dog'). In this study, we therefore derived two measures of basic-level overlap for a range of categories. The first was a computational measure generated by a self-organising neural network trained to process pictures of living and non-living things; the second was a rating of perceived visual similarity generated by human subjects to the item names. The computational measure indicated that the pattern of crowded/uncrowded does not honour a living/non-living distinction. Nevertheless, different superordinates showed varied degrees of basic-level overlap, suggesting that specific token choice affects some superordinates more than others e.g., individual fruit and vegetable tokens show greater variability than any other items, while tools and vehicles produce more reliable or overlapping basic-level visual representations. Finally, subject ratings correlated significantly with the computational measures indicating that the neural model represents structural properties of the objects that are psychologically meaningful.


MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer's disease.
The cholinergic nucleus basalis of Meynert, which is important for memory functions, shows neuronal activation ('up-phase') during the early stages of Alzheimer's disease and neurodegeneration ('down-phase') in later stages of Alzheimer's disease. MicroRNA-132 (miR-132) and the transcription factor early growth response-1 (EGR1) were proposed as possible candidate molecules regulating such an up-down activity pattern of the nucleus basalis of Meynert during the course of Alzheimer's disease, as they both show this up-down pattern of expression in the prefrontal cortex during the course of Alzheimer's disease. Not only do these two molecules stimulate synaptic activity and plasticity, they are also involved in Alzheimer's disease pathology and might, in addition, affect cholinergic function. In the nucleus basalis of Meynert, we investigated the expression of miR-132 and EGR1 along the entire course of Alzheimer's disease. Forty-nine post-mortem nucleus basalis of Meynert samples were studied, ranging from non-demented controls (Braak stage = 0) to late Alzheimer's disease patients (Braak stage = VI), and from clinical Reisberg scale 1 to 7. Each Braak stage contained seven samples, that were all well matched for confounding factors, i.e. age (range 58-91), sex, post-mortem delay, cerebrospinal fluid pH (as a measure for agonal state), APOE genotype, clock time of death, tissue fixation time, and tissue storage time. The alterations of these two molecules were studied over the course of Alzheimer's disease in relation to the expression of 4G8-stained amyloid-β, hyperphosphorylated tau stained by antibody AT8, neuronal fibrillary tangles and neuropil threads stained by silver, and in relation to alterations in choline acetyltransferase. We found that the expression of miR-132 and EGR1 in the nucleus basalis of Meynert was quite stable during the early stages of Alzheimer's disease and decreased significantly only during late Alzheimer's disease stages. In addition, miR-132 and EGR1 showed a significant positive correlation with choline acetyltransferase expression (r = 0.49, P < 0.001 and r = 0.61, P < 0.001), while choline acetyltransferase expression showed a significantly negative correlation with hyperphosphorylated tau (r = -0.33, P = 0.021) but no correlation with 4G8-stained amyloid-β. From the functional changes of miR-132 and EGR1 along the course of Alzheimer's disease we conclude: (i) that these two molecules may play a role in keeping the cholinergic function intact in early Alzheimer's disease stages; and (ii) that these molecules may contribute to the late neurodegeneration of this cholinergic nucleus.


Towards an in vivo wireless mobile robot for surgical assistance.
The use of miniature in vivo robots that fit entirely inside the peritoneal cavity represents a novel approach to laparoscopic surgery. Previous work has demonstrated that mobile and fixed-base in vivo robots can be used to improve visualization of the surgical field and perform surgical tasks such as collecting biopsy tissue samples. All of these robots used tethers to provide for power and data transmission. This paper describes recent work focused on developing a modular wireless mobile platform that could be used for in vivo robotic sensing and manipulation applications. One vision for these types of self-contained in vivo robotic devices is that they could be easily carried and deployed by non-medical personnel at the site of an injury. Such wireless in vivo robots are much more transportable and lower cost than current robotic surgical assistants, and could ultimately allow a surgeon to become a remote first responder irrespective of the location of the patient.


High Sedentary Behavior Is Associated with Depression among Rural South Africans.
The study aimed to investigate the association between sedentary behavior and depression among rural South Africans. Data were analyzed from the cross-sectional baseline survey of the "Health and Aging in Africa: A Longitudinal Study of an INDEPTH community in South Africa (HAALSI)". Participants responded to various measures, including sociodemographic information, health status, anthropometric measures, and sedentary behavior. The sample included 4782 persons (40 years and above). Overall, participants engaged in <4 h (55.9%), 4-<8 h (34.1%), 8-<11 h (6.4%), or 11 or more h a day (3.5%) of sedentary behavior, and 17.0% screened positive for depression. In multivariable logistic regression, which was adjusted for sociodemographic variables (Model 1) (Odds Ratio, or OR: 2.45, Confidence Interval, or CI: 1.74, 3.46) and adjusted for sociodemographic and health variables, including physical activity (Model 2) (OR: 3.00, CI: 2.00, 4.51), high sedentary time (≥11 h) was independently associated with depression. In combined analysis, compared to persons with low or moderate sedentary behavior (<8 h) and moderate or high physical activity, persons with high sedentary behavior (≥8 h) and low physical activity were more likely to have depression in Model 1 (OR: 1.60, CI: 1.65, 3.13) and Model 2 (OR: 1.60, CI: 1.05, 2.44). Findings support that sedentary behavior and combined sedentary behavior and low physical activity may be a modifiable target factor for strategies to reduce depression symptoms in this rural population in South Africa.


Pharmacokinetic Model Analysis of Supralingual, Oral and Intravenous Deliveries of Mycophenolic Acid.
Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.


Rate of resolution of histologically verified intracranial tuberculomas.
The goal of this study was to determine the rate of radiological resolution of histopathologically proven tuberculomas treated with antituberculous therapy (ATT). The effects of the size of the tuberculomas, the number of tuberculomas, and the addition of corticosteroid therapy on the rate of resolution of the tuberculomas were also studied. Twenty-eight patients (age range, 5-48 yr; 14 male and 14 female patients) with histologically proven intracranial tuberculomas were prospectively monitored with contrast-enhanced computed tomographic scans. The patients received ATT consisting of rifampicin and isoniazid for a period of 18 months, with ethambutol and/or pyrazinamide for a minimum of 3 months. Fifteen patients also received corticosteroid therapy for 1 to 6 weeks. Of the 28 patients, 17 patients underwent partial excision, 6 underwent open biopsy, and 5 underwent stereotactic biopsy of their tuberculomas. Kaplan-Meier analysis revealed that, after 9 months of ATT, only 18.2% of the patients demonstrated complete resolution of their tuberculomas; even after 18 months of ATT, 69.2% of the patients had residual lesions. By 24 months, 54% of the patients demonstrated complete resolution of their tuberculomas. Although the number of tuberculomas, corticosteroid administration, prior treatment with ATT, and the duration of symptoms before presentation (<6 mo versus >6 mo) did not influence the rate of resolution, larger tuberculomas (maximal size, >4 cm) were observed to resolve more slowly than smaller tuberculomas (<4 cm) (P = 0.02). More than two-thirds of patients with partially excised or biopsied intracranial tuberculomas exhibited persistent lesions on computed tomographic scans, even after 18 months of ATT. Therefore, the duration of ATT for patients with intracranial tuberculomas should be based on the radiological responses of the tuberculomas. Our data suggest that some patients with intracranial tuberculomas might require prolonged periods of ATT.


