Two mcm3 mutations affect different steps in the initiation of DNA replication.
Mcm3 is a subunit of the hexameric MCM2-7 complex required for the initiation and elongation of DNA replication in eukaryotes. We have characterized two mutant alleles, mcm3-1 and mcm3-10, in Saccharomyces cerevisiae and showed that they are defective at different steps of the replication initiation process. Mcm3-10 contains a P118L substitution that compromises its interaction with Mcm5 and the recruitment of Mcm3 and Mcm7 to a replication origin. P118 is conserved between Mcm3, Mcm4, Mcm5, and Mcm7. An identical substitution of this conserved residue in Mcm5 (P83L of mcm5-bob1) strengthens the interaction between Mcm3 and Mcm5 and allows cells to enter S phase independent of Cdc7-Dbf4 kinase (Hardy, C. F., Dryga, O., Pahl, P. M. B., and Sclafani, R. A. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 3151-3155). Mcm3-1 contains a G246E mutation that diminishes the efficiency of replication initiation (Yan, H., Merchant, A. M., and Tye, B. K. (1993) Genes Dev. 7, 2149-2160) but not its interaction with Mcm5 or recruitment of the MCM2-7 complex to replication origin. These observations indicate that Mcm3-10 is defective in a step before, and Mcm3-1 is defective in a step after the recruitment of the MCM2-7 complex to replication origins.


European symposium on precision medicine in allergy and airways diseases: report of the European Union parliament symposium (October 14, 2015).
On 14 October 2015, the European Academy of Allergy and Clinical Immunology (EAACI), the European Rhinologic Society (ERS) and the European Medical Association (EMA) organized a symposium in the European Parliament in Brussels on Precision Medicine in Allergy and Airways Diseases, hosted by MEP David Borrelli and with active participation of the European Respiratory Society (ERS), the European Federations of Allergy and Airways Diseases Patients Associations (EFA), the Global Allergy and Asthma European Network (Ga2len), Allergic Rhinitis and Its Impact on Asthma (ARIA) and the Respiratory Effectiveness Group (REG). MEP Sirpa Pietikainen, Chair of the European Parliament Interest Group on Allergy and Asthma, underlined the importance of the need for a better diagnostic and therapeutic approach for patients with Allergies and Chronic Airways Diseases, and encouraged a joint initiative to control the epidemic of Allergy and Asthma in Europe. The socio-economic impact of allergies and chronic airways diseases cannot be underestimated, as they represent the most frequently diagnosed chronic non-communicable diseases in the EU. Despite the fact that 30% of the total European population is nowadays suffering from allergies and asthma, more than half of these patients are deprived from adequate diagnosis and treatment. Precision Medicine represents a novel approach in medicine, embracing 4 key features: personalized care based on molecular, immunologic and functional endotyping of the disease, with participation of the patient in the decision making process of therapeutic actions, and taking into account predictive and preventive aspects of the treatment. Implementation of Precision Medicine into clinical practice may help to achieve the arrest of the Epidemic of Allergies and Chronic Airways Diseases. This report summarizes the key messages delivered during the symposium by the speakers, including the EU Commissioner for Health and Food Safety Vitenys Andriukaitis. The Commissioner underscored the need for optimal patient care in Europe, supporting joint action plans for disease prevention, patient empowerment and cost-effective treatment strategies leading to a better health status of European citizens.


Maggot debridement therapy for postsurgical wound infection in scoliosis: a case series in five patients.
Case series of 5 patients who developed resistant wound infection after scoliosis surgery. To present maggot debridement therapy (MDT) as an effective alternative to the conventional treatment in postsurgical infection in scoliosis. Numerous clinical reports have been published that describe outstanding effects of MDT, most notable on debridement, cleansing, disinfection, and healing of indolent wounds, many of which have previously failed to respond to conventional treatment. However, till date no reports have been found in the literature describing its use for the treatment of wound infection after scoliosis surgery, which has relatively longer and deeper wound. A total of 5 patients (2 females and 3 males) who developed wound infection after scoliosis correction surgery were included in this study. All were operated for neuromuscular scoliosis using posterior approach with pedicle screw fixation. All developed deep wound infection within 2 to 6 weeks of surgery, which was resistant to all kinds of conventional therapy. MDT applied in all using prepared commercially available maggot bags, and dressing was changed twice a week till wound shows signs of healing. After confirming negative culture, MDT was stopped and routine dressings or secondary closure was done. During the treatment, wound appearance, size, and development of healing were observed. There were 1 patient with paralytic scoliosis and 4 with cerebral palsy. All wound healed completely within 5.2 ± 1.8 weeks of MDT or 8.8 ± 3.8 cycles of MDT. There was no recurrence on final follow-up of 21.6 ± 5.9 months. Wound size was also decreased from 24.2 ± 3.3 cm of pre-MDT to 11.8 ± 4.5 cm post-MDT showing 51.2% reduction in wound size. There was partial implant removal in 2 cases before MDT; however, no further implant extraction was needed in any case after MDT. Treatment was tolerated well by all patients without any obvious complications due to MDT. We would propose to use MDT for the treatment of wound infection after scoliosis surgery as an effective alternative to conventional treatment. In this way, implant extraction could be avoided without losing any correction.


Proanthocyanidins are the major anti-diabetic components of cinnamon water extract.
Cinnamon consumption has been found to associate with the attenuation of diabetes mellitus. The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as a causative factor of type 2 diabetes mellitus (T2DM). Here, we investigated whether cinnamon has any beneficial effect on the toxic aggregation of hIAPP. We found that cinnamon water extract (CWE) inhibited the amyloid formation of hIAPP in a dose-dependent manner, and identified proanthocyanidins as the major anti-amyloidogenic compounds of CWE. Proanthocyanidins affected the secondary structures of hIAPP and delayed the structural transition from unstructured coils to β-sheet-rich structures. Further studies showed that proanthocyanidins not only inhibited the formation of hIAPP oligomers, but also significantly attenuated the membrane damaging and cytotoxic effects caused by the hIAPP aggregation. Together, these results suggest a possible way by which cinnamon shows beneficial effects on T2DM, and indicate a potential pharmacological usage of proanthocyanidins as an anti-diabetic drug candidate.


Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity.
Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal-fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called 'hypoxamir' regulated by HIF-1α, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity. Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25-24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription-PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation. Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1α in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFα) were increased in OW and OB placentas of females but not males, and in silico analysis suggested that activation of miR-210 expression in these placentas might be activated by NFκB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFα showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFα-mediated inhibition of mitochondrial respiration. Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFκB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses.


Intraday reliability and sensitivity of four functional ability tests in older women.
Functional tests are commonly used to evaluate the functional ability of older individuals; however, intraday reliability and sensitivity are required to enable informed decisions on whether repeated trials are necessary and to ensure that the values obtained from a single session are a patient's true score. This study aimed to investigate the intraday reliability and sensitivity of four commonly used functional tests in older individuals. Seventy-one healthy older women (mean [SD]: age, 71.7 [7.3] yrs; body mass, 64.8 [10.2] kg; stature, 1.58 [0.07] m) performed the 6-m maximum walking speed, timed 8-foot up-and-go, chair sit-and-reach, and back scratch tests three times in one single session, with 1 min between trials. Reliability between all trials was examined using intraclass correlation coefficient, and sensitivity was examined using typical error. All tests were highly reliable (intraclass correlation coefficient range, 0.89-0.99), indicating no need for a familiarization trial. Typical error between trials 2 and 1 were 0.06 m·s-1, 0.42 s, 1.13 cm, 0.92 cm for the 6-m maximum walking speed, timed 8-foot up-and-go, chair sit-and-reach, and back scratch tests, respectively. Practitioners should perform two trials to examine whether the difference between them is less than the typical error reported here. These results should help practitioners ensure that scores obtained from an individual from these functional tests are a true reflection of their functional ability rather than measurement error.


Analysis of carbon sink effects for saline constructed wetlands vegetated with mangroves to treat mariculture wastewater and sewage.
In this study, two saline mangrove artificial wetlands, Datang Saline Constructed Wetland (DSCW) created for treating mariculture wastewater and sewage, vegetated with Avicennia marina, and Mangrove Wetland Park (MWP) created for mangrove conservation, vegetated with Rhizophora stylosa, were selected for assessment of carbon sequestration and carbon budget based on measuring greenhouse gas (GHG) emissions and net primary productivities. The average GHG flux and net carbon sequestration flux as carbon dioxide equivalent (CO2 eq.) were measured. The results showed that the GHG flux emitted from DSCW and MWP were 2,128 and 2,148 g CO2 eq./m2-yr, respectively, while the flux of net sequestered carbon was 2,909 and 3,178 g CO2 eq./m2-yr, respectively, which achieved carbon budget values of -676 and -230 g CO2 eq./m2-yr, respectively, exhibiting carbon source effects. Some amounts of N2O, with a high global warming potential of 265, emitted from both artificial wetland systems might cause high GHG flux as CO2 eq. emitted from the wetland systems. It was concluded that both the nitrogenous contents and environmental conditions suitable for microbial production of N2O might be the main factors to change the wetland systems from carbon sinks to carbon sources.


