Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell.
The nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders. We used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability. Although both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability. Taken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference.


Is it possible to differentiate between pseudopneumoperitoneum and similar pathologies ultrasonographically?
The goal of the work was comparing gas ultrasound images below the right diaphragm in two groups: in people with intestinal interposition below the diaphragm and ones with pneumoperitoneum and extracting the traits differentiating these two conditions. Retrospectively, the documentation of 22 patients with intestinal interposition below the diaphragm (group 1) was utilized. Clinical material was used for comparison, previously published, composed of 15 cases of pneumoperitoneum following laparotomy and of 14 cases following that symptom as a result of ulcer perforation - group 2 (in total n = 29). Moreover, the distance in millimeters of the gas surface reflecting ultrasounds from the parietal peritoneum was measured, the smoothness of the surface, parietal peritoneum enhancement at the place of gas adherence, gas continuity below the diaphragm with gas in the intestine located below the liver. Direct adherence of the gas surface to the diaphragm was observed in 100% of the cases of emphysema, but in no cases of intestinal interposition. Yet, in the group of patients with colonic interposition (n = 21) there was always a small gap (2-3 mm) and the gas surface among those patients in 100% of the cases was uneven. In differentiation between pneumoperitoneum and liver-diaphragm interposition of the intestine one should take into account - apart from gas movement below the diaphragm at body position changing - the presence of protrusion and section enhancement of the diaphragmatic peritoneum as well as the distance of the gas from the diaphragm, the smoothness of its surface and the continuity with the intestine below the liver. Interpositions of small diaphragm-liver penetration may subside in erect position.


Robust Stability Analysis of Delayed Stochastic Neural Networks via Wirtinger-Based Integral Inequality.
We discuss stability analysis for uncertain stochastic neural networks (SNNs) with time delay in this letter. By constructing a suitable Lyapunov-Krasovskii functional (LKF) and utilizing Wirtinger inequalities for estimating the integral inequalities, the delay-dependent stochastic stability conditions are derived in terms of linear matrix inequalities (LMIs). We discuss the parameter uncertainties in terms of norm-bounded conditions in the given interval with constant delay. The derived conditions ensure that the global, asymptotic stability of the states for the proposed SNNs. We verify the effectiveness and applicability of the proposed criteria with numerical examples.


Methylphenidate and TBI in ADHD and co-occurring epilepsy and mental disorders: a self-controlled case series study.
It is suggested that medication for attention-deficit hyperactivity disorder (ADHD) links to lower risk of traumatic brain injury (TBI). Little is known about whether the beneficial effect of methylphenidate is persistent in individuals with other comorbid mental disorders and epilepsy. We identified 90,634 participants who were less than 18 years old and diagnosed with ADHD from Taiwan's National Health Insurance Research Database (NHIRD) from January 1, 2000 to December 31, 2013. Cox proportional hazards models with hazard ratio (HR) and 95% confidence interval were conducted to compare the risks of TBI event between groups of ADHD-only and ADHD with co-occurring other mental disorders. Within-individual comparisons using a self-controlled case series study design were conducted using conditional Poisson regression models with relative incidence (RR) and 95% CI to examine the effect of methylphenidate on TBI with adjustment for medication of psychotropics and anticonvulsants. For children and adolescents with ADHD, we found comorbid mental disorders and epilepsy increase the risk of TBI, with HRs ranged from 1.21 to 1.75. For the effect of MPH, we found reduced risks for TBI in ADHD (RR = 0.83, 95% CI = 0.70-0.98). Similar results were found among individuals with co-occurring oppositional defiant disorders or conduct disorder, MDD, tic disorders and epilepsy. Methylphenidate treatment was linked to lower risk for TBI in patients with ADHD and the inverse association was persistent among those with other comorbid mental disorders and epilepsy.


Enhanced incorporation of transgenic DNA into zebrafish chromosomes by a retroviral integration protein.
Manufacture of lines of fish containing specific transgenes is difficult because most fish that hatch from embryos injected with foreign DNA are mosaic; few have the transgenic DNA integrated in germ-line cells. To determine whether the process of integration of exogenously supplied DNA into fish genomes could be accelerated, we examined the ability of the Moloney murine leukemia virus (MoMLV) integration protein (IN) to function in embryonic zebrafish cells. We used partially purified IN from a baculovirus/insect cell expression system and unpurified IN from extracts of psi-2 mouse cells that carry a MoMLV provirus. Both forms of IN were able to enhance expression in zebrafish 10 days after fertilization. At day 14 of development, fish injected with IN had higher levels of transgenic DNA than control fish. The ability of IN to enhance integration of transgenic constructs was demonstrated by a ligation-mediated polymerase chain reaction procedure, which was employed to detect junction fragments of foreign and host genomic DNA, generated by IN-mediated integration.


Characterization of the antibody response in inbred mice to a high-molecular-weight polysaccharide from Pseudomonas aeruginosa immunotype 1.
We explored the genetic basis for the differing immune responses observed in inbred strains of mice to a high-molecular-weight polysaccharide (PS) from Pseudomonas aeruginosa immunotype 1 (IT-1). Previous studies have shown that C3H mice immunized with this antigen produce only immunotype-specific antibody. BALB/c mice immunized with IT-1 PS produce both anti-IT-1 PS antibody and antibody cross-reactive with PS from P. aeruginosa immunotype 2 (IT-2). In the current study, we observed that, in addition, these two strains differ in their ability to respond to low immunizing doses of IT-1 PS. C3H mice generated a protective antibody response after a 1-microgram immunization, whereas BALB/c mice failed to produce protective antibody after receiving 1 microgram of PS. Both strains generated protective levels of antibody after a 50-micrograms immunization. Genetic analysis of these response patterns indicates that the ability to produce cross-reactive antibody and the ability to respond to a 1-microgram immunization are independently inherited traits. In addition, the responsiveness of C3H mice to a 1-microgram immunization with the production of protective levels of antibody is not linked to the mouse major histocompatibility (H-2) complex, to sex-linked genes, or to a single gene outside the H-2 complex.