Dexmedetomidine mitigates sevoflurane-induced cell cycle arrest in hippocampus.
Epidemiologic studies suggest the possibility of a modestly elevated risk of adverse neurodevelopmental outcomes in children exposed to anesthesia during early childhood. Sevoflurane is widely used in pediatric anesthetic practice because of its rapid induction and lower pungency. However, it is reported that sevoflurane leads to the long-term cognitive impairment. Some evidence revealed that the selective α2-adrenoreceptor agonist dexmedetomidine (DEX) exerts neuroprotective effects in various brain injury models of animals. But the role of DEX on sevoflurane-induced neuro-damage remains elusive. In our study, we isolated the hippocampal neuron cells from newborn neonatal rats and verified the purity of neurons by immunocytochemistry. We employed the flow cytometry and western blot to examine the effect of sevoflurane, DEX and α2-adrenergic receptor antagonist yohimbine on cell cycle distribution. Immunocytochemistry results showed the purity of neurons > 94%, which provided a good model for neural pharmacology experiments. The exposure of sevoflurane-induced cell cycle arrest at S phase and suppressed the expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB). The addition of DEX suppressed sevoflurane-induced cell cycle arrest and the inhibitory of BDNF and TrkB expression. But the function of DEX was partly blocked by a α2 adrenergic receptor blocker yohimbine. Sevoflurane suppressed neuron cell proliferation via inhibiting the expression of BDNF and TrkB, and DEX relieved the neurotoxicity induced by sevoflurane via α2 adrenergic receptor. These findings provided new evidence that DEX exerted as a neuroprotective strategy in sevoflurane-induced neuro-damage, and provided new basis for the clinical application of DEX.


[Effect of slow repetitive transcranial magnetic stimulation on depression in patients with Parkinson disease].
Parkinson's disease (PD), that has usually been associated with movement disorders, is also associated with depression in about 40% of patients [1-9]. Transcranial magnetic stimulation (TMS) is a new non-invasive technique for direct stimulation of the cerebral cortical neurons [1]. Several open studies have shown that repetitive TMS (rTMS) at both rapid (rapid rTMSi > 1 Hz) and low frequencies (slow rTMSi < 1 Hz) may have antidepressant action [2-6]. The study included 8 patients diagnosed as PD fulfilling the DSM-IV criteria for major depression (5 patients) and dysthymia (3 patients). Magnetic stimulator, 200 Mag-Stim, total output 2 T and a circular coil of 90 mm, were used. For ten consecutive days, between noon and 1 p.m. the patients were stimulated with apprx. 80% of the output (1.6 T) at 0.5 Hz. The daily treatment implied stimulation of both sides of the head (first the right, then the left) at four sites (prefrontal, frontal, parietal and occipital regions) with 5 stimulations each site (20 stimulations per hemisphere). Before the beginning of the study, 2-3 hours after the last stimulation (day 10), 7 and 14 days after completion of the treatment, the patients were subjected to scoring on the Hamilton Depression Rating Scale [11] and Unified Parkinson's Disease Rating Scale (UPDRS) [12]. The HDRS values before initiation of rTMS were 19.2 +/- 3.1, with significant fall (p < 0.01) after 10 days of stimulation (14.9 +/- 3.2), 17 days (12.2 +/- 2.7) and 24 days (13.6 +/- 5.3) after the beginning of the study, suggesting that the antidepressive effect persisted even two weeks after discontinuation of stimulation. The UPDRS values were monitored concomitantly. The values on this scale failed to alter significantly. In conclusion, rTMS is a relatively safe and painless method associated with antidepressant action in PD patients. Treatment of depression in PD is of great importance, but the choice of medication is accompanied with numerous limitations [20]. Antidepressant action of rTMS and its maintenance for two weeks after discontinuation of stimulation enables usage of this method in PD in phases of exacerbation of depressive symptoms at least over the period required to reach the full effect of selected medication.


Designing prenatal care messages for low-income Mexican women.
Communication theories and research data were used to design cross-cultural health education messages. A University of California Los Angeles-Universidad Autonoma in Tijuana, Mexico, research team used the methods of ethnographic and survey research to study behaviors, attitudes, and knowledge concerning prenatal care of a sample of pregnant low-income women living in Tijuana. This audience provided information that served as a framework for a series of messages to increase awareness and change prenatal care behaviors. The message design process was guided by persuasion theories that included Petty and Caccioppo's elaboration likelihood model, McGuire's persuasion matrix, and Bandura's social learning theory. The results from the research showed that poor women in Tijuana tend to delay or not seek prenatal care. They were not aware of symptoms that could warn of pregnancy complications. Their responses also revealed pregnant women's culturally specific beliefs and behaviors regarding pregnancy. After examination of these and other results from the study, prenatal care messages about four topics were identified as the most relevant to communicate to this audience: health services use, the mother's weight gain, nutrition and anemia, and symptoms of high-risk complications during pregnancy. A poster, a calendar, a brochure, and two radio songs were produced and pretested in focus groups with low-income women in Tijuana. Each medium included one or more messages addressing informational, attitudinal, or behavioral needs, or all three, of the target population.


Long time persistence of residual 53BP1/γ-H2AX foci in human lymphocytes in relationship to apoptosis, chromatin condensation and biological dosimetry.
Novel assay for radiosensitivity is based on measurements of residual DNA repair foci produced by several proteins including phosphorylated H2AX (γ-H2AX), recombinase Rad51 (Rad51) and tumour suppressor p53 binding protein 1 (53BP1), which co-localise with radiation-induced DNA double-strand breaks (DSB). Here, we studied dose-response for residual 53BP1, Rad51, and γ-H2AX foci in relationship to apoptosis and chromatin condensation in human G(0)-lymphocytes. Residual foci, apoptosis and condensation of chromatin were studied following irradiation with γ-rays at doses of 0.5-10 Gy. No clear dose response for residual Rad51 was seen. Residual 53BP1/γ-H2AX foci remained in human lymphocytes up to four weeks after irradiation. No foci formed during radiation-induced apoptosis. We provide evidence that irreversible apoptotic condensation of chromatin is responsible for arrest of residual foci and preventing de novo focus formation. Similar linear dose dependences up to 2 Gy were observed for the 53BP1/γ-H2AX foci at all studied time points. At higher doses, saturation and decline were caused by preferential elimination of apoptotic lymphocytes with residual foci. While primary 53BP1 and γ-H2AX foci almost completely co-localised, co-localisation of residual foci did not exceed 17%, indicating that 53BP1 and γ-H2AX proteins may remain for different times at the locations of DSB repair. Prolonged persistence of residual 53BP1/γ-H2AX foci may be used for biological dosimetry within the dose range up to 2 Gy. While foci are not formed during radiation-induced apoptosis in human lymphocytes, elimination of apoptotic cells with residual foci may affect the dose response.