ATP-dependent partitioning of the DNA template into supercoiled domains by Escherichia coli UvrAB.
The helicase action of the Escherichia coli UvrAB complex on a covalently closed circular DNA template was monitored using bacterial DNA topoisomerase I, which specifically removes negative supercoils. In the presence of E. coli DNA topoisomerase I and ATP, the UvrAB complex gradually introduced positive supercoils into the input relaxed plasmid DNA template. Positive supercoils were not produced when E. coli DNA topoisomerase I was replaced by eukaryotic DNA topoisomerase I or when both E. coli and eukaryotic DNA topoisomerases I were added simultaneously. These results suggest that like other DNA helix-tracking processes, the ATP-dependent action of the UvrAB complex on duplex DNA simultaneously generates both positive and negative supercoils, which are not constrained by protein binding but are torsionally strained. The supercoiling activity of UvrAB on UV-damaged DNA was also studied using UV-damaged plasmid DNA and a mutant UvrA protein that lacks the 40 C-terminal amino acids and is defective in preferential binding to UV-damaged DNA. UvrAB was found to preferentially supercoil the UV-damaged DNA template, whereas the mutant protein supercoiled UV-damaged and undamaged DNA with equal efficiency. Our results therefore suggest that the DNA helix-tracking activity of UvrAB may be involved in searching and/or prepriming the damaged DNA for UvrC incision. A possible role of supercoiled domains in the incision process is discussed.


Renewed Attention on the Pupil Light Reflex.
In a recent study, Ebitz and Moore described how subthreshold electrical microstimulation of the macaque frontal eye fields (FEF) modulates the pupillary light reflex. This elegant study suggests that the influence of the FEF and prefrontal cortex on attentional modulation of cortical visual processing extends to the subcortical circuit that mediates a very basic reflex, the pupillary light reflex.


Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling.
During infection of macrophages, prolonged signaling by Mycobacterium tuberculosis (Mtb) or its 19-kDa lipoprotein (LpqH; Rv3763) inhibits IFN-gamma-induced expression of several immune function genes, including class II transactivator (CIITA), which regulates class II MHC. Mtb does not inhibit early IFN-gamma signaling events, e.g., Stat1alpha activation. This study analyzed downstream mechanisms that regulate the transcription of MHC2TA, the gene encoding CIITA. Chromatin immunoprecipitation showed that IFN-gamma induced acetylation of histones H3 and H4 at the CIITA promoter IV (pIV). In contrast, IFN-gamma-dependent histone acetylation at CIITA pIV was inhibited by Mtb or 19-kDa lipoprotein. Mtb 19-kDa lipoprotein also inhibited IFN-gamma-dependent recruitment of Brahma-related gene 1, a chromatin remodeling protein, to CIITA pIV. Mtb 19-kDa lipoprotein did not inhibit histone acetylation in TLR2(-/-) macrophages. Furthermore, 19-kDa lipoprotein did not inhibit CIITA expression or IFN-gamma-dependent histone acetylation of CIITA pIV in macrophages treated with inhibitors of MAPKs p38 or ERK. Thus, CIITA expression was inhibited by TLR2-induced MAPK signaling that caused histone hypoacetylation at CIITA pIV and suppression of CIITA transcription. Chromatin remodeling at MHC2TA is a novel target of inhibition by Mtb. These mechanisms may diminish class II MHC expression by infected macrophages, contributing to immune evasion by Mtb.


Epileptic activity in Alzheimer's disease: causes and clinical relevance.
Epileptic activity is frequently associated with Alzheimer's disease; this association has therapeutic implications, because epileptic activity can occur at early disease stages and might contribute to pathogenesis. In clinical practice, seizures in patients with Alzheimer's disease can easily go unrecognised because they usually present as non-motor seizures, and can overlap with other symptoms of the disease. In patients with Alzheimer's disease, seizures can hasten cognitive decline, highlighting the clinical relevance of early recognition and treatment. Some evidence indicates that subclinical epileptiform activity in patients with Alzheimer's disease, detected by extended neurophysiological monitoring, can also lead to accelerated cognitive decline. Treatment of clinical seizures in patients with Alzheimer's disease with select antiepileptic drugs (AEDs), in low doses, is usually well tolerated and efficacious. Moreover, studies in mouse models of Alzheimer's disease suggest that certain classes of AEDs that reduce network hyperexcitability have disease-modifying properties. These AEDs target mechanisms of epileptogenesis involving amyloid β and tau. Clinical trials targeting network hyperexcitability in patients with Alzheimer's disease will identify whether AEDs or related strategies could improve their cognitive symptoms or slow decline.


The effect of temperature on the outward currents in the soma of molluscan neurones in voltage-clamp conditions.
The delayed outward current in snail neurones was separated into two components with different temperature sensitivity: (i) a persistent component and (ii) a transient (inactivating) component. The effect of cooling on the value of the transient current is strongly dependent upon the value of the conditioning potential. It was supposed that cooling causes a decrease in the negative surface potential in the vicinity of the potassium pathways and removes their inactivation. Simultaneously cooling depresses the potassium conductance. The effect on surface potential is more distinct with conditioning potentials at which a significant fraction of the transient outward current is inactivated. The effect of cooling on the transient component of the fast outward current was similar to that on the transient component of the delayed outward current.


The impact of drought on the association between food security and mental health in a nationally representative Australian sample.
The association between food insecurity and mental health is established. Increasingly, associations between drought and mental health and drought and food insecurity have been observed in a number of countries. The impact of drought on the association between food insecurity and mental health has received little attention. Population-based study using data from a nationally representative panel survey of Australian adults in which participants report behaviour, health, social, economic and demographic information annually. Exposure to drought was modelled using annual rainfall data during Australia's 'Big Dry'. Regression modelling examined associations between drought and three indicative measures of food insecurity and mental health, controlling for confounding factors. People who reported missing meals due to financial stress reported borderline moderate/high distress levels. People who consumed below-average levels of core foods reported more distress than those who consumed above the average level, while people consuming discretionary foods above the average level reported greater distress than those consuming below the threshold. In all drought exposure categories, people missing meals due to cost reported higher psychological distress than those not missing meals. Compared to drought-unadjusted psychological distress levels, in most drought categories, people consuming higher-than-average discretionary food levels reported higher levels of distress. Exposure to drought moderates the association between measures of food insecurity and psychological distress, generally increasing the distress level. Climate adaptation strategies that consider social, nutrition and health impacts are needed.


Validation of a novel combination hearing aid and tinnitus therapy device.
Most patients with tinnitus also have hearing loss. Hearing aids have been well-documented to provide amelioration for both hearing and tinnitus problems. Some hearing aids have built-in noise/sound generators that are intended to provide added benefit to patients with tinnitus. It has not been proven, however, whether these "combination instruments" are more effective for tinnitus management than hearing aids alone. The purpose of this study was to collect initial data addressing this question. Thirty individuals meeting study requirements (bothersome tinnitus, hearing aid candidate, and no use of hearing aids for the previous 12 months) were enrolled. All participants initially completed the primary outcome questionnaire (Tinnitus Functional Index [TFI]) and then returned to be fitted with combination instruments. The hearing aid portion of the devices was adjusted to optimize hearing ability. Participants were then randomized to either the experimental group (n = 15) or the control group (n = 15). The experimental group had the noise feature of the instruments activated and adjusted to achieve optimal relief from tinnitus. The control group did not have the noise portion activated. Following the hearing aid fitting, all study participants also received brief tinnitus counseling. Participants returned 1 to 2 weeks later for a follow-up appointment to confirm proper fit of the instruments and to make any necessary programming adjustments. Additionally, they returned 3 months after the fitting to complete the TFI, which also concluded their participation in the study. Both groups revealed significant improvement, as indicated by reductions in mean TFI index scores. Differences between groups at 3 months were not statistically significant. However, the experimental group showed a mean reduction in the TFI score that was 6.4 points greater than that for the control group. The difference approached significance (p = 0.09), suggesting that a larger group of participants may have resulted in a significant difference between groups. This possibility is tempered by the fact that effect sizes, which control for variation, were very similar between groups. Results of this study suggest that the use of hearing aids alone or hearing aids plus the use of sound generators both provide significant benefit with respect to alleviating effects of tinnitus. A larger controlled clinical trial is needed to obtain more definitive results regarding the two configurations of hearing aids.


Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy.
Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.