A novel sensitive fluorescent probe with double channels for highly effective recognition of biothiols.
Biothiols play a crucial role in maintaining redox balance in organisms, and anomalous levels of biothiols in human organs can lead to various sicknesses and biological disorders. This work developed a novel sensitive fluorescent probe TZ-NBD with double channels for highly efficient recognition of biothiols. TZ-NBD adopts 4-Chloro-7-nitrobenzofurazan (NBD-Cl) as the recognition moiety with simultaneous fluorescence output. By incorporating NBD-Cl with the other fluorophore, benzothiazole dihydrocyclopentachromene derivative (TZ-OH), the dual-channel sensitive fluorescence probe TZ-NBD was built. The existence of Cys/ Hcy could significantly trigger both the green and red fluorescent emissions, which were derived from fluorophores amine-substituted NBD and TZ-OH, respectively. While exposing to GSH, only the red-channel fluorescence signal could be detected, indicating the release of TZ-OH. The phenomena was mainly attributed to the fact that sulfur-substituted NBD has nearly no fluorescence, while amine-substituted NBD shows obvious green fluorescence. In our study, TZ-NBD exhibited dual-channel sensitivity, fast response, and excellent selectivity to biothiols in vitro. Moreover, TZ-NBD was favorably utilized for recognition of biothiols in vivo. We believe that the sensitive fluorescence probe with double channels can afford an alternate approach for monitoring biothiols in organisms and would be useful for studying diseases associated with biothiols.


Stress and the quality of life in the parents of young people with intellectual disabilities.
This paper reports the results of a study into stress and quality of life in the parents of young people with an intellectual disability. Research in this area often finds that parents suffer stress as a result of having a son or daughter with an intellectual disability. According to Glidden (1993), this has led to the mistaken perception amongst researchers and professionals in the field that these parents are maladjusted. Glidden's work with parents adopting children with an intellectual disability suggest the parenting may be a satisfying experience and suggests a research focus based on outcomes. In this study the participants, including 102 parents of young people with (44) and without (58) an intellectual disability, were mailed a stress questionnaire and quality of life questionnaire. The results of the analysis of these data demonstrate that the families with a member with a disability report significantly greater stress, they also demonstrated that as stress increases the quality of life decreases. Governments need to address this problem if current policies of integrating people with intellectual disabilities into the community are to be successful. This paper also discusses the reasons natural parents of people with disabilities are dissatisfied while adopting parents are not and suggests further research into this important topic.


Gut microbiota of obese subjects with Prader-Willi syndrome is linked to metabolic health.
The gut microbiota has been implicated in the aetiology of obesity and associated comorbidities. Patients with Prader-Willi syndrome (PWS) are obese but partly protected against insulin resistance. We hypothesised that the gut microbiota of PWS patients differs from that of non-genetically obese controls and correlate to metabolic health. Therefore, here we used PWS as a model to study the role of gut microbiota in the prevention of metabolic complications linked to obesity. We conducted a case-control study with 17 adult PWS patients and 17 obese subjects matched for body fat mass index, gender and age. The subjects were metabolically characterised and faecal microbiota was profiled by 16S ribosomal RNA gene sequencing. The patients' parents were used as a non-obese control group. Stool samples from two PWS patients and two obese controls were used for faecal microbiota transplantations in germ-free mice to examine the impact of the microbiota on glucose metabolism. The composition of the faecal microbiota in patients with PWS differed from that of obese controls, and was characterised by higher phylogenetic diversity and increased abundance of several taxa such as Akkermansia, Desulfovibrio and Archaea, and decreased abundance of Dorea. Microbial taxa prevalent in the PWS microbiota were associated with markers of insulin sensitivity. Improved insulin resistance of PWS was partly transmitted by faecal microbiota transplantations into germ-free mice. The gut microbiota of PWS patients is similar to that of their non-obese parents and might play a role for the protection of PWS patients from metabolic complications.


Workers of a drywood termite do not work.
Social insects (ants, bees, wasps and termites) are considered as prime examples of altruism in which individuals (workers) forego their own reproduction to help other individuals reproduce. Such a behaviour is favoured by natural selection because the workers rear close kin and in doing so enhance their inclusive fitness. Here I show, however, that this does not generally apply to termite workers which are scarcely investigated. In the basal drywood termite Cryptotermes secundus the 'workers', which form the large majority of a colony, did not stay to raise relatives. There is no brood caring behaviour and they do not engage in costly help. They are large immature offspring that develop into either winged (dispersing) or unwinged (replacement) reproductives and the probability that they did so was unaffected by the number of brood in the nest as a brood addition experiment showed. Thus, in contrast to general perception where termite workers are considered equivalent to workers in Hymenoptera, the 'large immatures' of C. secundus did not behave as workers that help in raising younger siblings. This apparently is not necessary as the colony lives inside its food. These results, which are likely to be typical for wood-dwelling termites, open the possibility that large complex group living can evolve without altruistic helping and that costly altruistic helping by workers in termites evolved only as a second step.


Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS).
Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications. To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS). Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS. Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters. There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with dupilumab. Our data support the use of dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.


Stepwise implementation of a new diagnostic algorithm for multidrug-resistant tuberculosis in Haiti.
The uptake of tests endorsed by the World Health Organization to detect and appropriately confirm multidrug-resistant tuberculosis (MDR-TB) in low-income countries remains insufficient. To validate the implementation of line-probe assays (LPA) and liquid culture to develop an algorithm to detect MDR-TB in the challenging setting of Haiti. Through an EXPAND-TB (Expanding Access to New Diagnostics for TB) partnership, proficiency testing and validation of 221 acid-fast bacilli positive specimens were performed. Sensitivity, cost and processing time were analysed. Using liquid vs. solid culture shortened the turnaround time from 54 to 19 days, with a sensitivity of 100% vs. 98.6% and a total cost reduction of 13%. LPA detected all TB and MDR-TB cases at a lower cost than culture, in a mean time of 7.5 days. The combined use of molecular and liquid culture techniques accelerates the accurate diagnosis of TB and susceptibility testing against first-line drugs in a significantly shorter time, and is less expensive. The implementation of this new algorithm could significantly and accurately improve the screening and treatment follow-up of patients affected with TB and MDR-TB.