Microtubule-Mediated Inositol Lipid Signaling Plays Critical Roles in Regulation of Blebbing.
Cells migrate by extending pseudopods such as lamellipodia and blebs. Although the signals leading to lamellipodia extension have been extensively investigated, those for bleb extension remain unclear. Here, we investigated signals for blebbing in Dictyostelium cells using a newly developed assay to induce blebbing. When cells were cut into two pieces with a microneedle, the anucleate fragments vigorously extended blebs. This assay enabled us to induce blebbing reproducibly, and analyses of knockout mutants and specific inhibitors identified candidate molecules that regulate blebbing. Blebs were also induced in anucleate fragments of leukocytes, indicating that this assay is generally applicable to animal cells. After cutting, microtubules in the anucleate fragments promptly depolymerized, followed by the extension of blebs. Furthermore, when intact cells were treated with a microtubule inhibitor, they frequently extended blebs. The depolymerization of microtubules induced the delocalization of inositol lipid phosphatidylinositol 3,4,5-trisphosphate from the cell membrane. PI3 kinase-null cells frequently extended blebs, whereas PTEN-null cells extended fewer blebs. From these observations, we propose a model in which microtubules play a critical role in bleb regulation via inositol lipid metabolism.


Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging.
Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are currently conceived as those endowed with the strongest ability to provide information about the trajectories of healthy and unhealthy aging. We review the available data on miRNAs in aging and underpin the evidence suggesting that circulating miRNAs (and cognate shuttles), especially those involved in the regulation of inflammation (inflamma-miRs) may constitute biomarkers capable of reliably depicting healthy and unhealthy aging trajectories.


EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair.
Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones.


MRI in treatment of adult gliomas.
Diffuse astrocytomas of the adult cerebral hemispheres are unique among tumours in human beings in the extent to which their imaging features are related to histopathological characteristics and clinical behaviour. However, understanding is still restricted about the value of imaging features in the measurement of response and of progression in these tumours. The present approach used in clinical trials, which consists of an anatomical measurement of the enhancing tumour on MRI, has many problems, and might not be acceptable as a surrogate endpoint for survival in patients with glioblastoma who are enrolled in clinical trials. Dynamic imaging techniques, such as capillary permeability mapping, are being used in studies of new drugs that target specific molecular features of gliomas; however, the validity of these techniques has not been elucidated. Diffusion imaging can be valuable for fibre-tract mapping to assist surgical planning and might become useful in measuring early response to treatment in densely cellular tumours. Functional imaging techniques can be used to localise motor, sensory, and language-control areas before surgery. Intraoperative MRI has produced improvements in the extent of tumour resection, and molecular imaging is another technique on the horizon, which could come to have a role in clinical trials in the near future. Thus, as a rapidly expanding sphere of investigation, brain-tumour imaging is producing great excitement. The aim of these new techniques is to aid the identification of more effective treatments.


Five-year impact of quality improvement for depression: results of a group-level randomized controlled trial.
Quality improvement (QI) programs for depressed primary care patients can improve health outcomes for 6 to 28 months; effects for longer than 28 months are unknown. To assess how QI for depression affects health outcomes, quality of care, and health outcome disparities at 57-month follow-up. A group-level randomized controlled trial. Forty-six primary care practices in 6 managed care organizations. Of 1356 primary care patients who screened positive for depression and enrolled in the trial, 991 (73%, including 451 Latinos and African Americans) completed 57-month telephone follow-up. Clinics were randomly assigned to usual care or to 1 of 2 QI programs supporting QI teams, provider training, nurse assessment, and patient education, plus resources to support medication management (QI-meds) or psychotherapy (QI-therapy) for 6 to 12 months. Probable depressive disorder in the previous 6 months, mental health-related quality of life in the previous 30 days, primary care or mental health specialty visits, counseling or antidepressant medications in the previous 6 months, and unmet need, defined as depressed but not receiving appropriate care. Combined QI-meds and QI-therapy, relative to usual care, reduced the percentage of participants with probable disorder at 5 years by 6.6 percentage points (P =.04). QI-therapy improved health outcomes and reduced unmet need for appropriate care among Latinos and African Americans combined but provided few long-term benefits among whites, reducing outcome disparities related to usual care (P =.04 for QI-ethnicity interaction for probable depressive disorder). Programs for QI for depressed primary care patients implemented by managed care practices can improve health outcomes 5 years after implementation and reduce health outcome disparities by markedly improving health outcomes and unmet need for appropriate care among Latinos and African Americans relative to whites; thus, equity was improved in the long run.


A major direct GABAergic pathway from zona incerta to neocortex.
Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.


Campylobacter jejuni strain discrimination and temperature-dependent glycome expression profiling by lectin microarray.
Gram-negative Campylobacter jejuni is the leading cause of bacterial gastroenteritis in humans worldwide and the most frequently identified infectious trigger in patients developing Guillain-Barré syndrome (GBS). While C. jejuni is pathogenic in humans, it is a commensal in avian hosts. Bacterial cell surface carbohydrates are important virulence factors and play roles in adherence, colonisation and infection. The mechanisms leading to infection or persistent colonisation of C. jejuni are not well understood but host temperature may provide an important stimulus for specific adaptation. Thus, examination of the modulation of the total surface glycome of C. jejuni in response to temperature may help shed light on commensal and pathogenic mechanisms for this species. C. jejuni strains 81116 and 81-176 were cultured at 37 and 42°C to simulate human and avian host conditions, respectively, and whole cells were profiled on lectin microarrays constructed to include a wide range of binding specificities. C. jejuni 81116 profiles indicated that the previously characterised lipopolysaccharide (LPS)-like molecule and N-linked glycans were the predominantly recognised cell surface structures while capsular polysaccharide (CPS), lipooligosaccharides (LOS) and N-linked glycosylation were best recognised for strain 81-176 at 37°C. The profiles of both strains varied and were distinguishable at both temperatures. At the higher temperature, reduced dominance of the LPS-like structure was associated with strain 81116 and a change in the relative distribution of CPS and LOS structures was indicated for strain 81-176. This change in LOS molecular mass species distribution between temperatures was confirmed by SDS-PAGE analysis. Additionally, opposite behaviour of certain lectins was noted between the plate agglutination assay and the microarray platform. Insights into the important glycosylation involved in C. jejuni host cell tropism at different growth temperatures were gained using the lectin microarray platform.


Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a "state-of-the-art" review.
Throughout the history of automobile development, chrysotile asbestos has been an essential component of vehicle brake linings and pads. Acceptable alternatives were not fully developed until the 1980s, and these were installed in vehicles produced over the past decade. This article presents a "state-of-the-art" analysis of what was known over time about the potential environmental and occupational health hazards associated with the presence of chrysotile asbestos in brake linings and pads. As part of this analysis, the evolution of automobile brakes and brake friction materials, beginning with the early 1900s, is described. Initial concerns regarding exposures to asbestos among workers involved in the manufacture of friction products were raised as early as 1930. Between 1930 and 1959, eight studies were conducted for which friction product manufacturing workers were part of the population assessed. These studies provided evidence of asbestosis among highly exposed workers, but provided little information on the magnitude of exposure. The U.S. Public Health Service proposed the first occupational guideline for asbestos exposure in 1938. The causal relationship between asbestos exposure and lung cancer was confirmed in 1955 in asbestos textile workers in the United Kingdom, and later, in 1960, in South Africa, mesothelioma was attributed to asbestos exposure to even relatively low airborne concentrations of crocidolite. Between 1960 and 1974, five epidemiology studies of friction product manufacturing workers were conducted. During this same time period, the initial studies of brake lining wear (dust or debris) emissions were conducted showing that automobile braking was not a substantial contributor of asbestos fibers greater than 5 microm in length to ambient air. The first exposure surveys, as well as preliminary health effects studies, for brake mechanics were also conducted during this period. In 1971, the Occupational Safety and Health Administration promulgated the first national standards for workplace exposure to asbestos. During the post-1974 time period, most of the information on exposure of brake mechanics to airborne asbestos during brake repair was gathered, primarily from a series of sampling surveys conducted by the National Institute of Occupational Safety and Health in the United States. These surveys indicated that the time-weighted average asbestos