Quantifying the Economic and Cultural Biases of Social Media through Trending Topics.
Online social media has recently irrupted as the last major venue for the propagation of news and cultural content, competing with traditional mass media and allowing citizens to access new sources of information. In this paper, we study collectively filtered news and popular content in Twitter, known as Trending Topics (TTs), to quantify the extent to which they show similar biases known for mass media. We use two datasets collected in 2013 and 2014, including more than 300.000 TTs from 62 countries. The existing patterns of leader-follower relationships among countries reveal systemic biases known for mass media: Countries concentrate their attention to small groups of other countries, generating a pattern of centralization in which TTs follow the gradient of wealth across countries. At the same time, we find subjective biases within language communities linked to the cultural similarity of countries, in which countries with closer cultures and shared languages tend to follow each other's TTs. Moreover, using a novel methodology based on the Google News service, we study the influence of mass media in TTs for four countries. We find that roughly half of the TTs in Twitter overlap with news reported by mass media, and that the rest of TTs are more likely to spread internationally within Twitter. Our results confirm that online social media have the power to independently spread content beyond mass media, but at the same time social media content follows economic incentives and is subject to cultural factors and language barriers.


Relationship between menopause and periodontal disease: a cross-sectional study in a Portuguese population.
Menopause is associated with important systemic and oral changes. Many researchers have tried to evaluate the influence of hormonal changes associated with menopause in the periodontium, however results are contradictory. Evaluate the possible effects of menopause on the severity of periodontal disease and tooth loss, by considering several general, oral and periodontal parameters. 102 women with chronic periodontitis, and at least six teeth, were divided into two groups: a study group (SG) consisting of 68 menopausal women and a control group (CG) consisting of 34 premenopausal women. The participants had extensive anamnesis, made by a single senior periodontologist, which collected demographic data, medical and gynaecological history and habits. Additionally, oral and periodontal parameters including: number of teeth, plaque index, presence of calculi, probing depth, bleeding on probing, gingival recession and attachment loss were recorded. The following statistical tests were used: Chi-square, Fisher's t-test for independent samples, non-parametric Wilcoxon-Mann-Whitney, and linear multiple regression. The number of teeth was significantly lower in postmenopausal women (SG 10.8 ± 5.9, CG 6.8 ± 4.6), however, after adjusting for age, smoking and plaque index, the difference was no longer statistically significant (P=0.169). The attachment loss was slightly higher in the study group, although the difference is not significant (SG 4.31 ± 1.08, CG 4.05 ± 1.28). Menopause does not appear to significantly influence the severity of periodontal disease and tooth loss. Other factors may exert a greater influence on the progression of periodontal disease rather than menopause itself.


Laboratory malaria diagnostic capacity in health facilities in five administrative zones of Oromia Regional State, Ethiopia.
Quality laboratory services are a requisite to guide rational case management of malaria. Using a pre-tested, standardized assessment tool, we assessed laboratory diagnostic capacity in 69 primary, secondary and tertiary health facilities as well as specialized laboratories in five administrative zones in Oromia Regional State, Ethiopia, during February and March 2009. There was marked variability in laboratory diagnostic capacity among the facilities assessed. Of 69 facilities surveyed, 53 provided both comprehensive malaria laboratory diagnosis and outpatient treatment services, five provided malaria microscopy services (referring elsewhere for treatment), and 11 primary care health posts provided rapid diagnostic testing and outpatient malaria treatment. The facilities' median catchment population was 39, 562 and 3581 people for secondary/tertiary and primary health facilities, respectively. Depending on facility type, facilities provided services 24 hrs a day, had inpatient capacity, and access to water and electricity. Facilities were staffed by general practitioners, health officers, nurses or health extension workers. Of the 58 facilities providing laboratory services, 24% of the 159 laboratory staff had received malaria microscopy training in the year prior to this survey, and 72% of the facilities had at least one functional electric binocular microscope. Facilities had variable levels of equipment, materials and biosafety procedures necessary for laboratory diagnosis of malaria. The mean monthly number of malaria blood films processed at secondary/tertiary facilities was 225, with a mean monthly 56 confirmed parasitologically. In primary facilities, the mean monthly number of clinical malaria cases seen was 75, of which 57 were tested by rapid diagnostic test (RDTs). None of the surveyed laboratory facilities had formal quality assurance/quality control protocols for either microscopy or RDTs. This is the first published report on malaria diagnostic capacity in Ethiopia. While our assessment indicated that malaria laboratory diagnosis was available in most facilities surveyed, we observed significant gaps in laboratory services which could significantly impact quality and accessibility of malaria diagnosis, including laboratory infrastructure, equipment, laboratory supplies and human resources.


Identification of Mutagenic Aromatic Amines in River Samples with Industrial Wastewater Impact.
Aromatic amines are one of the most important classes of compounds contributing to surface water mutagenicity due to their widespread occurrence as precursors and transformation products of dyes, pharmaceuticals, agrochemicals, and other compound classes. In this study, we implemented a workflow including novel analytical and data evaluation methods aiming to identify aromatic amines in six mutagenic wastewater effluents from a chemical-industrial area in Germany, collected by the passive sampler Blue Rayon. We identified 14 amines including the two potent mutagenic aromatic amines 2,3- and 2,8-phenazinediamine, which were reported for the first time as environmental contaminants. These two isomers accounted between 4.2 and 86% of the mutagenicity of the blue rayon extracts and may be byproducts of dye production at the studied site.


Changes in prostanoid synthesis in response to diet and hypertension in one-kidney, one clip rats.
This study was designed to examine the effects of diets that alter prostaglandin biosynthesis on the blood pressure in one-kidney, one clip rats with established hypertension and to compare the prostanoid generating capacity of hypertensive animals with those that remained normotensive. Rats attaining blood pressures of at least 180 mm Hg within 8 weeks of nephrectomy and renal artery stenosis were paired by weight and blood pressure and then placed on either a safflower oil or a prostaglandin I2 inhibitory diet (cod liver oil-linseed oil mix) for 4 weeks. Animals with blood pressures of less than 150 mm Hg were also paired for the same two dietary regimens. Comparison between the two blood pressure groups revealed that on both dietary regimens hypertensive rats produced significantly more aortic 6-keto-prostaglandin F1 alpha and serum thromboxane B2. Rats on the cod liver oil-linseed oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid and significantly impaired ability to generate serum thromboxane B2 (36%), aortic 6-keto-prostaglandin F1 alpha (65%), renal homogenate 6-keto-prostaglandin F1 alpha (64%) and prostaglandin E2 (58%), and urinary prostaglandin E2 (70%) and 6-keto-prostaglandin F1 alpha (52%). Despite these differences in prostanoid synthesizing capacity, no differences in blood pressure were observed between the safflower oil-fed rats and rats fed cod liver oil-linseed oil within either the hypertensive or normotensive groups. These results suggest that prostanoids do not play a major role in maintaining blood pressure in established one-kidney, one clip hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


P2Y12 Inhibitor Pre-Treatment in Non-ST-Elevation Acute Coronary Syndrome: A Decision-Analytic Model.
Current guidelines recommend initiation of a P2Y12 inhibitor for all patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) at the time of diagnosis (pre-treatment); however, there are no randomized trials directly comparing pre-treatment with initiation at the time of angiography to support this practice. We explore clinical and institutional parameters potentially associated with benefit with this strategy in a decision-analytic model based on available evidence from randomised trials. A decision analysis model was constructed comparing three P2Y12 inhibitors in addition to aspirin in patients with NSTE-ACS. Based on clinical trial data, the cumulative probability of 30 day mortality, myocardial infarction (MI) and major bleeding were determined, and used to calculate the net clinical benefit (NCB) with and without pre-treatment. Sensitivity analysis was performed to assess the relationship between NCB and baseline ischemic risk, bleeding risk, time to angiography and local surgical revascularization rates. Pre-treatment with ticagrelor and clopidogrel was associated with a greater than 50% likelihood of providing a >1% increase in 30 day NCB when baseline estimated ischemic risk exceeds 11% and 14%, respectively. Prasugrel pre-treatment did not achieve a greater than 50% probability of an increase in NCB regardless of baseline ischemic risk. Institutional surgical revascularization rates and time to coronary angiography did not correlate with the likelihood of benefit from P2Y12 pre-treatment. In conclusion, pre-treatment with P2Y12 inhibition is unlikely to be beneficial to the majority of patients presenting with NSTE-ACS. A tailored assessment of each patient's individual ischemic and bleeding risk may identify those likely to benefit.


The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in ARNT-deficient cells.
Hypoxia-inducible factor-1 (HIF-1), a DNA-binding complex implicated in the regulation of gene expression by oxygen, has been shown to consist of a heterodimer of two basic helix-loop-helix Per-AHR-ARNT-Sim (PAS) proteins, HIF-1alpha, and HIF-1beta. One partner, HIF-1beta, had been recognized previously as the aryl hydrocarbon receptor nuclear translocator (ARNT), an essential component of the xenobiotic response. In the present work, ARNT-deficient mutant cells, originally derived from the mouse hepatoma line Hepa1c1c7, have been used to analyze the role of ARNT/HIF-1beta in oxygen-regulated gene expression. Two stimuli were examined: hypoxia itself and desferrioxamine, an iron-chelating agent that also activates HIF-1. Induction of the DNA binding and transcriptional activity of HIF-1 was absent in the mutant cells, indicating an essential role for ARNT/HIF-1beta. Analysis of deleted ARNT/HIF-1beta genes indicated that the basic, helix-loop-helix, and PAS domains, but not the amino or carboxyl termini, were necessary for function in the response to hypoxia. Comparison of gene expression in wild type and mutant cells demonstrated the critical importance of ARNT/HIF-1beta in the hypoxic induction of a wide variety of genes. Nevertheless, for some genes a reduced response to hypoxia and desferrioxamine persisted in these mutant cells, clearly distinguishing ARNT/HIF-1beta-dependent and ARNT/HIF-1beta-independent mechanisms of gene activation by both these stimuli.