Early empiric antifungal therapy of infections in neutropenic patients comparing fluconazole with amphotericin B/flucytosine.
We compared the efficacy and tolerability of fluconazole (FCA) with amphotericin B/flucytosine (ABF) in neutropenic patients with haematological malignancies. Antifungal therapy started on day 4 when fever was unresponsive to antibiotics or on day 1 together with the antibiotics, if there was evidence of mycosis. If patients did not respond to FCA after 7 days they switched to ABF. 98 patients, 51 FCA and 47 ABF were included in the study. Response to fever was achieved in 28/51 FCA patients and in another 16 after switching to ABF. So in overall 44/51 (86.2%) of the FCA and 37/47 (78.8%) of the ABF group defervescence was observed. 46 patients (21 FCA, 25 ABF) developed radiological signs of pneumonia. Resolution of infiltrates was achieved in 5/21 FCA and 20/25 ABF patients, and another 10 of 15 initially not responding patients showed regression when switched to ABF, 5 of these had highly suspected aspergillosis. Adverse events occured in 19.6% of FCA and 97.9% of ABF patients. In conclusion fluconazole and amphotericin B/flucytosine seem to be equally effective. In view of its lower toxicity fluconazole may be preferred as first line empiric antifungal agent, but in case of nonresponse, pneumonia or aspergillosis it may be replaced by amphotericin B combined with flucytosine.


Reliability analysis of DOOF for Weibull distribution.
Hierarchical Bayesian method for estimating the failure probability p(i) under DOOF by taking the quasi-Beta distribution B(p(i-1), 1, 1, b) as the prior distribution is proposed in this paper. The weighted Least Squares Estimate method was used to obtain the formula for computing reliability distribution parameters and estimating the reliability characteristic values under DOOF. Taking one type of aerospace electrical connector as an example, the correctness of the above method through statistical analysis of electrical connector accelerated life test data was verified.


Health Issues Due to the Global Prevalence of Sedentariness and Recommendations towards Achieving a Healthier Behaviour.
Sedentariness has progressed in recent years. Here, we summarize the high prevalence of objectively measured sedentariness and the list of health problems associated with sedentariness. According to the literature, a minimum sedentary time of 8 h/d may avoid the harmful effects of sedentariness. Our review of the literature shows that many countries worldwide exceed this threshold. The coronavirus disease 2019 pandemic has increased the proportion of time spent seated in chairs and/or other types of furniture. Furthermore, prolonged sedentariness will continue to increase because it is assumed that people, at least those in desk jobs, perform their work better when sitting than when standing. Many practical solutions should be implemented to help people reduce their sedentary time. People need to be aware that prolonged sedentariness causes health problems. They need to measure the amount of time spent being sedentary to self-guide their behaviour. They should adopt a new lifestyle to avoid prolonged sedentariness and prolonged standing. In addition, we point out that they should frequently change their posture to avoid fatigue and health issues. For global public health, there is an urgent need to adopt an intermediate healthy/healthier behaviour between too much time spent in the sitting and standing positions.


[Ultrastructure of the tarsal receptor complex in the gamasid mite Histionyssus criceti (Hirstionyssidae)].
The main distant receptor organ of H. criceti, situated on the tarsus of each first leg, was studied by scanning and transmitting electron microscopy. The organ contains 6 types of sensilla, including 4 distant ones (two types of olfactory sensilla, differing in wall thickness, and 2 types of probable chemo-thermosensitive sensilla, possessing different double-walled hairs), and also taste organs of common structure and microchaeta. Cilia of all the sensilla contain 13 pairs of peripheral fibers. Comparative analysis of fine structure of distant sensilla in bloodsucking insects, ticks and mites made it possible to show, that blood-sucking gamasids and ticks possess similar number of homologous sensillar types, that formed on a common ground as the specific adaptation to blood-sucking.


Vertebrate Nup53 interacts with the nuclear lamina and is required for the assembly of a Nup93-containing complex.
The nuclear pore complex (NPC) is an evolutionarily conserved structure that mediates exchange of macromolecules across the nuclear envelope (NE). It is comprised of approximately 30 proteins termed nucleoporins that are each present in multiple copies. We have investigated the function of the human nucleoporin Nup53, the ortholog of Saccharomyces cerevisiae Nup53p. Both cell fractionation and in vitro binding data suggest that Nup53 is tightly associated with the NE membrane and the lamina where it interacts with lamin B. We have also shown that Nup53 is capable of physically interacting with a group of nucleoporins including Nup93, Nup155, and Nup205. Consistent with this observation, depletion of Nup53 using small interfering RNAs causes a decrease in the cellular levels of these nucleoporins as well as the spindle checkpoint protein Mad1, likely due to destabilization of Nup53-containing complexes. The cellular depletion of this group of nucleoporins, induced by depleting either Nup53 or Nup93, severely alters nuclear morphology producing phenotypes similar to that previously observed in cells depleted of lamin A and Mad1. On basis of these data, we propose a model in which Nup53 is positioned near the pore membrane and the lamina where it anchors an NPC subcomplex containing Nup93, Nup155, and Nup205.


OCT angiography features associated with macular edema recurrence after intravitreal bevacizumab treatment in branch retinal vein occlusion.
We aimed to evaluate the relationship between the capillary abnormalities including nonperfusion area (NPA) in optical coherence tomography angiography (OCTA) images and the recurrence of macular edema (ME) secondary to branch retinal vein occlusion (BRVO) after intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF; bevacizumab). The records of 40 patients who underwent intravitreal bevacizumab injection for ME secondary to BRVO and had at least six months of follow-up were reviewed. Central retinal thickness (CRT; μm) and macular edema type were evaluated prior to treatment. After ME resolution, nonperfusion areas in the 1 mm (NPA1) and 1-3 mm (NPA3) zones on the Early Treatment Diabetic Retinopathy Study (ETDRS) circle within the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were measured using OCTA images. Furthermore, other microvascular abnormalities in the both SCP and DCP were compared between groups. ME recurred in 25 of 40 (62.5%) eyes. The NPA1 of the SCP and DCP (p = 0.002, 0.004, respectively), NPA3 of the SCP and DCP (p = 0.002, 0.008, respectively), and initial CRT (p = 0.022) differed significantly between eyes with and without ME recurrence. In multivariate logistic regression analyses, the NPA1 of the DCP (OR: 344.718; p = 0.029) and NPA3 of the SCP (OR: 4.072; p = 0.018) were significantly associated with ME recurrence. Other microvascular abnormalities were not significantly different between two groups. The central NPA and parafoveal NPA of the SCP in OCTA images correlated strongly with ME recurrence in BRVO patients after intravitreal anti-VEGF injection.