"Everyone Has a Role": Perspectives of Service Users With First-Episode Psychosis, Family Caregivers, Treatment Providers, and Policymakers on Responsibility for Supporting Individuals With Mental Health Problems.
Varying perceptions of who should be responsible for supporting individuals with mental health problems may contribute to their needs remaining unmet. A qualitative descriptive design was used to explore these perceptions among key stakeholders. Focus groups were conducted with 13 service users, 12 family members, and 18 treatment providers from an early psychosis intervention program in Montreal, Canada. Individual interviews were conducted with six mental health policy-/decision-makers. Participants across stakeholder groups assigned a range of responsibilities to individuals with mental health problems, stakeholders in these individuals' immediate and extended social networks (e.g., families), macro-level stakeholders with influence (e.g., government), and society as a whole. Perceived failings of the health care system and the need for greater sharing of roles and responsibilities also emerged as important themes. Our findings suggest that different stakeholders should collectively assume certain responsibilities and that systems-level failings may contribute to unmet needs for mental health support.


Does surgical sympathectomy improve clinical outcomes in patients with refractory angina pectoris?
A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was: In patients with angina pectoris refractory to medical therapy, does surgical sympathectomy improve clinical outcomes? A total of 528 papers were identified using the search protocol described, of which 6 represented the best evidence to answer the clinical question. There were 5 case series and 1 prospective cohort study. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. All 5 of the case series demonstrated an improvement in symptoms, exercise tolerance or quality of life in patients undergoing surgical sympathectomy. An early case series investigating an open approach had a high morbidity and mortality rate, but the 4 other series used a minimally invasive technique and had low morbidity and zero perioperative mortality rates. The cohort study compared surgical sympathectomy with transmyocardial laser revascularization (TMR) and concluded TMR to be superior. However, this study looked only at unilateral sympathectomy, whereas all 5 case series focused on bilateral surgery. We conclude that the best currently available evidence does suggest that patients report an improvement in their symptoms and quality of life following surgical sympathectomy, but the low level of this evidence does not allow for a statistically proved recommendation.


Representing descriptors derived from multiple conformations as uncertain features for machine learning.
Uncertainty was introduced into the chemical descriptors of 11 datasets by conformational analysis in order to incorporate three-dimensional information and to investigate the resulting predictive performance of a state-of-the-art machine learning method, random forests, for binary classification tasks. A number of strategies for handling uncertainty in random forests were evaluated. The study showed that when incorporating three-dimensional information as uncertainty into chemical descriptors, the use of uniform probability distributions over the range of possible values, in conjunction with fractional distribution of compounds clearly outperforms the use of normal distributions as well as sampling from both normal and uniform distributions. The main conclusion of this study is that, even when distributions of uncertain values are provided, the random forest method can generate models that are almost as accurate from the expected values of these distributions alone. Hence, there seems to be little advantage to using the more elaborate methods of incorporating uncertainty in chemical descriptors when using random forests rather than replacing the distributions with single-point values. The results also show that random forest models with similar performances can also be generated using three-dimensional descriptor information derived from single (lowest-energy or Corina-derived) conformations.


Anatomical perspective, approach, and experience with multichannel intracochlear implantation.
An overall review of the authors' anatomical perspective, approach, and experience with multichannel intracochlear implantation is presented. This report includes pertinent anatomical observations and experimental surgical procedures on fresh temporal bones. Although the scala tympani in the basal turn of the cochlea has an adequate space laterally for the insertion of electrodes, in the upper turns the adequate space is located medially. This is, in practice, the single-most limiting factor for an electrode, inserted via the round window, to reach the apical turns without damaging the basilar membrane. An experimental surgical procedure is described in which a second electrode is inserted in the middle turn via a mastoidotomy-tympanotomy approach and reaches a point near the apex. Studies of horizontal sections of human temporal bones include a review of potential structures that could be stimulated by the electrical currents generated by electrodes. The wall of the carotid artery, located at 750 microns from the basal turn at the level of the round window niche, is considered a potential structure to be affected by long-term stimulation. Anatomical principles and surgical considerations for the mastoidotomy-tympanotomy approach are described as an alternative to the facial recess approach. In the authors' experience, this procedure is technically easier, eliminates the possibility of postauricular flap complications, provides a better angle for insertion of electrodes, requires shorter hospitalization, and permits faster recovery than the facial recess approach. The authors' clinical approach, results, and observations are reviewed. Of note is a successful home-based rehabilitation program.


In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype.
The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone-lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650-63. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.


Gray scale response from optically addressed spatial light modulators incorporating surface-stabilized ferroelectric liquid crystals.
We demonstrate the capability of optically addressed spatial light modulators that incorporate surfacestabilized ferroelectric liquid crystals to reproduce gray scale. This capability is based on temporal averaging and is observed in an operating mode in which the applied voltage repeatedly cycles the device between writing and erasing at operating frequencies between 100 and 2000 Hz. A gray scale response is observed for write-light intensities below a saturation level that increases from 100 microW/cm(2) at 100 Hz to 2 mW/cm(2) at 2 kHz. We develop a procedure to determine the modulation transfer function from measurements of the diffraction efficiency as a function of spatial frequency and write-light intensity in a device with a nonlinear transfer characteristic. At an operating frequency of 500 Hz, the modulation transfer function is greater than or equal to 0.50 at a spatial frequency of 40 line pairs/mm.


Skingineering I: engineering porcine dermo-epidermal skin analogues for autologous transplantation in a large animal model.
Extended full thickness skin defects still represent a considerable therapeutic challenge as ideal strategies for definitive autologous coverage are still not available. Tissue engineering of whole skin represents an equally attractive and ambitious novel approach. We have recently shown that laboratory-grown human skin analogues with near normal skin anatomy can be successfully transplanted on immuno-incompetent rats. The goal of the present study was to engineer autologous porcine skin grafts for transplantation in a large animal model (pig study = intended preclinical study). Skin biopsies were taken from the pig's abdomen. Epidermal keratinocytes and dermal fibroblasts were isolated and then expanded on culture dishes. Subsequently, highly concentrated collagen hydrogels and collagen/fibrin hydrogels respectively, both containing dermal fibroblasts, were prepared. Fibroblast survival, proliferation, and morphology were monitored using fluorescent labelling and laser scanning confocal microscopy. Finally, keratinocytes were seeded onto this dermal construct and allowed to proliferate. The resulting in vitro generated porcine skin substitutes were analysed by H&E staining and immunofluorescence. Dermal fibroblast proliferation and survival in pure collagen hydrogels was poor. Also, the cells were mainly round-shaped and they did not develop 3D-networks. In collagen/fibrin hydrogels, dermal fibroblast survival was significantly higher. The cells proliferated well, were spindle-shaped, and formed 3D-networks. When these latter dermal constructs were seeded with keratinocytes, a multilayered and partly stratified epidermis readily developed. This study provides compelling evidence that pig cell-derived skin analogues with near normal skin anatomy can be engineered in vitro. These tissue-engineered skin substitutes are needed to develop a large animal model to establish standardized autologous transplantation procedures for those studies that must be conducted before "skingineering" can eventually be clinically applied.