Role of essential oils in control of Rhizoctonia damping-off in tomato with bioactive Monarda herbage.
Plants in the genus Monarda produce complex essential oils that contain antifungal compounds. The objectives of this research were to identify selections of monarda that reduce Rhizoctonia damping-off of tomato, and to determine relationships between essential oil composition of 13 monarda herbages (dried and ground leaves) and disease suppression. Herbages were grouped into five chemotypes, based on essential oil composition and effective concentrations for reducing growth by 50% for Rhizoctonia solani. Replicated and repeated disease control assays were conducted with monarda herbages in greenhouse medium, with or without Rhizoctonia. Percent survival, seedling height, and stem diameter were evaluated at 8 weeks. Survival, seedling height, and stem diameter in herbage-only treatments were not different from the control (no-herbage, no-pathogen) for most herbage treatments. In the pathogen control (no-herbage + Rhizoctonia), seedling survival was 10% that of the control. In pathogen-infested media, seedling survival ranged from 65 to 80% for treatments with thymol chemotypes and 55 to 65% for carvacrol chemotypes. Effective control of Rhizoctonia damping-off was correlated with phenolic monoterpenes; herbages classified as carvacrol chemotypes effectively protected tomato seedlings from Rhizoctonia damping-off disease without phytotoxicity. This study provides evidence that monarda herbages have potential as growing media amendments for control of Rhizoctonia damping-off disease.


Phytochemistry predicts habitat selection by an avian herbivore at multiple spatial scales.
Animal habitat selection is a process that functions at multiple, hierarchically. structured spatial scales. Thus multi-scale analyses should be the basis for inferences about factors driving the habitat selection process. Vertebrate herbivores forage selectively on the basis of phytochemistry, but few studies have investigated the influence of selective foraging (i.e., fine-scale habitat selection) on habitat selection at larger scales. We tested the hypothesis that phytochemistry is integral to the habitat selection process for vertebrate herbivores. We predicted that habitats selected at three spatial scales would be characterized by higher nutrient concentrations and lower concentrations of plant secondary metabolites (PSMs) than unused habitats. We used the Greater Sage-Grouse (Centrocercus urophasianus), an avian herbivore with a seasonally specialized diet of sagebrush, to test our hypothesis. Sage-Grouse selected a habitat type (black sagebrush, Artemisia nova) with lower PSM concentrations than the alternative (Wyoming big sagebrush, A. tridentata wyomingensis). Within black sagebrush habitat, Sage-Grouse selected patches and individual plants within those patches that were higher in nutrient concentrations and lower in PSM concentrations than those not used. Our results provide the first evidence for multi-scale habitat selection by an avian herbivore on the basis of phytochemistry, and they suggest that phytochemistry may be a fundamental driver of habitat selection for vertebrate herbivores.


Gastric cancer stem cells: evidence, potential markers, and clinical implications.
Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.


Personal, social, and environmental correlates of physical activity in urban African-American women.
African-American women are at risk of chronic diseases for which regular physical activity can provide benefits. This group, however, remains predominantly sedentary. Little research has been undertaken to elucidate the multiple factors that influence their physical activity levels. This study was designed to determine associations among personal, social environmental, and physical environmental factors with physical activity level in urban African-American women. The Women and Physical Activity Survey, an interviewer-administered survey consisting of demographic, personal, and social and physical environmental factors, was given to 234 African-American women living in Baltimore, Maryland. Physical activity level was determined from the Behavioral Risk Factor Surveillance System survey. Women were divided into three groups: meeting current recommendations for moderate or vigorous physical activity, insufficiently active, and inactive. Comparisons were made between the group of women that met recommendations versus women who did not, and women who reported any activity versus women who were inactive. Twenty-one percent (48) of women met recommendations for physical activity, 61% (143) were insufficiently active, and 18% (43) were inactive. Women who had a partner or who had no children were less likely to engage in some physical activity. Inactive women were more likely than women who participated in some physical activity to know people who exercised. Women who belonged to community groups were more likely to be inactive than women who met current recommendations for physical activity. Women with fewer social roles were more likely to meet current recommendations. Physical environment factors were not associated with physical activity level. Further exploration is needed to determine how personal and social environmental and physical environmental factors relate to physical activity in African-American women.


Regulation of Mutagenic DNA Polymerase V Activation in Space and Time.
Spatial regulation is often encountered as a component of multi-tiered regulatory systems in eukaryotes, where processes are readily segregated by organelle boundaries. Well-characterized examples of spatial regulation are less common in bacteria. Low-fidelity DNA polymerase V (UmuD'2C) is produced in Escherichia coli as part of the bacterial SOS response to DNA damage. Due to the mutagenic potential of this enzyme, pol V activity is controlled by means of an elaborate regulatory system at transcriptional and posttranslational levels. Using single-molecule fluorescence microscopy to visualize UmuC inside living cells in space and time, we now show that pol V is also subject to a novel form of spatial regulation. After an initial delay (~ 45 min) post UV irradiation, UmuC is synthesized, but is not immediately activated. Instead, it is sequestered at the inner cell membrane. The release of UmuC into the cytosol requires the RecA* nucleoprotein filament-mediated cleavage of UmuD→UmuD'. Classic SOS damage response mutants either block [umuD(K97A)] or constitutively stimulate [recA(E38K)] UmuC release from the membrane. Foci of mutagenically active pol V Mut (UmuD'2C-RecA-ATP) formed in the cytosol after UV irradiation do not co-localize with pol III replisomes, suggesting a capacity to promote translesion DNA synthesis at lesions skipped over by DNA polymerase III. In effect, at least three molecular mechanisms limit the amount of time that pol V has to access DNA: (1) transcriptional and posttranslational regulation that initially keep the intracellular levels of pol V to a minimum; (2) spatial regulation via transient sequestration of UmuC at the membrane, which further delays pol V activation; and (3) the hydrolytic activity of a recently discovered pol V Mut ATPase function that limits active polymerase time on the chromosomal template.


Family history and risk for ischemic stroke: sibling history is more strongly correlated with the disease than parental history.
Current data concerning the association between family history and the risk for developing stroke have been controversial. There has been very little data on the influence of family history on intracranial atherosclerosis (ICAS), stroke severity, and recovery, especially among Asian populations. We evaluated the association between family history and the risk for stroke and investigated the relationships between family history and ICAS, stroke severity, and short-term stroke outcome in Korean stroke patients. In this case-control study, we recruited 400 patients with acute ischemic stroke, along with the same number of age- and gender-matched control subjects. Assessments of first-degree family history of stroke, myocardial infarction, hypertension and diabetes mellitus were obtained by structured questionnaires, followed by reviews of the clinical and neuro-radiological findings of the stroke patients. A family history of stroke was associated with an increased risk of ischemic stroke (OR, 2.65; 95% CI, 1.75 to 4.01), and the correlation remained significant after multivariate analysis. The odds ratios of paternal, maternal, and sibling history were 2.07, 2.16, and 4.21, respectively. The risk of stroke did not differ significantly with the presence of ICAS, stroke severity, and stroke outcome. Family history of stroke was an independent risk factor for ischemic stroke. A positive sibling history was more strongly correlated with the incidence of stroke than a positive parental history, and this finding may indicate the possible role of environmental factors in a shared household in addition to the genetic factors involved in family medical history.


Evolution of adaptive immunity from transposable elements combined with innate immune systems.
Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems.


Tetratricopeptide repeats are essential for PcrH chaperone function in Pseudomonas aeruginosa type III secretion.
The type III secretion system (T3SS) is a specialized apparatus evolved by Gram-negative bacteria to deliver effector proteins into host cells, thus facilitating the establishment of an infection. Effector translocation across the target cell plasma membrane is believed to occur via pores formed by at least two secreted translocator proteins, the functions of which are dependent upon customized class II T3SS chaperones. Recently, three internal tetratricopeptide repeats (TPRs) were identified in this class of chaperones. Here, defined mutagenesis of the class II chaperone PcrH of Pseudomonas aeruginosa revealed these TPRs to be essential for chaperone activity towards the translocator proteins PopB and PopD and subsequently for the translocation of exoenzymes into host cells.


Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB x NZW)F1 mice.
Disease activity in systemic lupus erythematosus is closely associated with the appearance of immunoglobulin (Ig)G antibody to native DNA in both humans and mice. Like normal antibody responses, the anti-DNA autoantibody first appears as IgM and then switches to IgG. Structural studies of IgG anti-DNA suggest that these antibodies are the products of clonally selected, specifically stimulated B cells. The origins of the IgM anti-DNA have been less clear. To determine whether the earlier appearing IgM anti-DNA antibody in autoimmune mice also derives from clonally selected, specifically stimulated B cells or B cells activated by nonselective, polyclonal stimuli, we have analyzed the molecular and serological characteristics of a large number of monoclonal IgM anti-DNA antibodies from autoimmune (NZB x NZW)F1 mice. We have also analyzed IgM and IgG anti-DNA hybridomas obtained from the same individual mice to determine how the later-appearing IgG autoantibody may be related to the earlier-appearing IgM autoantibody within an individual mouse. The results demonstrate that: (a) IgM anti-DNA, like IgG, has the characteristics of a specifically stimulated antibody; (b) IgM and IgG anti-DNA antibodies have similar variable region structures and within individual mice may be produced by B cells derived from the same clonal precursors; (c) recurrent germline and somatically derived VH and VL structures may influence the specificity of anti-DNA monoclonal antibody for denatured vs. native DNA; and (d) the results provide a structural explanation for the selective development of IgG antibody to native DNA as autoimmunity to DNA progresses in (NZB x NZW)F1 mice.


Developing clinical prediction models when adhering to minimum sample size recommendations: The importance of quantifying bootstrap variability in tuning parameters and predictive performance.
Recent minimum sample size formula (Riley et al.) for developing clinical prediction models help ensure that development datasets are of sufficient size to minimise overfitting. While these criteria are known to avoid excessive overfitting on average, the extent of variability in overfitting at recommended sample sizes is unknown. We investigated this through a simulation study and empirical example to develop logistic regression clinical prediction models using unpenalised maximum likelihood estimation, and various post-estimation shrinkage or penalisation methods. While the mean calibration slope was close to the ideal value of one for all methods, penalisation further reduced the level of overfitting, on average, compared to unpenalised methods. This came at the cost of higher variability in predictive performance for penalisation methods in external data. We recommend that penalisation methods are used in data that meet, or surpass, minimum sample size requirements to further mitigate overfitting, and that the variability in predictive performance and any tuning parameters should always be examined as part of the model development process, since this provides additional information over average (optimism-adjusted) performance alone. Lower variability would give reassurance that the developed clinical prediction model will perform well in new individuals from the same population as was used for model development.


P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps.
P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 μg/mL) and verapa- mil (125 μg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.


Artificial photosynthesis: closing remarks.
This paper derives from my closing remarks lecture at the 198th Faraday Discussion meeting on Artificial Photosynthesis, Kyoto, Japan, February 28-March 2. The meeting had sessions on biological approaches and fundamental processes, molecular catalysts, inorganic assembly catalysts, and integration of systems for demonstrating realistic devices. The field has had much progress since the previous Faraday Discussion on Artificial Photosynthesis in Edinburgh, UK, in 2011. This paper is a personal account of recent discussions and developments in the field, as reflected in and discussed during the meeting. First it discusses the general directions of artificial photosynthesis and some considerations for a future solar fuels technology. Then it comments on some scientific directions in the area of the meeting.


Incidence and impact on prognosis of peri-procedural myocardial infarction in 2760 elective patients with stable angina pectoris in a historical prospective follow-up study.
The clinical significance of myocardial infarction related to treatment with percutaneous coronary intervention (PCI) has been subject of great discussion. This subject has been studied for many years using different definitions of peri-procedural myocardial infarction and different biomarkers, the results have varied greatly depending on methods and time of the study. This study was to determine the incidence and prognostic significance of elevated cardiac biomarkers after elective PCI in patients with stable angina pectoris using the current cut-off set by the Third Universal Definition of Myocardial Infarction and current biomarkers. We performed a historical prospective follow-up study of all patients with stable angina pectoris who underwent elective PCI at Aalborg University Hospital, Denmark from January 1(st) 2000 to December 31(st) 2012. We stratified patients according to peak post-PCI troponin T (cTnT) and Creatine Kinase MB mass (CK-MBmass). Follow-up for time to all-cause mortality was mean 5.8 years and total 15,891 years and mean 3.7 years and total 10,160 years for the combined endpoint of all-cause mortality and new onset heart failure. During the follow up period 399 of 2760 patients died (14.5 %) and 1095 (39.7 %) suffered the combined endpoint. Post-PCI concentration of cTnT and CK-MBmass was elevated above the defined cut-off in 419 patients (15.2 %) and 113 patients (4.1 %) respectively. There was no statistically significant difference between the groups in stratified analysis of the hazard rates by time regarding all-cause mortality for cTnT nor CK-MBmass. Regarding the combined endpoint the results were ambiguous. The results were unchanged in multivariable analyses that included age and gender. The incidence of elevated biomarkers after elective PCI in patients with stable angina pectoris using the defined cut-off (>5 x URL) was 15.2 % using cTnT and 4.1 % using CK-MBmass. The independent prognostic value for both cardiac biomarkers of any cut-off showed no statistical significance for all-cause mortality, whereas the combined endpoint (all-cause mortality or new-onset heart failure) were ambiguous in both short- and long-term follow-up.


A modified version of fluctuating asymmetry, potential for the analysis of Aesculus hippocastanum L. compound leaves.
My research interest was to create a new, simple and tractable mathematical framework for analyzing fluctuating asymmetry (FA) in Aesculus hippocastanum L. palmately compound leaves (each compound leaf with 7 obviate, serrate leaflets). FA, being random differences in the development of both sides of a bilaterally symmetrical character, has been proposed as an indicator of environmental and genetic stress. In the present paper the well-established Palmer's procedure for FA has been modified to improve the suitability of the chosen index (FA1) to be used in compound leaf asymmetry analysis. The processing steps are described in detail, allowing us to apply these modifications for the other Palmer's indices of FA as well as for the compound leaves of other plant species.


[Effect of post-exposure prophylaxis with oseltamivir for those in contacts with influenza patients in pediatric wards].
During the influenza season, outbreaks of influenza may occur in the pediatric wards due to spread from the patients hospitalized with influenza, or from those hospitalized during the latency period and develop influenza afterwards. Post-exposure prophylaxis with neuraminidase inhibitors has been reported to be effective in preventing outbreaks among household members and nursing home residents. However, for nosocomial spread, its effectiveness and possible adverse effects are to be determined. During the 2002/2003 influenza season, we experienced a total of 3 nosocomial outbreaks of influenza in the pediatric wards in two hospitals in the Kanto district, Japan. Since the number of contacts who developed influenza had been increasing despite the isolation precaution implemented, post-exposure prophylaxis with oseltamivir (2 mg/kg/dose, maximum 75 mg/dose, once a day for 7-10 days) was implemented with a permission from the parents to terminate the outbreaks. In the outbreaks (one with influenza A, two with influenza B), a total of 29 inpatients had contact with influenza patients: among those 29, 13 were given post-exposure prophylaxis, 16 were not. Out of 16 patients who did not receive post-exposure prophylaxis, 11 (69%) developed influenza: out of 13 with post-exposure prophylaxis, none developed influenza. Those patients who developed influenza were given oseltamivir (2 mg/kg/dose, maximum 75 mg/dose, twice a day for 5 days) and accommodated in a private room or a room with other patients with influenza of the same type. No significant adverse effects due to oseltamivir were observed among those who were enrolled in this study.


Renal Transplant Outcomes in Waitlist Candidates with a Previous Inactive Status Due to Being Temporarily Too Sick.
In 2003, the United Network for Organ Sharing (UNOS) changed its policy to allow candidates with 'inactive' status to accrue time on the waitlist. In this study, we assessed the transplant outcomes among deceased donor kidney transplant (DDKT) recipients who were temporarily inactive specifically due to medical reason, i.e., being temporarily too sick (reason 7). Using the UNOS database, adult DDKT recipients were divided into two groups: those who had never been inactivated (active group) and those with a history of being inactive due to reason 7 (reason 7 group). Patient and graft survival, 3-year risk of death, and graft failure were examined and compared. After 3 years of follow-up, patient survival in the reason 7 group was significantly lower than that of the active group (88.14% versus 91.93%, p < 0.01). The reason 7 group had a 20% increased risk of death (hazard ratio, HR 1.20, confidence interval, CI 1.04 - 1.38), a 16% increase in graft failure (HR 1.16, CI 1.06-1.28), and a 15% decrease in death-censored graft failure (HR 1.15, CI 1.01-1.31). Recipients with a history of reason 7 have lower patient and graft survival when compared to the active group. Nonetheless, the margins of difference are minimal. Candidates with a history of reason 7 should not be discouraged from transplantation once they return to active status. Standardized criteria for placing candidates on inactive status should be developed to reduce disparities among transplant centers.