Assessing the need for routine safety testing for patients being treated with dupilumab for moderate-to-severe atopic dermatitis.
Atopic dermatitis (also known as AD or eczema) is a common skin disease that can cause intense and persistent itching and rashes. Skin creams or ointments are not suitable or effective for some patients with moderate-to-severe AD. In these patients, oral (taken by mouth) or injected medications may be required. Some of those oral or injected treatments could be toxic and often have unwanted side effects, especially when used for a longer period of time, so patients must be regularly tested to see whether those treatments are harming their blood or organs. Dupilumab is a newer injectable drug for treating moderate-to-severe AD. Dupilumab specifically targets key molecules in the body that cause AD. Dupilumab has been tested for up to one year in more than 2000 patients enroled in placebo-controlled clinical trials. During those trials, patients provided blood and urine samples for laboratory testing while they were being treated with dupilumab or placebo (dummy drug). In this paper, the authors from Germany and the U.S.A, analysed how blood cells, blood chemistry, and urine chemistry changed during treatment, to check whether dupilumab is safe to use without the need for regular laboratory tests. After performing many routine laboratory tests on patients' blood and urine, they found that there were no clinically important changes in test results that could be linked to dupilumab. They concluded that patients using dupilumab for moderate-to-severe AD do not need routine laboratory testing. This is a summary of the study: Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS).


Elevated CO2 impairs olfactory-mediated neural and behavioral responses and gene expression in ocean-phase coho salmon (Oncorhynchus kisutch).
Elevated concentrations of CO2 in seawater can disrupt numerous sensory systems in marine fish. This is of particular concern for Pacific salmon because they rely on olfaction during all aspects of their life including during their homing migrations from the ocean back to their natal streams. We investigated the effects of elevated seawater CO2 on coho salmon (Oncorhynchus kisutch) olfactory-mediated behavior, neural signaling, and gene expression within the peripheral and central olfactory system. Ocean-phase coho salmon were exposed to three levels of CO2 , ranging from those currently found in ambient marine water to projected future levels. Juvenile coho salmon exposed to elevated CO2 levels for 2 weeks no longer avoided a skin extract odor that elicited avoidance responses in coho salmon maintained in ambient CO2 seawater. Exposure to these elevated CO2 levels did not alter odor signaling in the olfactory epithelium, but did induce significant changes in signaling within the olfactory bulb. RNA-Seq analysis of olfactory tissues revealed extensive disruption in expression of genes involved in neuronal signaling within the olfactory bulb of salmon exposed to elevated CO2 , with lesser impacts on gene expression in the olfactory rosettes. The disruption in olfactory bulb gene pathways included genes associated with GABA signaling and maintenance of ion balance within bulbar neurons. Our results indicate that ocean-phase coho salmon exposed to elevated CO2 can experience significant behavioral impairments likely driven by alteration in higher-order neural signal processing within the olfactory bulb. Our study demonstrates that anadromous fish such as salmon may share a sensitivity to rising CO2 levels with obligate marine species suggesting a more wide-scale ecological impact of ocean acidification.


Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing.
Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.


Assessment of Changes in Diversity in Dermatology Clinical Trials Between 2010-2015 and 2015-2020: A Systematic Review.
Although there have been increased efforts in dermatologic research to improve representation of patient sex, race, and ethnicity, there are limited data evaluating resulting changes. To characterize the diversity of participants in dermatologic clinical trials conducted in the US published from 2015 to 2020 pertaining to common dermatologic conditions affecting all patient demographic categories compared with findings from 2010-2015. A systematic literature review through the PubMed database was conducted for randomized clinical trials published between July 1, 2015, and July 1, 2020, using keywords alopecia areata, acne, atopic dermatitis, lichen planus, psoriasis, seborrheic dermatitis, and vitiligo. Data collected included distribution of participant demographic characteristics, funding source, and journal type. Reflecting US Census data, studies were defined as unrepresentative of race and ethnicity if they included less than 20% ethnically or racially diverse participants or unrepresentative of sex if they included less than 45% women. Python was used for statistical analysis by χ2 tests or Fisher exact tests. A total of 392 randomized clinical trials were included. In comparison with the period from 2010-2015, the reporting rate for race and ethnicity in US studies has increased from 59.8% to 71.9% (P = .05). However, the proportion of reporting articles including at least 20% non-White representation remains unchanged at 38.1% with 37 of 97 reporting randomized clinical trials in 2010-2015 and 53 of 139 reporting randomized clinical trials in 2015-2020 (P = .99). Psoriasis studies included the least diversity, with 12.1% of studies recording at least 20% non-White participants and 29.5% of studies recording at least 45% female participants. The findings of this systematic review suggest that reporting racial and ethnic data since 2010-2015 has become more transparent. However, inclusion of representative patient populations may still be considered inadequate, particularly in psoriasis studies. Diversity in clinical trials is important for representation of the affected patient populations, and additional efforts are warranted in support of this endeavor.


Patterned surface anchoring of nematic droplets at miscible liquid-liquid interfaces.
We report on the internal configurations of droplets of nematic liquid crystals (LCs; 10-50 μm-in-diameter; comprised of 4-cyano-4'-pentylbiphenyl and 4-(3-acryloyloxypropyloxy)benzoic acid 2-methyl-1,4-phenylene ester) sedimented from aqueous solutions of sodium dodecyl sulfate (SDS) onto interfaces formed with pure glycerol. We observed a family of internal LC droplet configurations and topological defects consistent with a remarkably abrupt transition from homeotropic (perpendicular) to tangential anchoring on the surface of the LC droplets in the interfacial environment. Calculations of the interdiffusion of water and glycerol at the aqueous-glycerol interface revealed the thickness of the diffuse interfacial region of the two miscible liquids to be small (0.2-0.5 μm) compared to the diameters of the LC droplets on the experimental time-scale (15-120 minutes), leading us to hypothesize that the patterned surface anchoring was induced by gradients in concentration of SDS and glycerol across the diameter of the LC droplets in the interfacial region. This hypothesis received additional support from experiments in which the time of sedimentation of the LC droplets onto the interface was systematically increased and the droplets were photo-polymerized to preserve their configurations: the configurations of the LC droplets were consistent with a time-dependent decrease in the fraction of the surface area of each droplet exhibiting homeotropic anchoring. Specifically, LC droplets with <10% surface area with tangential anchoring exhibited a bulk point defect within the LC droplet, whereas droplets with >10% surface area with tangential anchoring exhibited a boojum defect within the tangential region and a disclination loop separated the regions with tangential and homeotropic anchoring. The topological charge of these LC droplet configurations was found to be consistent with the geometrical theorems of Poincaré and Gauss and also well-described by computer simulations performed by minimization of a Landau-de Gennes free energy. Additional experimental observations (e.g., formation of "Janus-like" particles with one hemisphere exhibiting tangential anchoring and the other perpendicular anchoring) and simulations (e.g., a size-dependent set of LC droplet configurations with <10% surface area exhibiting tangential anchoring) support our general conclusion that placement of LC droplets into miscible liquid-liquid interfacial environments with compositional gradients can lead to a rich set of LC droplet configurations with symmetries and optical characteristics that are not encountered in LC droplet systems in homogeneous, bulk environments. Our results also reveal that translocation of LC droplets across liquid-liquid interfaces can define new transition pathways that connect distinct configurations of LC droplets.


Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin.
Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.


Effect of Herbal and Fluoride Mouth Rinses on Streptococcus mutans and Dental Caries among 12-15-Year-Old School Children: A Randomized Controlled Trial.
To assess and compare the effect of herbal and fluoride mouth rinses on Streptococcus mutans count and glucan synthesis by Streptococcus mutans and dental caries, a parallel group placebo controlled randomized trial was conducted among 240 schoolchildren (12-15 years old). Participants were randomly divided and allocated into Group I (0.2% fluoride group), Group II (herbal group), and Group III (placebo group). All received 10 ml of respective mouth rinses every fortnight for a period of one year. Intergroup and intragroup comparison were done for Streptococcus mutans count and glucan synthesis by Streptococcus mutans and dental caries. Streptococcus mutans count showed a statistically significant difference between Group I and Group III (p = 0.035) and also between Group II and Group III (p = 0.039). Glucan concentration levels showed a statistically significant difference (p = 0.024) between Group II and Group III at 12th month. Mean DMF scores showed no statistical difference between the three groups (p = 0.139). No difference in the level of significance was seen in the intention-to-treat and per-protocol analysis. The present study showed that both herbal and fluoride mouth rinses, when used fortnightly, were equally effective and could be recommended for use in school-based health education program to control dental caries. Trial registration number is CTRI/2015/08/006070.


The burden of atopic dermatitis in adults in Italy.
Moderate-to-severe atopic dermatitis (AD) generates a considerable consumption of healthcare resources and significant economic consequences for the patients and their families, healthcare systems (NHS) and society. Several studies on the burden of AD in paediatric patients are available in literature, while data in adults is scant. The purpose of this study was to estimate the direct and indirect costs of moderate to severe AD in adult patients in Italy. Patients with Eczema Area and Severity Index (EASI) Score >20 were included in a multicentre, observational study conducted in six outpatient dermatology clinics throughout the national territory. Data were retrospectively gathered through a case report form investigating healthcare resources consumption, out-of-pocket expenses and patients' and caregivers' productivity loss. Descriptive statistics was used to illustrate data. Univariate generalized linear model with gamma distribution and identity function link was used to describe association between costs and disease severity. A total of 50 patients with a diagnosis of moderate-to-severe DA (EASI Score ≥20), equal to 89% of the total, were included in the analysis. The total annual burden of the disease, direct and indirect costs, amounted to € 4284 per patient; 19.3% accounted for direct medical costs, 19.9% for direct non-medical and 60.8% for indirect costs due to productivity loss. Moderate-to-severe AD in adults represents an important cost for the society imposing a high financial burden for the NHS, but even more for patients and caregivers. Results from this study may support identification of potential factors impacting on the choice of new therapeutic options to improve the clinical and economic management of this devastating disease.


A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes.
Zinc transporter eight (SLC30A8) is a major target of autoimmunity in human type 1A diabetes and is implicated in type 2 diabetes in genome-wide association studies. The type 2 diabetes nonsynonymous single nucleotide polymorphism (SNP) affecting aa(325) lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investigation of its relationship to type 1 diabetes. ZnT8A radioimmunoprecipitation assays were performed in 421 new-onset type 1 diabetic Caucasians using COOH-terminal constructs incorporating the known human aa(325) variants (Trp, Arg, and Gln). Genotypes were determined by PCR-based SNP analysis. RESULTS-Sera from 224 subjects (53%) were reactive to Arg(325) probes, from 185 (44%) to Trp(325)probes, and from 142 (34%) to Gln(325)probes. Sixty subjects reacted only with Arg(325) constructs, 31 with Trp(325) only, and 1 with Gln(325) only. The restriction to either Arg(325) or Trp(325) corresponded with inheritance of the respective C- or T-alleles. A strong gene dosage effect was also evident because both Arg- and Trp-restricted ZnT8As were less prevalent in heterozygous than homozygous individuals. The SLC30A8 SNP allele frequency (75% C and 25% T) varied little with age of type 1 diabetes onset or the presence of other autoantibodies. The finding that diabetes autoimmunity can be defined by a single polymorphic residue has not previously been documented. It argues against ZnT8 autoimmunity arising from molecular mimicry and suggests a mechanistic link between the two major forms of diabetes. It has implications for antigen-based therapeutic interventions because the response to ZnT8 administration could be protective or immunogenic depending on an individual's genotype.


Managed care preapproval and its effect on the cost of Utah worker compensation claims.
To determine the effect of preauthorization of chiropractic services costs in non-surgical back injury cases in a managed care environment. The program was implemented in the chiropractic provider group by the Worker Compensation Fund of Utah. The results were compared with those of similar injury claims in a separate provider group in which there was no preauthorization program. The study was a retrospective review of approximately 5000 claims from 1986 and 5000 claims from 1989 of injured workers in the Utah Worker Compensation Fund. We extracted approximately 1000 nonsurgical back-related injury claims from each year. Cost comparisons between medical and chiropractic provider groups in the management of nonsurgical compensable back pain in both 1986 and 1989. Treatment costs in cases managed by chiropractic physicians increased 12% between 1986 and 1989. Treatment cost in cases managed by medical physicians increased 71% in the same time period. Compensation (wage replacement) costs increased 21% for the chiropractic group and 114% for the medical group. Retrospective analysis of worker compensation databases continue to struggle with issues related to measurement of severity, appropriate condition identification, adequate inclusion of all related costs and unbiased case selection. Treatment costs appeared to be controlled under the auspices of a preapproval program required of the chiropractic physician whereas medical costs escalated in the absence of price controls.