Skipping breakfast: longitudinal associations with cardiometabolic risk factors in the Childhood Determinants of Adult Health Study.
The long-term effects of skipping breakfast on cardiometabolic health are not well understood. The objective was to examine longitudinal associations of breakfast skipping in childhood and adulthood with cardiometabolic risk factors in adulthood. In 1985, a national sample of 9-15-y-old Australian children reported whether they usually ate breakfast before school. During follow-up in 2004-2006, 2184 participants (26-36 y of age) completed a meal-frequency chart for the previous day. Skipping breakfast was defined as not eating between 0600 and 0900. Participants were classified into 4 groups: skipped breakfast in neither childhood nor adulthood (n = 1359), skipped breakfast only in childhood (n = 224), skipped breakfast only in adulthood (n = 515), and skipped breakfast in both childhood and adulthood (n = 86). Diet quality was assessed, waist circumference was measured, and blood samples were taken after a 12-h fast (n = 1730). Differences in mean waist circumference and blood glucose, insulin, and lipid concentrations were calculated by linear regression. After adjustment for age, sex, and sociodemographic and lifestyle factors, participants who skipped breakfast in both childhood and adulthood had a larger waist circumference (mean difference: 4.63 cm; 95% CI: 1.72, 7.53 cm) and higher fasting insulin (mean difference: 2.02 mU/L; 95% CI: 0.75, 3.29 mU/L), total cholesterol (mean difference: 0.40 mmol/L; 95% CI: 0.13, 0.68 mmol/L), and LDL cholesterol (mean difference: 0.40 mmol/L; 95% CI: 0.16, 0.64 mmol/L) concentrations than did those who ate breakfast at both time points. Additional adjustments for diet quality and waist circumference attenuated the associations with cardiometabolic variables, but the differences remained significant. Skipping breakfast over a long period may have detrimental effects on cardiometabolic health. Promoting the benefits of eating breakfast could be a simple and important public health message.


Long-term cyclosporin A exposure suppresses cathepsin-B and -L activity in gingival fibroblasts.
Gingival overgrowth is a common side-effect following administration of cyclosporin A. We reported previously that lysosomal protease cathepsin-L activity, but not cathepsin-B, was significantly suppressed by short-term cyclosporin A exposure in human gingival fibroblasts. Although this suppression may lead to decreased degradation of gingival connective tissue, a net increase in matrix proteins, and gingival overgrowth, the effects of cyclosporin A need to be more elucidated, considering the long-term use for patients following organ transplantation. The aim of the present study was to evaluate the effects of clinically relevant doses of cyclosporin A on cultured human gingival fibroblasts. We evaluated the effects of long-term cyclosporin A exposure on cell proliferation, mRNA expression of various proteases and both cathepsin-B and -L activity in human gingival fibroblasts. Human gingival fibroblasts were isolated from three donors' healthy gingiva and cultured from five to eight passages with or without 200 ng/ml of cyclosporin A. Proliferative activity of cyclosporin A-treated cells was examined using MTT assay. Total RNA and cellular proteins were collected for semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and for measurement of the cathepsin-B and -L activity. Long-term cyclosporin A exposure had no effects on cell proliferation. Accumulation of cathepsin-B, -H and -L mRNA was markedly suppressed by long-term cyclosporin A exposure, whereas accumulation of another lysosomal enzyme N-acetyl-beta-D-glucosaminidase mRNA, which is involved in remodeling of gingival epithelium, was not apparently impaired in cyclosporin A-treated cells. Accumulation of matrix metalloprotease-1 (MMP-1) and tissue inhibitor of matrix metalloprotease-1 (TIMP-1) mRNA, which are involved in remodeling of extracellular matrix, also was not impaired. In addition, we demonstrated that long-term cyclosporin A exposure significantly suppressed not only the activity of the active form of cathepsin-(B + L) compared to the activity in non-treated cells (p = 0.0458), but also the activity of the active form of cathepsin-B (p < 0.0001) in human gingival fibroblasts. The decreased ability of protein degradation by not only cathepsin-L but also cathepsin-B is, at least, one of the several factors developing the cyclosporin A-induced gingival overgrowth.


Eight-year seroprevalence of HBV, HCV and HIV in Diyarbakir training and research hospital.
Distribution of HBV, HCV and HIV results of the inpatients or outpatients, who had been treated for various diagnoses in Diyarbakır Training and Research Hospital between 2005 and 2012, among years was investigated. Files of the patients, who had been treated as inpatient or outpatient 992. to any diagnosis between 01/01/2005 and 31/12/2012 in the clinics or policlinics of Diyarbakır 581 due Training and Research Hospital, were retrospectively reviewed using patient file database. Serum samples (235.534 for HBsAg, 196.727 for Anti-HBs antibody, 98.497 for HBeAg, 97.417 for Anti-HBe antibody, 225.483 for HCV and 138.923 for HIV) of these patients, which had been processed in microbiology laboratory, were studied by chemiluminescence technique using Roche E-170 (Modular Analytics System) device. Prevalence rates between 2005 and 2012 were as follows: 15.9%-9% for HBsAg, 32.9%-52.3% for Anti-HBs, 2.5%-1.8% for HBeAg, 30.4%-25.2% for Anti-HBe, 1%-0.7% for Anti-HCV, and 0.1%-1% for Anti-HIV. Increase in Anti-HBs prevalence is the successful outcome of routine immunization in population. This suggests that, governmental policies focused on this subject have resulted in successful outcomes and that people also take care about this. A prevalence rate decreasing to 9% from 15.9% for HBsAg and prevalence rate increasing to 52.3% from 32.9% for Anti-HBs antibody positivity in 8-year period in our region is quite meaningful. Such favorable developments in our region are of great valuable in terms of indicating to what extent could struggle against HBV is controlled by education and awareness.


Conformational mechanism for the stability of microtubule-kinetochore attachments.
Regulating the stability of microtubule (MT)-kinetochore attachments is fundamental to avoiding mitotic errors and ensuring proper chromosome segregation during cell division. Although biochemical factors involved in this process have been identified, their mechanics still need to be better understood. Here we introduce and simulate a mechanical model of MT-kinetochore interactions in which the stability of the attachment is ruled by the geometrical conformations of curling MT-protofilaments entangled in kinetochore fibrils. The model allows us to reproduce, with good accuracy, in vitro experimental measurements of the detachment times of yeast kinetochores from MTs under external pulling forces. Numerical simulations suggest that geometrical features of MT-protofilaments may play an important role in the switch between stable and unstable attachments.