Potential combined effects of maternal smoking and coffee intake on foetal death within the Danish National Birth Cohort.
Several studies have linked coffee intake and smoking to foetal death, but a possible interaction between both exposures remains unknown. We studied, within the Danish National Birth Cohort, the potential interaction between smoking and coffee drinking while pregnant on the risk of foetal (early and late) death. The study included 90 086 pregnant women, with information about their smoking habit and coffee intake in early pregnancy, and several potential confounding factors. Interaction was studied by calculating both the hazard ratio (HR) in Cox's regression (linear and smoothed restricted cubic spline) and the interaction contrast ratio (ICR). Women who neither smoked nor drank coffee were used as the reference group. Drinking more than 3 cups/d of coffee was associated with the highest risk of foetal death, spontaneous abortion and stillbirth for all smoking status (non-smoker, ≤10 or > 10 cigarettes/d). Among smokers, the combination with drinking <3 cups/d of coffee presented the lowest HRa for foetal death, spontaneous abortion and stillbirth. The ICRs were negative when considering smokers who had a coffee intake up to 3 cups/d, but they were positive for those who had a higher coffee intake, suggesting the effect of coffee intake may be non-linear. Our results suggest that the combined effect of smoking and coffee intake during pregnancy on the risk of foetal death is coffee-dose-dependent. A low coffee intake may reduce the risk of foetal death associated with smoking while a high coffee intake increases the risk.


Environmentally responsive polymeric materials: effect of the topological structure on self-assembly.
A novel amphiphilic homopolymer (PAGC8), containing two hydrophilic head groups and double hydrophobic tails in each repeat unit, has been prepared by solution polymerization and named as "a geminized amphiphilic homopolymer" in this paper, which is capable of self-assembling into various nanoobjects depending on the solution concentration and solvent properties. Characterization of the self-assembly behaviors was carried out by steady-state fluorescence, transmission electron microscopy and nuclear magnetic resonance techniques. Particular emphasis was dedicated to the environmental responsiveness of the assemblies. The morphologies were observed to transform from micelle-type to vesicles on adding a certain amount of ethanol. It is noteworthy that the assemblies were able to trap hydrophilic (rhodamine B) and hydrophobic (Sudan Red) molecules. Subsequently different nanoobjects were found after the encapsulation. To probe the effect of the topological structure on the self-assembly behaviors, the properties of an additional homopolymer with single charge pendant architecture on the backbone were investigated for comparison. Significant differences in structure between the two architectures brought out remarkable variations in aggregates, which were non-responsive to the solvent environment, or encapsulation of molecules. Based on the experimental results, we proposed a possible mechanism of the morphological transitions of the assemblies.


Time-dependent changes in prostaglandin excretion in response to frusemide in man.
1. To evaluate in man by a non-invasive technique the possible role of prostaglandin (PG) compounds in initial renal haemodynamic effects after frusemide we studied the urinary excretion of PGE2 and of PGF2 alpha before and at 15 min and 120 min after intravenous injection of this drug. 2. An increase of PGE2 and of PGF2 alpha excretion was found in all 19 volunteer subjects within 15 min after frusemide, and PG excretion had returned towards control values at 120 min. The stimulation of PGF2 alpha excretion by frusemide was markedly lower in men than in women, but this difference was statistically not significant. 3. No clear-cut relation was found between urinary PG compounds, on the one hand, and urinary volume, urinary sodium and urinary potassium, on the other hand, during the study. 4. The results support the assumption that the rapid increase of urinary PG compounds after frusemide, which parallels the changes in renal haemodynamics, may be an indicator of an activation of the PG system, in part or predominantly, in the vascular compartment.


The intracellular plasma membrane-connected compartment in the assembly of HIV-1 in human macrophages.
In HIV-infected macrophages, newly formed progeny virus particles accumulate in intracellular plasma membrane-connected compartments (IPMCs). Although the virus is usually seen in these compartments, it is unclear whether HIV assembly is specifically targeted to IPMCs or whether some viruses may also form at the cell surface but are not detected, as particles budding from the latter site will be released into the medium. To investigate the fidelity of HIV-1 targeting to IPMCs compared to the cell surface directly, we generated mutants defective in recruitment of the Endosomal Sorting Complexes Required for Transport (ESCRT) proteins required for virus scission. For mutants unable to bind the ESCRT-I component Tsg101, HIV release was inhibited and light and electron microscopy revealed that budding was arrested. When expressed in human monocyte-derived macrophages (MDM), these mutants formed budding-arrested, immature particles at their assembly sites, allowing us to capture virtually all of the virus budding events. A detailed morphological analysis of the distribution of the arrested viruses by immunofluorescence staining and confocal microscopy, and by electron microscopy, demonstrated that HIV assembly in MDMs is targeted primarily to IPMCs, with fewer than 5 % of budding events seen at the cell surface. Morphometric analysis of the relative membrane areas at the cell surface and IPMCs confirmed a large enrichment of virus assembly events in IPMCs. Serial block-face scanning electron microscopy of macrophages infected with a budding-defective HIV mutant revealed high-resolution 3D views of the complex organisation of IPMCs, with in excess of 15,000 associated HIV budding sites, and multiple connections between IPMCs and the cell surface. Using detailed quantitative analysis, we demonstrate that HIV assembly in MDMs is specifically targeted to IPMCs. Furthermore, 3D analysis shows, for the first time, the detailed ultrastructure of an IPMC within a large cell volume, at a resolution that allowed identification of individual virus assembly events, and potential portals through which virus may be released during cell-cell transfer. These studies provide new insights to the organisation of the HIV assembly compartments in macrophages, and show how HIV particles accumulating in these protected sites may function as a virus reservoir.


Impulse control disorders in Parkinson's disease: recent advances.
The aim is to review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICDs) in Parkinson's disease. Large cross-sectional and case-control multicentre studies show that ICDs in Parkinson's disease are common, with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity, suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data point towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possible inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation. Recent large-scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in Parkinson's disease, which can guide prevention of these behaviours and optimize therapeutic approaches.


Inhibitory specificity against various trypsins and stability of ovomucoid from Japanese quail egg white.
The inhibitory specificity and stability of ovomucoid from Japanese quail egg white (OMJPQ) were examined to understand its nutritional significance. OMJPQ showed strong inhibitory activities toward trypsins from various origins including human, and the trypsin inhibitions occurred at molar ratios of enzyme to inhibitor between 1/1 and 2/1. On the other hand, an equimolar mixture of the second and third domains of OMJPQ inhibited bovine trypsin more strongly than the corresponding native OMJPQ did. This distinction was partly explained by the presence of steric hindrance on the formation of a 2:1 trypsin-OMJPQ complex. OMJPQ retained about 100% of its original activity over a pH range from 1 to 12 after a 24-h incubation at 37 degrees C. The inhibitor was most thermostable between pH 2 and 5, where more than 70% of its original activity was maintained after a 1-h incubation at 100 degrees C and about 25% of the activity even after a 30-min incubation at 121 degrees C. OMJPQ was also considerably resistant to pepsin attack. Pepsin digestion of the protein resulted in only about 40% loss of the original trypsin-inhibitory activity even after a 24-h digestion. Furthermore, the addition of bovine serum albumin to the digestion mixture brought about rapid elevation in the trypsin-inhibitory activity during an initial 30-min digestion. SDS-PAGE and immunoblot suggested that this was due to the liberation of active inhibitory domains from the native molecule by inter-domain proteolysis.


Barriers in the implementation of isoniazid preventive therapy for people living with HIV in Northern Ethiopia: a mixed quantitative and qualitative study.
Isoniazid preventive therapy is a key public health intervention for the prevention of tuberculosis disease among people living with HIV. Despite the confirmed efficacy of isoniazid preventive therapy and global recommendations existing for decades, its implementation remains limited. In resource constrained settings, few have investigated why isoniazid preventive therapy is not implemented on full scale. This study was designed to investigate the level of isoniazid preventive therapy implementation and reasons for suboptimal implementation in Tigray region of Ethiopia. A review of patient records combined with a qualitative study using in-depth interviews and focus group discussions was conducted in 11 hospitals providing isoniazid preventive therapy in the Tigray Region. The study participants were health providers working in the HIV clinics of the 11 hospitals in the province. Health providers were interviewed about their experience of providing isoniazid preventive therapy and challenges faced during its implementation. All conversations were audio-recorded. Record review of 16,443 HIV patients registered for care in these hospitals between September 2011 and April 2014 was done to determine isoniazid preventive therapy utilization. Data were collected from April to August 2014. Fifty health providers participated in the study. Overall isoniazid preventive therapy coverage of the region was estimated to be 20 %. Isoniazid stock out, fear of creating isoniazid resistance, problems in patient acceptance, and lack of commitment of health managers to scale up the program were indicated by health providers as the main barriers hindering implementation of isoniazid preventive therapy. Implementation of isoniazid preventive therapy in Tigray region of Ethiopia had low coverage. Frequent interruption of isoniazid supplies raises the concern of interrupted therapy resulting in creation of isoniazid resistance. Health managers, drug suppliers and partners working in HIV and tuberculosis programs should be committed to ensure an uninterrupted supply of isoniazid and full scale implementation of isoniazid preventive therapy to eligible people living with HIV.


Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair.
Melatonin, one of the evolutionarily most ancient, highly conserved and most pleiotropic hormones still operative in man, couples complex tissue functions to defined changes in the environment. Showing photoperiod-associated changes in its activity levels in mammals, melatonin regulates, chronobiological and reproductive systems, coat phenotype and mammary gland functions. However, this chief secretory product of the pineal gland is now recognized to also exert numerous additional functions which range from free radical scavenging and DNA repair via immunomodulation, body weight control and the promotion of wound healing to the coupling of environmental cues to circadian clock gene expression and the modulation of secondary endocrine signalling (e.g. prolactin release, oestrogen receptor-mediated signalling). Some of these activities are mediated by high-affinity membrane (MT1, MT2) or specific cytosolic (MT3/NQO2) and nuclear hormone receptors (ROR alpha), while others reflect receptor-independent antioxidant activities of melatonin. Recently, it was shown that mammalian (including human) skin and hair follicles are not only melatonin targets, but also sites of extrapineal melatonin synthesis. Therefore, we provide here an update of the relevant cutaneous effects and mechanisms of melatonin, portray melatonin as a major skin protectant and sketch how its multi-facetted functions may impact on skin biology and pathology. This is illustrated by focussing on recent findings on the role of melatonin in photodermatology and hair follicle biology. After listing a number of key open questions, we conclude by defining particularly important, clinically relevant perspectives for how melatonin may become therapeutically exploitable in cutaneous medicine.


Does individual programme size affect screening performance? Results from the United Kingdom NHS breast screening programme.
The size (number of women screened) of the 95 individual NHS breast screening programmes (NHSBSPs) varies by a factor of 10. This study investigates the impact of size on the performance of individual programmes. Data were collated from the 95 United Kingdom screening programmes on the standard statistical returns for the past 5 years (1 April 1995-31 March 2000). Additional information was obtained from questionnaires. The number of women screened between 1 April 1999 and 31 March 2000 determined the size of a programme. The bottom 25% were defined as small, the middle 50% as medium, and the top 25% as large. On average large programmes screened about four times as many women as small programmes and medium programmes about twice as many. Performance was evaluated using cancer detection rates, referral rates for assessment, and positive predictive value (PPV) of assessment using PPV referral diagrams. The performance of smaller programmes was shown to be marginally poorer than medium and large sized programmes in that they detected fewer cancers and had a lower PPV. The smallest 25% of programmes had an invasive cancer detection rate 13% less than the medium and large programmes. However, if these programmes had an equivalent detection rate to the medium/large programmes the national detection rate would only increase by about 2%. This is because the 75% of programmes described as medium and large screen about 90% of all women. It is therefore important to place the clinical importance of these findings in context when considering any envisaged possible solutions. Although the performance of smaller programmes was shown to be poorer than that of the larger programmes, it is not clear from this study exactly why this is so. A likely contributory factor based on experience of evaluating the NHSBSP is that performance problems in larger programmes have been easier to detect by quality assurance staff. The size of the small programmes and the few screen detected cancers (and inherent statistical instability in detection rates) mean that problems are difficult to identify. As a consequence small programmes which are genuinely performing marginally below specific standards are likely to receive less attention than larger programmes, and even under close scrutiny the causes are less likely to be found.


Stress compensation with antireflection coatings for ultrafast laser applications: from theory to practice.
Each complicated coating, in particular, a dispersive mirror consists of dozens of layers. Thin films layers have mechanical stresses. After summing up stresses from all layers, the resulting stress is high enough to bend even a relatively thick substrate. To avoid this effect we suggest depositing an antireflection coating (AR) at the back-side of the substrate which together with suppression of unwanted reflections from the back side will also compensate this stress. We demonstrate unique, extremely thick and sophisticated AR coating consisting of 71 layers with the total physical thickness of 7.5 µm. This AR coating completely compensates stress from the dispersive mirror coated on the front side and minimizes unwanted reflections.


Laparoscopic sleeve gastrectomy for super obese patients: forty-eight percent excess weight loss after 6 to 8 years with 93% follow-up.
In this study, we report long-term outcomes of high-risk, high-BMI (body mass index) patients who underwent laparoscopic sleeve gastrectomy (LSG). Short- and medium-term data appear to support the effectiveness of LSG, but long-term data to support its durability are sparse. A prospective database was reviewed on all high-risk patients who underwent LSG as part of a staged approach for surgical treatment of severe obesity between January 2002 and February 2004. We included only patients who did not proceed to second-stage surgery (gastric bypass). Analyzed data included demographics, BMI, comorbidities, and surgical outcomes. All partial gastrectomies were performed using a 50F bougie. Seventy-four patients underwent LSG, and follow-up data were available on 69 of 74 patients (93%). The mean age was 50 years (25-78) and the mean number of co-morbidities was 9.6. Perioperative mortality (<30 days) was zero, and the incidence of short- and long-term postoperative complications was 15%. The mean overall follow-up time period was 73 months (38-95). Mean excess weight loss (EWL) at 72, 84, and 96 months after LSG was 52%, 43%, and 46%, respectively, with an overall EWL of 48%. The mean BMI decreased from 66 kg/m(2) (43-90) to 46 kg/m(2) (22-73). Seventy-seven percent of the diabetic patients showed improvement or remission of the disease. This study reports the longest follow-up of LSG patients thus far and supports the effectiveness, safety, and durability of laparoscopic sleeve gastrectomy as a definitive therapeutic option for severe obesity, even in high-risk, high-BMI patients.


Omega-3 Polyunsaturated Fatty Acids in Prevention of Mood and Anxiety Disorders.
Psychiatric disorders in general, and major depression and anxiety disorders in particular, account for a large burden of disability, morbidity and premature mortality worldwide. Omega-3 polyunsaturated fatty acids (PUFAs) have a range of neurobiological activities in modulation of neurotransmitters, anti-inflammation, anti-oxidation and neuroplasticity, which could contribute to psychotropic effects. Here we reviewed recent research on the benefits of omega-3 PUFA supplements in prevention against major depression, bipolar disorders, interferon-α-induced depression patients with chronic hepatitis C viral infection, and posttraumatic stress disorder. The biological mechanisms underlying omega-3 PUFAs'psychotropic effects are proposed and reviewed. Nutrition is a modifiable environmental factor that might be important in prevention medicine, which have been applied for many years in the secondary prevention of heart disease with omega-3 PUFAs. This review extends the notion that nutrition in psychiatry is a modifiable environmental factor and calls for more researches on prospective clinical studies to justify the preventive application of omega-3 PUFAs in daily practice.


High resolution examination of the role of sleep disturbance in predicting functioning and psychotic symptoms in schizophrenia: A novel experience sampling study.
Sleep disturbance is common in schizophrenia, but its role in predicting functioning and psychotic symptoms has yet to be rigorously examined. The purpose of this study was to conduct a prospective, high-resolution examination of the relationship between nightly sleep and next-day functioning and psychotic symptoms in people with a diagnosis of schizophrenia. Experience sampling methodology was integrated with actigraphy and sleep diaries across 7 days in 22 patients with a diagnosis of schizophrenia. Momentary assessments of mood, psychotic symptoms, and functioning were gathered at 5 points each day following pseudorandom schedules. Multilevel modeling was performed to evaluate the links between variables. Objective and subjective sleep disturbance predicted reduced next-day functioning, which remained significant after controlling for psychotic symptom severity. Increased sleep fragmentation and reduced subjective and objective sleep efficiency predicted greater next-day auditory hallucinations, whereas increased objective sleep fragmentation and reduced subjective sleep quality predicted greater paranoia and delusions of control. Negative affect on awakening mediated a proportion of these relationships (range: 17.9-57.3%). For the first time, we show that sleep disturbance is a predictor of next-day impaired functioning and psychotic symptom severity in people with a diagnosis of schizophrenia. Therefore, interventions targeting sleep may have the potential to directly and indirectly enhance functional and symptomatic recovery in those experiencing psychosis. (PsycINFO Database Record


Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology.
Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4(+)CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.


Improving the science and evidence base of disaster response: a policy research study.
In order to elicit the knowledge, experience, and attitudes of individuals involved in disaster response with regard to evidence-based best practices, Evidence Aid and its institutional partners, Georgetown University and the Uniformed Services University of the Health Sciences, carried out a Policy Delphi study in 2015-2016. Purposive and snowball methods were used to select study participants. The Delphi study comprised two rounds of iterative questions, with the questionnaires completed online. In addition, participants at the Evidence Aid conference in November 2016 discussed the findings in focus groups. Excel was used to analyze the quantitative data and Glaser and Strauss (1967) to analyze the qualitative data. Thirty-six participants responded to the first round of the study, 165 responded to the second round, and 30 participated in the focus group discussions. The salient findings include 1) ensuring that all key stakeholders are engaged in planning for and responding to disasters in a collaborative, coordinated manner-including local community members; 2) using, insofar as possible, evidence-based responses; 3) increasing and strengthening research to ensure that such data are available; and 4) addressing ethical, legal and social issues throughout the planning, immediate response, and post-disaster periods. Recent humanitarian disasters, due to natural and man-made hazards or a combination of the two, reinforce the need for more effective, efficient, humane responses at the local, national and international levels. This study has yielded findings that can be used to strengthen planning and response by taking into account, where possible, evidence based on research that has been carried out with the engagement of community members and with support by key stakeholders. The most effective means of facilitating the development and implementation of consistent, coordinated policies and practices might be for the United Nations Office for Disaster Risk Reduction to take the lead in engaging key organizations in the required discussions and collaborations.