Identification of progenitor cancer stem cell in lentigo maligna melanoma.
The potential role of stem cells in neoplasia has aroused considerable interest over the past few years. A number of known biologic characteristics of melanomas support the theory that they may originate in a mutated stem cell. Melanocytic stem cell markers have been described recently. Moreover, the CD133 cells that show surface markers for CD34 are stem cells primitive. These stem cells are capable of differentiating into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. The identification of cancer stem/initiating cells with a crucial role in tumor formation may open up new pharmacologic perspectives. The purpose of this study is to detect the expression of CD133 and CD34, two putative markers of cancer stem cells in the lentigo maligna melanoma. Thirty cases of lentigo maligna melanoma were analyzed using indirect immunohistochemical staining. The vast majority of the samples analyzed showed the presence of rare cells, which were clearly positive for CD133 and CD34. Strong CD133 and CD34 staining was found in the outer root sheath of the mid-lower hair follicles, intermixed with atypical melanocytes extending along layers of the hair follicles. A number of these staminal cells were adjacent and intermixed with melanoma cells. This study supports the stem cell origin of this tumor and suggests that the precursor of the melanoma in question is a stem-like cell rather than the primitive melanoblast committed to be exclusively involved in melanocytic differentiation.


Treatment of a dog with an insulinoma-related peripheral polyneuropathy with corticosteroids.
A crossbreed dog with a history of a chronic progressive tetraparesis had an insulinoma-related peripheral polyneuropathy. Frequent feeding and treatment with corticosteroids resulted in recovery from a non-ambulatory to an almost completely normal clinical state, despite the persistence of hypoglycaemia and hyperinsulinism. After euthanasia for uncontrollable seizures, the presence of a beta-cell carcinoma of the pancreas and extensive axonal degeneration of the peripheral nerves was confirmed by histopathological examination. These findings may indicate an immune-mediated pathogenesis for insulinoma-related peripheral polyneuropathy.


Factors affecting the chain length of group A streptococci. II. Quantative M-anti-M relationships in the long chain test.
Minute amounts of M protein were detected in culture supernates of virulent Group A streptococci by type-specific inhibition of the long chain and the bactericidal tests for anti-M antibody. The amount of M protein that was detected by the inhibition of these biological systems was less than could be demonstrated by precipitation tests. All strains of streptococci rich in M protein which were studied formed long chains when grown in sufficient concentrations of anti-M antibody. Very low concentrations of anti-M antibody escaped detection by the long chain test when strains of excessive M protein content were employed. Under such conditions the bactericidal test detected anti-M antibody more sensitively than the long chain test owing to the smaller inoculum employed in the former method. The scission of streptococcal chains may be inhibited by union of antibodies with surface antigens other than M protein. Long chains were formed when M-negative, R-positive strains were grown in sera containing anti-R antibody.


The shrinking lungs syndrome in systemic lupus erythematosus.
A comprehensive review of the literature on shrinking lungs syndrome (SLS) in systemic lupus erythematosus involved a MEDLINE search (1965-1997) of case reports and clinical series of patients with the diagnosis of SLS. A total of 49 well-documented cases of SLS were reviewed. Shrinking lungs syndrome is characterized by unexplained dyspnea, a restrictive pattern on pulmonary function test results, and an elevated hemidiaphragm. The cause of SLS remains controversial, with several authors attributing the disorder to diaphragmatic weakness and others suggesting that chest wall restriction accounts for the clinical syndrome. No definitive therapy exists. Corticosteroids have been reported to lessen symptoms and improve pulmonary function in some patients with SLS, but other methods of treatment have occasionally been found to be helpful. Clinical presentation, method of diagnosis, pathogenesis, and treatment modalities are summarized in this review. An uncommon complication of systemic lupus erythematosus, SLS causes significant morbidity and, occasionally, mortality.


A method for prioritizing risk groups for early SARS-CoV-2 Vaccination, By the Numbers.
Given the limited supply of two COVID-19 vaccines, it will be important to choose which risk groups to prioritize for vaccination in order to get the most health benefits from that supply. In order to help decide how to get the maximum health yield from this limited supply, we implemented a logistic regression model to predict COVID-19 death risk by age, race, and sex and did the same to predict COVID-19 case risk. Our predictive model ranked all demographic groups by COVID-19 death risk. It was highly concentrated in some demographic groups, e.g. 85+ year old Black, Non-Hispanic patients suffered 1,953 deaths per 100,000. If we vaccinated the 17 demographic groups at highest COVID-19 death ranked by our logistic model, it would require only 3.7% of the vaccine supply needed to vaccinate all the United States, and yet prevent 47% of COVID-19 deaths. Nursing home residents had a higher COVID-19 death risk at 5,200 deaths/100,000, more than our highest demographic risk group. Risk of prison residents and health care workers (HCW) were lower than that of our demographic groups with the highest risks.We saw much less concentration of COVID-19 case risk in any demographic groups compared to the high concentration of COVID-19 death in some such groups. We should prioritize vaccinations with the goal of reducing deaths, not cases, while the vaccine supply is low. SARS-CoV-2 vaccines protect against severe COVID-19 infection and thus against COVID-19 death per vaccine studies. Allocating at least some of the early vaccine supplies to high risk demographic groups could maximize lives saved. Our model, and the risk estimate it produced, could help states define their vaccine allocation rules.


Knowledge, attitude and practice of standard precautions of infection control by hospital workers in two tertiary hospitals in Nigeria.
Standard precautions are recommended to prevent transmission of infection in hospitals. However, their implementation is dependent on the knowledge and attitudes of healthcare workers (HCW). This study describes the knowledge, attitude and practice (KAP) of standard precautions of infection control among HCW of two tertiary hospitals in Nigeria is described. A cross-sectional study was undertaken in 2011/2012 among HCW in two tertiary hospitals in Nigeria. Data was collected via a structured self-administered questionnaire assessing core elements of KAP of standard precautions. Percentage KAP scores were calculated and professional differences in median percentage KAP scores were ascertained. A total of 290 HCW participated in the study (76% response rate), including 111 (38.3%) doctors, 147 (50.7%) nurses and 32 (11%) laboratory scientists. Overall median knowledge and attitude scores toward standard precautions were above 90%, but median practice score was 50.8%. The majority of the HCW had poor knowledge of injection safety and complained of inadequate resources to practise standard precautions. House officers, laboratory scientists and junior cadres of nurses had lower knowledge and compliance with standard precautions than more experienced doctors and nurses. Our results suggest generally poor compliance with standard precautions of infection control among HCW in Nigeria. Policies that foster training of HCW in standard precautions and guarantee regular provision of infection control and prevention resources in health facilities are required in Nigeria.