Effects of exposure to vehicle exhaust on health.
Exposure to combustion engine exhaust and its effect on crews of roll-on roll-off ships and car ferries and on bus garage staff were studied. The peak concentrations recorded for some of the substances studied were as follows: total particulates (diesel only) 1.0 mg/m3, benzene (diesel) 0.3 mg/m3, formaldehyde (gasoline and diesel) 0.8 mg/m3, and nitrogen dioxide (diesel) 1.2 mg/m3. The highest observed concentration of benzo(a)pyrene was 30 ng/m3 from gasoline and diesel exhaust. In an experimental study volunteers were exposed to diesel exhaust diluted with air to achieve a nitrogen dioxide concentration of 3.8 mg/m3. Pulmonary function was affected during a workday of occupational exposure to engine emissions, but it normalized after a few days with no exposure. The impairment of pulmonary function was judged to have no appreciable, adverse, short-term impact on individual work capacity. In the experimental exposure study, no effect on pulmonary function was observed. Analyses of urinary mutagenicity and thioether excretion showed no sign of exposure to genotoxic compounds among the occupationally exposed workers or among the subjects in the experimental study.


Effects of posture on gastric emptying of nonnutrient liquids and antropyloroduodenal motility.
The effects of posture on gastric emptying, intragastric distribution, and antropyloroduodenal motility after ingestion of a nonnutrient liquid have been evaluated. In seven healthy volunteers antropyloroduodenal pressures were measured for 30 min after ingestion of 150 ml of normal saline in two different positions: sitting and left lateral. Saline drinks were radiolabeled and ingested both before and after intravenous atropine (4 micrograms/kg). Rates of emptying from both the total (P < 0.05) and the proximal (P < 0.05) stomach were faster in the sitting position than in the left lateral position. There were more long (> 6 cm) antropyloric pressure waves (P < 0.05) and isolated pyloric pressure waves (P < 0.05) in the sitting position. Intravenous atropine slowed emptying in both positions (P < 0.05) and in the sitting position decreased (P < 0.05) the number of antropyloric pressure waves. After atropine, gastric emptying was also faster in the sitting compared with the decubitus position (P < 0.05), although there was no difference in antropyloric or isolated pyloric pressure waves between the two postures. We conclude that the effects of gravity on gastric emptying of nonnutrient liquids are likely to reflect changes in both antropyloric motility and intragastric distribution.


Structural basis of Ets1 cooperative binding to widely separated sites on promoter DNA.
Ets1 is a member of the Ets family of transcription factors. Ets1 is expressed in autoinhibited form and its DNA binding depends on partner proteins bound to adjacent sequences or the relative positioning of a second Ets-binding site (EBS). The autoinhibition of Ets1 is mediated by structural coupling of regions flanking the DNA-binding domain. The NMR structure of Ets1 revealed that the inhibitory regions comprised of helices HI1 and HI2 and H4 are packed together on the Ets domain to form an inhibitory module. The crystal structure of Ets1 unexpectedly revealed a homodimer in which homodimerisation occurs via swapping of HI1 helices. Modeling of DNA binding indicates that the Ets1 dimer can bind to two antiparallel pieces of DNA. To verify this, we crystallized and solved the structure of the complex comprised of Ets1 dimer and two pieces of DNA. DNA binding by Ets1 dimer resulted in formation of additional intermolecular protein•DNA interactions, implying that the complex formation is cooperative.


Gut glucose metabolism in rainbow trout: implications in glucose homeostasis and glucosensing capacity.
The main objective of the present study was to evaluate the relative contribution of the intestine to glucose homeostasis in rainbow trout. In a first set of in vivo experiments trout were subjected to oral glucose treatments alone or in combination with insulin injections to assess changes in glucose-related enzymes activities, metabolite levels, and mRNA levels. Rainbow trout gut displays an important glucose metabolism that includes the ability to store glucose as glycogen (mostly in the muscle layers) and a large capacity to oxidize glucose. This constitutes a surprising result for a carnivorous fish. In a second set of in vivo experiments, trout received an oral amino acid solution alone or in combination with insulin injection to determine whether other factors besides fasting could regulate gluconeogenesis in intestine. The results confirm the absence of regulation of gluconeogenesis in trout gut, which does not respond to hormones, glucose, lactate, or amino acid changes, either in vivo or in vitro. We also fully characterized gut glucose metabolism in vitro. We observed that a large amount of glucose is oxidized to lactate, supporting the importance of glucose in gut metabolism. Moreover, we corroborated the minor actions of insulin in trout gut, whereas other hormones such as glucagon-like peptide-1 and C-peptide appear to be major hormonal regulators of glucose metabolism in fish gut. Finally, we obtained the first evidence for the existence of a glucosensing mechanism in the midgut of this carnivorous species.


An attempt to improve antipsychotic medication adherence by feedback of medication possession ratio scores to prescribers.
Poor medication adherence is well documented for patients with severe and persistent mental illness. The State of Missouri implemented an early alert system to notify caregivers when patients fail to refill essential prescriptions in a timely manner and as an educational resource for providers on best practices for improving treatment adherence. Missouri Medicaid patients who were prescribed at least 1 of 9 orally-administered antipsychotic medications and who had at least 1 medication possession ratio (MPR) score below 0.8 were included in the adherence intervention group. Their prescribing clinicians and case managers were messaged electronically 2 times per week at the point that failure to refill the targeted prescription was identified. Notification occurred when the prescription had lapsed at 7 days, 30 days, and 45 days, and occurred in real time. In addition, MPR scores were provided monthly for the most recent 6-month period. Change in MPR scores was measured for the intervention group and for a matched control group. Trends in MPR scores were analyzed for both groups pre, during, and post intervention. In both the intervention and postintervention periods, there was a significant difference in the MPR scores between the two groups. The intervention group had a significantly greater increase in MPR score between preintervention and intervention periods. After the conclusion of the intervention, the MPR score decreased somewhat but was still higher than during the preintervention period. Results suggest that clinicians and patients need specific data about adherence in order to address the issue.


Seasonal concentrations and determinants of indoor particulate matter in a low-income community in Dhaka, Bangladesh.
Indoor exposure to particulate matter (PM) increases the risk of acute lower respiratory tract infections, which are the leading cause of death in young children in Bangladesh. Few studies, however, have measured children's exposures to indoor PM over time. The World Health Organization recommends that daily indoor concentrations of PM less than 2.5μm in diameter (PM(2.5)) not exceed 25μg/m(3). This study aimed to describe the seasonal variation and determinants of concentrations of indoor PM(2.5) in a low-income community in urban Dhaka, Bangladesh. PM(2.5) was measured in homes monthly during May 2009 to April 2010. We calculated the time-weighted average, 90th percentile PM(2.5) concentrations and the daily hours PM(2.5) exceeded 100μg/m(3). Linear regression models were used to estimate the associations between fuel use, ventilation, indoor smoking, and season to each metric describing indoor PM(2.5) concentrations. Time-weighted average PM(2.5) concentrations were 190μg/m(3) (95% CI 170-210). Sixteen percent of 258 households primarily used biomass fuels for cooking and PM(2.5) concentrations in these homes had average concentrations 75μg/m(3) (95% CI 56-124) greater than other homes. PM(2.5) concentrations were also associated with burning both biomass and kerosene, indoor smoking, and ventilation, and were more than twice as high during winter than during other seasons. Young children in this community are exposed to indoor PM(2.5) concentrations 7 times greater than those recommended by World Health Organization guidelines. Interventions to reduce biomass burning could result in a daily reduction of 75μg/m(3) (40%) in time-weighted average PM(2.5) concentrations.