Parental depressive symptoms and childhood cancer: the importance of financial difficulties.
Research suggests a relationship between caring for a child with cancer and psychological distress in caregivers. Less evident is the role which financial difficulties might play in this relationship. We sought to determine if caring for a child with cancer was related to clinically relevant depressive symptoms among parents, whether or not financial difficulties mediated this relationship, and if financial difficulties were independently associated with symptoms of depression among parents of children with cancer. Data are from 215 parents of children diagnosed with cancer or brain tumors (n = 75) and a comparison group of parents of healthy children (n = 140). Multiple logistic regression analyses were used to assess the factors associated with reporting clinically relevant depressive symptoms. Caring for a child with cancer was associated with increased odds of clinically relevant depressive symptoms in parents (OR = 4.93; 95 % CI 1.97-12.30), controlling for covariates. The mediating effect of financial burden on this relationship was not statistically significant. However, among parents of children with cancer, negative financial life events increased the likelihood of reporting symptoms of depression (OR = 4.89; 95 % CI 1.26-18.96). Caring for a child with cancer was associated with depressive symptoms for parents. Financial difficulties were the strongest correlate of these symptoms among parents of children with cancer. Our results suggest that it may not only be the burden of caring for the child with cancer but also the associated financial difficulties that contribute to a higher likelihood of depressive symptoms in parents.


Early antibiotics improve survival following out-of hospital cardiac arrest.
Therapeutic hypothermia (TH) has become standard management following out of hospital cardiac arrest (OHCA). Recent evidence suggests TH increases the incidence of pneumonia. We retrospectively assessed infective indicators after OHCA and evaluated the effect of antibiotics on survival. We identified all patients admitted to the ICU of a regional primary angioplasty hospital following OHCA from May 2007 to December 2010. We collected demographic and outcome data, evidence of infection and the use of antimicrobial therapy. 138 patients were admitted to ICU following OHCA. The mortality rate was 68.1% with mean ICNARC predicted mortality of 77.5%. Of 138 patients, 135 (97.8%) had at least one positive marker of infection within 72 h. 53 of 138 patients (38.4%) received antibiotics during the first 7 days of their ICU stay. The hospital mortality rate for these patients was significantly less than those not receiving antibiotics (56.6% vs. 75.3%; p=0.025) with NNT of 5. Multivariate analysis demonstrated that antibiotic use was an independent predictor of survival. The post-arrest management of OHCA is commonly complicated by infections, the accurate diagnosis of which is impaired by the associated increase in inflammatory markers, body temperature control, delay in the processing of samples and poor quality chest radiography. We have shown a significant reduction in mortality in patients who received antibiotics compared with patients who did not. This suggests that a formal clinical trial is warranted.


Engineering the properties of terahertz filters using multilayer aperture arrays.
We experimentally demonstrate the ability to create additional transmission resonances in a double-layer aperture array by varying the interlayer gap spacing. In the case of periodic aperture arrays, these additional resonances are sharply peaked, while for random aperture arrays the resonances are broad. Surprisingly, these additional resonances only occur when the interlayer gap spacing is greater than half the aperture spacing on a single array. Since there is no corresponding periodicity in the random arrays, these resonances occur regardless of how small the gap spacing is made. This phenomenon can be accurately modeled only if the correct frequency-dependent complex dielectric function of a metal film perforated with subwavelength apertures is used. Using THz time-domain spectroscopy, we are able to directly obtain the complex dielectric response function from the THz experimental transmission measurements. We conclude by demonstrating several passive free-space THz filters using multilayer aperture arrays. Importantly, we show that the magnitude of the lowest order resonance can be approximately maintained, while the background transmission can be significantly suppressed leading to a significant improvement in the optical filter fidelity.


Comparison of Hemorrhagic Risk in Intracranial Arteriovenous Malformations Between Conservative Management and Embolization as the Single Treatment Modality.
Embolization has been discussed as a feasible single modality treatment for intracranial arteriovenous malformations (AVMs). To compare hemorrhagic risk between embolization and conservative management in a multivariate survival analysis. We retrospectively reviewed records of patients with intracranial AVMs evaluated at our institution from 1990 to 2013. We included patients recommended to undergo embolization without other treatment modalities and patients managed conservatively. Multivariate Cox regression analysis of hemorrhage-free survival was performed, with the survival interval right-censored to date of either last follow-up or salvage treatment. We identified 205 patients matching our inclusion criteria, with 160 patients in the noninterventional group and 45 in the embolization group. The average age of all patients was 40.2 ± 19.5 yr, with younger patients undergoing embolization more often (P = .026). Fifty-one (31.9%) conservatively managed patients and 13 (28.9%) patients treated by embolization (P = .703) presented with hemorrhage. Other baseline characteristics were similar between the 2 management groups. During an average follow-up period of 7.7 yr, 30 patients (14.6%) experienced hemorrhage recurrence. Multivariate Cox regression revealed older age (P = .031) and hemorrhagic presentation (P < .001) to be statistically associated with follow-up hemorrhage. In a subset analysis of unruptured AVMs, embolization was associated with a 4-fold hazard ratio of hemorrhage compared to conservative management (P = .044). Older age and initial presentation with hemorrhage were associated with increased risk of hemorrhage during follow-up. Treatment of AVMs with embolization as the sole modality may increase hemorrhagic risk compared with conservative management, especially in unruptured AVMs.


Suppressor analysis of mutations in the 5'-untranslated region of COB mRNA identifies components of general pathways for mitochondrial mRNA processing and decay in Saccharomyces cerevisiae.
The cytochrome b gene in Saccharomyces cerevisiae, COB, is encoded by the mitochondrial genome. Nuclear-encoded Cbp1 protein is required specifically for COB mRNA stabilization. Cbp1 interacts with a CCG element in a 64-nucleotide sequence in the 5'-untranslated region of COB mRNA. Mutation of any nucleotide in the CCG causes the same phenotype as cbp1 mutations, i.e., destabilization of both COB precursor and mature message. In this study, eleven nuclear suppressors of single-nucleotide mutations in CCG were isolated and characterized. One dominant suppressor is in CBP1, while the other 10 semidominant suppressors define five distinct linkage groups. One group of four mutations is in PET127, which is required for 5' end processing of several mitochondrial mRNAs. Another mutation is linked to DSS1, which is a subunit of mitochondrial 3' --> 5' exoribonuclease. A mutation linked to the SOC1 gene, previously defined by recessive mutations that suppress cbp1 ts alleles and stabilize many mitochondrial mRNAs, was also isolated. We hypothesize that the products of the two uncharacterized genes also affect mitochondrial RNA turnover.


New conductivity detection response equation for anions eluted with fully and partially ionised eluents in non-suppressed ion chromatography.
A response equation for conductivity detection in ion chromatography has been derived. This equation is applicable to non-suppressed ion chromatography using both fully ionised and partially ionised eluents. A prime assumption of this equation is that when partially ionised eluents are used (such as benzoic acid), both the ionised and neutral components of the eluent species contribute to the detector response of anionic analytes. Experimental evidence is provided to support this assumption in that pH changes accompanying the elution of an analyte have been measured. These pH changes are proportional to the concentration of analyte injected onto the column, in accordance with predictions from the response equation. Furthermore, it is shown that protonated eluents (such as benzoic acid) give more sensitive detection than equivalent ionised eluents (such as potassium benzoate) and the signal enhancement achieved using a protonated eluent species is in accordance with theory.


Molecular epidemiology reveals the role of war in the spread of HIV in Ukraine.
Ukraine has one of the largest HIV epidemics in Europe, historically driven by people who inject drugs (PWID). The epidemic showed signs of stabilization in 2012, but the recent war in eastern Ukraine may be reigniting virus spread. We investigated the movement of HIV-infected people within Ukraine before and during the conflict. We analyzed HIV-1 subtype-A pol nucleotide sequences sampled during 2012-2015 from 427 patients of 24 regional AIDS centers and used phylogeographic analysis to reconstruct virus movement among different locations in Ukraine. We then tested for correlations between reported PWID behaviors and reconstructed patterns of virus spread. Our analyses suggest that Donetsk and Lugansk, two cities not controlled by the Ukrainian government in eastern Ukraine, were significant exporters of the virus to the rest of the country. Additional analyses showed that viral dissemination within the country changed after 2013. Spearman correlation analysis showed that incoming virus flow was correlated with the number of HIV-infected internally displaced people. Additionally, there was a correlation between more intensive virus movement and locations with a higher proportion of PWID practicing risky sexual behaviors. Our findings suggest that effective prevention responses should involve internally displaced people and people who frequently travel to war-affected regions. Scale-up of harm reduction services for PWID will be an important factor in preventing new local HIV outbreaks in Ukraine.