Identification of lncRNAs associated with the pathogenesis of ankylosing spondylitis.
Ankylosing spondylitis (AS) is a chronic autoimmune disease affecting the sacroiliac joint. To date, few studies have examined the association between long non-coding RNAs (lncRNAs) and AS pathogenesis. As such, we herein sought to characterize patterns of AS-related lncRNA expression and to evaluate the potential role played by these lncRNAs in this complex autoimmune context. We conducted a RNA-seq analysis of peripheral blood mononuclear cell (PBMC) samples isolated from five AS patients and corresponding controls. These data were then leveraged to characterize AS-related lncRNA expression patterns. We further conducted GO and KEGG enrichment analyses of the parental genes encoding these lncRNAs, and we confirmed the validity of our RNA-seq data by assessing the expression of six lncRNAs via qRT-PCR in 15 AS and control patient samples. Pearson correlation analyses were additionally employed to examine the associations between the expression levels of these six lncRNAs and patient clinical index values. We detected 56,575 total lncRNAs in AS and control patient samples during our initial RNA-seq analysis, of which 200 and 70 were found to be up- and down-regulated (FC > 2 or < 0.05; P < 0.05), respectively, in AS samples relative to controls. In qRT-PCR validation assays, we confirmed the significant upregulation of NONHSAT118801.2, ENST00000444046, and NONHSAT183847.1 and the significant downregulation of NONHSAT205110.1, NONHSAT105444.2, and NONHSAT051856.2 in AS patient samples. We further found the expression of NONHSAT118801.2 and NONHSAT183847.1 to be positively correlated with disease severity. Overall, our findings highlight several lncRNAs that are specifically expressed in PBMCs of AS patients, indicating that they may play key functions in the pathogenesis of this autoimmune disease. Specifically, we determined that NONHSAT118801.2 and NONHSAT183847.1 may influence the occurrence and development of AS.


Designs and operational characteristics of inhalation exposure equipment--a review.
The development of equipment for use in the experimental study of the effects of inhalable airborne materials has been reviewed. Reference is made to early descriptions of apparatus employed in the mid-nineteenth century up to the present conventional stainless steel and glass units. Whole body chambers, head only arrangements and face mask devices are described. Factors governing the operational characteristics of chambers when utilized in the static or dynamic mode are discussed. The question of uniformity of distribution of the airborne agent in chamber atmospheres has been examined at some length. It is concluded that unusual arrangements to improve distribution are ineffective or produce only marginal improvements. In addition, brief reference has been made to a number of special areas of investigation and to certain considerations of interest to the operator of inhalation equipment. A list of useful reviews and monographs is provided.


A temporal precedence based clustering method for gene expression microarray data.
Time-course microarray experiments can produce useful data which can help in understanding the underlying dynamics of the system. Clustering is an important stage in microarray data analysis where the data is grouped together according to certain characteristics. The majority of clustering techniques are based on distance or visual similarity measures which may not be suitable for clustering of temporal microarray data where the sequential nature of time is important. We present a Granger causality based technique to cluster temporal microarray gene expression data, which measures the interdependence between two time-series by statistically testing if one time-series can be used for forecasting the other time-series or not. A gene-association matrix is constructed by testing temporal relationships between pairs of genes using the Granger causality test. The association matrix is further analyzed using a graph-theoretic technique to detect highly connected components representing interesting biological modules. We test our approach on synthesized datasets and real biological datasets obtained for Arabidopsis thaliana. We show the effectiveness of our approach by analyzing the results using the existing biological literature. We also report interesting structural properties of the association network commonly desired in any biological system. Our experiments on synthesized and real microarray datasets show that our approach produces encouraging results. The method is simple in implementation and is statistically traceable at each step. The method can produce sets of functionally related genes which can be further used for reverse-engineering of gene circuits.


Repellency of essential oils to mosquitoes (Diptera: Culicidae).
The repellency of different concentrations (5, 10, 25, 50, 75, and 100%) and combinations of 5 essential oils (Bourbon geranium, cedarwood, clove, peppermint, and thyme) to Aedes aegypti (L.) and Anopheles albimanus Wiedemann when applied to human skin was determined in laboratory tests. Cedarwood oil failed to repel mosquitoes and only high concentrations of peppermint oil repelled Ae. aegypti. None of the oils tested prevented mosquito bite when used at the 5 or 10% concentration. Thyme and clove oils were the most effective mosquito repellents and provided 1 1/2 to 3 1/2 h of protection, depending on oil concentration. Clove oil (50%) combined with geranium oil (50%) or with thyme oil (50%) prevented biting by An. albimanus for 1 1/4 to 2 1/2 h. The potential for using essential oils as topical mosquito repellents may be limited by user acceptability; clove, thyme, and peppermint oils can be irritating to the skin, whereas both human subjects in this study judged the odor of clove and thyme oils unacceptable at concentrations > or = 25%.