On the Baldwin effect.
In this article the effects of altering the rate and amount of learning on the Baldwin effect are examined. Using a version of the abstract tunable NK model, it is shown that the adaptation process is sensitive to the rate of learning, particularly as the correlation of the underlying fitness landscape varies. Typically a high learning rate proves most beneficial as landscape correlation decreases. It is also shown that the amount of learning can have a significant effect on the adaptation process, where increased amounts of learning prove beneficial under higher learning rates on uncorrelated landscapes.


Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).
To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.


Universal risk factors for multifactorial diseases: LifeLines: a three-generation population-based study.
The risk for multifactorial diseases is determined by risk factors that frequently apply across disorders (universal risk factors). To investigate unresolved issues on etiology of and individual's susceptibility to multifactorial diseases, research focus should shift from single determinant-outcome relations to effect modification of universal risk factors. We present a model to investigate universal risk factors of multifactorial diseases, based on a single risk factor, a single outcome measure, and several effect modifiers. Outcome measures can be disease overriding, such as clustering of disease, frailty and quality of life. "Life course epidemiology" can be considered as a specific application of the proposed model, since risk factors and effect modifiers of multifactorial diseases typically have a chronic aspect. Risk factors are categorized into genetic, environmental, or complex factors, the latter resulting from interactions between (multiple) genetic and environmental factors (an example of a complex factor is overweight). The proposed research model of multifactorial diseases assumes that determinant-outcome relations differ between individuals because of modifiers, which can be divided into three categories. First, risk-factor modifiers that determine the effect of the determinant (such as factors that modify gene-expression in case of a genetic determinant). Second, outcome modifiers that determine the expression of the studied outcome (such as medication use). Third, generic modifiers that determine the susceptibility for multifactorial diseases (such as age). A study to assess disease risk during life requires phenotype and outcome measurements in multiple generations with a long-term follow up. Multiple generations will also enable to separate genetic and environmental factors. Traditionally, representative individuals (probands) and their first-degree relatives have been included in this type of research. We put forward that a three-generation design is the optimal approach to investigate multifactorial diseases. This design has statistical advantages (precision, multiple-informants, separation of non-genetic and genetic familial transmission, direct haplotype assessment, quantify genetic effects), enables unique possibilities to study social characteristics (socioeconomic mobility, partner preferences, between-generation similarities), and offers practical benefits (efficiency, lower non-response). LifeLines is a study based on these concepts. It will be carried out in a representative sample of 165,000 participants from the northern provinces of the Netherlands. LifeLines will contribute to the understanding of how universal risk factors are modified to influence the individual susceptibility to multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline.


Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.
The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices.


No rationale for 1 variable per 10 events criterion for binary logistic regression analysis.
Ten events per variable (EPV) is a widely advocated minimal criterion for sample size considerations in logistic regression analysis. Of three previous simulation studies that examined this minimal EPV criterion only one supports the use of a minimum of 10 EPV. In this paper, we examine the reasons for substantial differences between these extensive simulation studies. The current study uses Monte Carlo simulations to evaluate small sample bias, coverage of confidence intervals and mean square error of logit coefficients. Logistic regression models fitted by maximum likelihood and a modified estimation procedure, known as Firth's correction, are compared. The results show that besides EPV, the problems associated with low EPV depend on other factors such as the total sample size. It is also demonstrated that simulation results can be dominated by even a few simulated data sets for which the prediction of the outcome by the covariates is perfect ('separation'). We reveal that different approaches for identifying and handling separation leads to substantially different simulation results. We further show that Firth's correction can be used to improve the accuracy of regression coefficients and alleviate the problems associated with separation. The current evidence supporting EPV rules for binary logistic regression is weak. Given our findings, there is an urgent need for new research to provide guidance for supporting sample size considerations for binary logistic regression analysis.


Species-Specific PCR Assays for Differentiating Heterodera filipjevi and H. avenae.
Heterodera avenae and H. filipjevi are economically important cyst nematodes that restrict production of cereal crops in the Pacific Northwest United States and elsewhere in the world. Identification of these two species is critical for recommending and implementing effective management practices. Primers were designed from the internal transcribed spacer (ITS) regions of H. avenae and H. filipjevi ribosomal DNA. The primers were highly specific when examined on target isolates but did not amplify DNA from nontarget Heterodera, Globodera, Meloidogyne, Pratylenchus, and other nematode species tested. Polymerase chain reaction (PCR) and amplification conditions were established, and H. avenae and H. filipjevi were clearly distinguished by PCR fragments of 242 and 170 bp, respectively. Robust PCR amplification was achieved with DNA extracted from a single egg or second-stage juvenile (J2) using a laboratory-made worm lysis buffer, and DNA from 0.5 egg or J2 using a commercial kit. The PCR assays were successfully employed for differentiation of H. filipjevi and H. avenae populations collected from eight locations in three Pacific Northwest states. This is the first report of a species-specific ITS PCR assay to detect and identify H. filipjevi. The assays for both species will enhance diagnosis of cereal cyst nematode species in infested fields.


Gender, Parenthood and Wage Differences: The Importance of Time-Consuming Job Characteristics.
Using data from the Swedish Level of Living Survey (2000, 2010), we investigate how the gender wage gap varies with occupational prestige and family status and also examine the extent to which this gap is explained by time-consuming working conditions. In addition, we investigate whether there is an association between parenthood, job characteristics and wage (as differentiated by gender). The analyses indicate that there are gender differences regarding prestige-based pay-offs among parents that are partly explained by fathers' greater access to employment characterized by time-consuming conditions. Separate analyses for men and women demonstrate the presence of a marriage wage premium for both genders, although only men have a parenthood wage premium. This fatherhood premium is however only present in high-prestigious occupations. Compared with childless men, fathers are also more advantaged in terms of access to jobs with time-consuming working conditions, but the wage gap between fathers and childless men is not explained by differences in access to such working conditions.


Calcium-calmodulin is required for abscisic acid-induced antioxidant defense and functions both upstream and downstream of H2O2 production in leaves of maize (Zea mays) plants.
* Using pharmacological and biochemical approaches, the role of calmodulin (CaM) and the relationship between CaM and hydrogen peroxide (H(2)O(2)) in abscisic acid (ABA)-induced antioxidant defense in leaves of maize (Zea mays) plants were investigated. * Treatment with ABA or H(2)O(2) led to significant increases in the concentration of cytosolic Ca(2+) in the protoplasts of mesophyll cells and in the expression of the calmodulin 1 (CaM1) gene and the content of CaM in leaves of maize plants, and enhanced the expression of the antioxidant genes superoxide dismutase 4 (SOD4), cytosolic ascorbate peroxidase (cAPX), and glutathione reductase 1 (GR1) and the activities of the chloroplastic and cytosolic antioxidant enzymes. The up-regulation of the antioxidant enzymes was almost completely blocked by pretreatments with two CaM antagonists. * Pretreatments with CaM antagonists almost completely inhibited ABA-induced H(2)O(2) production throughout ABA treatment, but pretreatment with an inhibitor or scavenger of reactive oxygen species (ROS) did not affect the initial increase in the contents of CaM induced by ABA. * Our results suggest that Ca(2+)-CaM is involved in ABA-induced antioxidant defense, and that cross-talk between Ca(2+)-CaM and H(2)O(2) plays a pivotal role in ABA signaling.


Sensitivity of low-field T2 images for detecting the presence and severity of histopathologic meniscal lesions in dogs.
The sensitivity of low-field magnetic resonance (MR) T2 images for predicting the presence of meniscal lesions was determined in 12 dogs with naturally-occurring cranial cruciate ligament rupture and three control dogs, using histopathology as the reference standard. Previously published grading systems were used to grade the severity of meniscal lesions on MR images, gross inspection and histopathology. Focal areas of increased signal intensity were detected in 11/12 symptomatic dogs and 3/3 control dogs. Lesions mimicking meniscal tears (pseudotears) were identified at junctions between meniscal margins and adjacent connective tissue in control dogs and dogs with naturally occurring disease. Histopathologic lesions were present in all menisci of both symptomatic and control dogs, including the menisci from two affected dogs that appeared grossly normal but were removed and submitted based on MR imaging findings. Histopathologic lesions identified included hyaline cartilage metaplasia and changes in the amount of ground substance and cellularity. The sensitivity of MR imaging for detecting the presence of meniscal histopathologic lesions was 90% in symptomatic dogs and 91% in control dogs. However, agreement between severity scores for the different tests was poor. Low-field MR imaging is a sensitive test for predicting the presence but not severity of meniscal histopathologic lesions in dogs with naturally-occurring cranial cruciate ligament rupture. Findings also supported previous studies indicating that histopathologic lesions can be present in dogs with grossly normal menisci. An improved grading system for comparing MR images and histopathologic severity of meniscal lesions in dogs is needed.


Maternal and fetal arterial blood gas data during general anaesthesia for caesarean delivery of preterm twin lambs.
Much remains to be understood with regards the effects of prolonged anaesthesia on maternal and fetal haemodynamics and oxygenation. With the aim of improving anaesthetic management of pregnant sheep undergoing recovery surgery under anaesthesia, paired maternal and fetal arterial blood samples were collected during caesarean delivery of twin preterm lambs to document the blood gas status of the ewe and fetus. Twenty-one Merino twin pregnant ewes at 126 (±1) days of gestation were anaesthetized for caesarean delivery of their fetuses. Arterial blood samples were collected from the radial artery of the ewe and umbilical artery of the fetus at the point of delivery. There was a significant difference between maternal PaCO2 and end-tidal CO2 and alveolar and arterial PaO2, indicating ventilation perfusion mismatch. Interestingly, the ewes were anaemic but the fetuses were not. These data underscore the need to undertake further work to determine the optimal anaesthetic regimen for twin pregnant ewes at different gestational ages in a biomedical research setting.


Arg-Leu-Tyr-Glu tetrapeptide inhibits tumor progression by suppressing angiogenesis and vascular permeability via VEGF receptor-2 antagonism.
The tetrapeptide Arg-Leu-Tyr-Glu (RLYE) is known to inhibit vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis in vitro. Herein, we examined its underlying mechanism and antitumor activity associated with vascular remodeling. RLYE inhibited VEGF-A-induced angiogenesis in a mouse model and suppressed VEGF-A-induced angiogenic signal cascades in human endothelial cells. However, RLYE showed no inhibitory effect on VEGF-A-induced proliferation and migration of multiple myeloma cells expressing VEGF receptor (VEGFR)-1, but not VEGFR-2. In addition, RLYE showed no inhibitory effect on angiogenic activities induced by VEGF-B, basic fibroblast growth factor, epithermal growth factor, sphingosine-1-phosphate, and placental growth factor. RLYE bound specifically to VEGFR-2 at the VEGF-A binding site, thereby blocking VEGF-A-VEGFR-2 binding and VEGF-A-induced VEGFR-2 internalization. The RLYE peptide inhibited tumor growth and metastasis via suppression of tumor angiogenesis in tumor-bearing mice. Moreover, RLYE showed a synergistic effect of the cytotoxic agent irinotecan on tumor cell apoptosis and tumor progression via tumor vessel normalization due to stabilization of VE-cadherin-mediated adherens junction, improvement of pericyte coverage, and inhibition of vascular leakage in tumors. Our results suggest that RLYE can be used as an antiangiogenic and tumor blood vessel remodeling agent for inhibition of tumor growth and metastasis by antagonizing VEGFR-2, with the synergistic anti-cancer effect via enhancement of drug delivery and therapeutic efficacy.


Synthesis of Janus Au@periodic mesoporous organosilica (PMO) nanostructures with precisely controllable morphology: a seed-shape defined growth mechanism.
Janus nanostructures that possess two or more distinct components and surface functions have attracted more and more attention. Here, we present a seed-shape defined growth mechanism for the preparation of anisotropic Janus nanostructures, in which the shape of periodic mesoporous organosilica (PMO) is determined by the shape of Au nanoparticles. Various shaped Au@PMO composite nanostructures, such as rods, spheres, and plates, are prepared based on this general growth mechanism. By adjusting the reaction parameters (temperature, surfactant), various shaped AuNR@PMO Janus nanostructures, including horsebean- and fingernail-like nanostructures, have been successfully prepared. We also demonstrate the potential applications of such composite nanostructures. As an example, the as-prepared rod-like Janus Au@PMO nanostructures show great performance in chemo-photothermal combination therapy because of the excellent photothermal effect of Au nanorods and the high surface area of PMO nanorods. This research may open a new direction to the controllable synthesis and practical application of dedicated nanostructures with desired properties.


Evaluation of the American version of the 30-item Endometriosis Health Profile (EHP-30).
Health status instruments, which measure the subjective functioning and well-being of respondents, are increasingly being used in international, multi-centre trials of new treatments. If the results of such trials in different countries are to be pooled, it is vitally important for researchers to know how comparable the instruments are across cultures. In this study, we evaluated the response rate, data quality, score reliability and scaling assumptions of the 30-item Endometriosis Health Profile (EHP-30) in the USA. Data were obtained from a multi-centre study which recruited 225 patients from 43 clinic sites in the United States of America. It was a randomised, evaluator-blinded, Phase III study. In the evaluation of the EHP-30 reported here, the two groups (Depot Medroxyprogesterone Acetate [DMPA] and Leuprolide Acetate [LA]) are combined, and analyses are based on the data gained at baseline. Questionnaires were self-completed by patients when they visited the clinics. Data completeness was very high, with 97.33% of respondents completing all of the items on the EHP-30. Furthermore, there were no more than a maximum of two missing responses for any given item. No floor and ceiling effects were found for any of the dimensions of the questionnaire. Internal consistency reliability was high for all dimensions (alpha ranged from 0.84 to 0.91). The psychometric properties of the instrument, outlined in the development of the UK version, are supported in the American context. The data presented here suggest that the EHP-30 is a valid and reliable measure that can be appropriately and meaningfully used in studies that include respondents from the USA.