Heliox enhances carbon dioxide clearance from lungs of normal rabbits during low bias flow oscillation.
To evaluate carbon dioxide clearance in normal rabbits during high-frequency oscillatory ventilation with helium-oxygen mixtures by using a low bias flow oscillation (LBFO) system designed to conserve expensive gas. A prospective, paired-controlled, interventional, in vivo animal laboratory study. Animal laboratory of a health science university. Twelve New Zealand White rabbits. Juvenile rabbits were anesthetized, paralyzed, and ventilated through a tracheostomy. LBFO was performed with a modified high-frequency oscillatory ventilation circuit that uses low bias flow (100 mL/kg) and a soda lime cartridge to clear carbon dioxide. LBFO-heliox trials were performed with 20%, 40%, 50%, 60%, and 70% helium (balanced with oxygen) for 30 mins. Each heliox trial was preceded by a paired control trial with 40% oxygen and 60% nitrogen for 30 mins. Ventilator settings in control and heliox trials were identical. During the second part of the study, four rabbits were made hypercapnic by decreasing the power (amplitude), and LBFO was performed with 70% helium against paired-control trials of 40% oxygen and 60% nitrogen. Arterial blood gases were measured at 15-min intervals and airway pressure amplitude was recorded. PaCO2 of control and heliox trials, alveolar PO2-PaO2 gradient of control, and 60% helium trials were compared by paired Student's t-test. At constant power, amplitude was unaffected by helium. Helium concentrations of 40%, 50%, 60%, and 70% decreased PaCO2 by 12%, 33%, 36%, and 46%, respectively. Alveolar PO2-PaO2 gradient was decreased by 40% during ventilation with 60% helium. Under hypercapnic conditions, 70% helium decreased PaCO2 by 20%. Helium concentrations > or = 40% facilitate carbon dioxide clearance from lungs of normal rabbits during LBFO. This could be accomplished inexpensively with LBFO due to preservation of heliox when using this device.


Influence of the hBN Dielectric Layers on the Quantum Transport Properties of MoS2 Transistors.
The encapsulation of single-layer 2D materials within hBN has been shown to improve the mobility of these compounds. Nevertheless, the interplay between the semiconductor channel and the surrounding dielectrics is not yet fully understood, especially their electron-phonon interactions. Therefore, here, we present an ab initio study of the coupled electrons and phonon transport properties of MoS2-hBN devices. The characteristics of two transistor configurations are compared to each other: one where hBN is treated as a perfectly insulating, non-vibrating layer and one where it is included in the ab initio domain as MoS2. In both cases, a reduction of the ON-state current by about 50% is observed as compared to the quasi-ballistic limit. Despite the similarity in the current magnitude, explicitly accounting for hBN leads to additional electron-phonon interactions at frequencies corresponding to the breathing mode of the MoS2-hBN system. Moreover, the presence of an hBN layer around the 2D semiconductor affects the Joule-induced temperature distribution within the transistor.


Differential destabilization of membranes by tryptophan and phenylalanine during freezing: the roles of lipid composition and membrane fusion.
The stability of cellular membranes during dehydration can be strongly influenced by the partitioning of amphiphilic solutes from the aqueous phase into the membranes. The effects of partitioning on membrane stability depend in a complex manner on the structural properties of the amphiphiles and on membrane lipid composition. Here, we have investigated the effects of the amphiphilic aromatic amino acids Trp and Phe on membrane stability during freezing. Both amino acids were cryotoxic to isolated chloroplast thylakoid membranes and to large unilamellar liposomes, but Trp had a much stronger effect than Phe. In liposomes, both amino acids induced solute leakage and membrane fusion during freezing. The presence of the chloroplast galactolipids monogalactosyldiacylglycerol or digalactosyldiacylglycerol in egg phosphatidylcholine (EPC) membranes reduced leakage from liposomes during freezing in the presence of up to 5 mM Trp, as compared to membranes composed of pure EPC. The presence of the nonbilayer-forming lipid phosphatidylethanolamine increased leakage. Membrane fusion followed a similar trend, but was dramatically reduced when the anthracycline antibiotic daunomycin was incorporated into the membranes. Daunomycin has been shown to stabilize the bilayer phase of membranes in the presence of nonbilayer lipids and was therefore expected to reduce fusion. Surprisingly, this had only a small influence on leakage. Collectively, these data indicate that Trp and Phe induce solute leakage from liposomes during freezing by a mechanism that is largely independent of fusion events.


A proposed method for measuring change beyond symptoms.
The initial report of the Patterns of Individual Change Scales battery presented the rationale, development, and conceptualization of this measurement package. Empirical data supported the reliability and validity of the scales as measures of patient characteristics that extended beyond the symptomatic domain. This article presents more extensive reliability and validity data. Ratings on two new samples were collected, and the interrater reliability coefficients for the scales were again of appreciable magnitude. Discriminant validity was examined, as was the factor structure of the battery. The results suggested that the scales tap three distinct sources of variance. Comparisons with symptom measures and case illustrations indicated that the measurement of changes in patients' functioning beyond symptoms is necessary and viable.


Subcellular Localization of Arabidopsis Pathogenesis-Related 1 (PR1) Protein.
The Arabidopsisthaliana pathogenesis-related 1 (PR1) is an important defense protein, so far it has only been detected in extracellular space and its subcellular sorting and transport remain unexplained. Using a green fluorescent protein (GFP) tagged full length, as well as a C-terminus truncated version of PR1, we observed that when expressed ectopically in Nicotiana benthamiana leaves, PR1 co-localizes only partially with Golgi markers, and much more prominently with the late endosome (LE)/multivesicular body (MVB) FYVE marker. The C-truncated version PR1ΔC predominantly localized to the endoplasmic reticulum (ER). The same localizations were found for stable Arabidopsis transformants with expression of PR1 and PR1ΔC driven by the native promoter. We conclude that the A. thaliana PR1 (AtPR1) undergoes an unconventional secretion pathway, starting from the C-terminus-dependent sorting from the ER, and utilizing further transportation via phosphatidyl-inositol-3-phosphate (PI(3)P) positive LE/MVB-like vesicles. The homology model of the PR1 structure shows that the cluster of positively charged amino acid residues (arginines 60, 67, 137, and lysine 135) could indeed interact with negatively charged phospholipids of cellular membranes. It remains to be resolved whether Golgi and LE/MVB localization reflects an alternative sorting or trafficking succession, and what the role of lipid interactions in it will be.


Atypical parkinsonism in the Caribbean island of Guadeloupe: etiological role of the mitochondrial complex I inhibitor annonacin.
On the French West Indian island of Guadeloupe, atypical parkinsonian patients represent two-thirds of all cases of parkinsonism, which is exceptionally frequent compared to epidemiological data from European countries where atypical parkinsonism accounts for only approximately 5% of all cases. The clinical entity was a unique combination of levodopa-resistant parkinsonism, tremor, myoclonus, hallucinations, REM sleep behavior disorder and fronto-subcortical dementia. Based on the presence or the absence of supranuclear gaze palsy, two subgroups of patients were distinguished. In patients with oculomotor signs that came to autopsy, neuronal loss was found to predominate in the substantia nigra and the striatum but other brain areas were also affected, including the frontal cortex. In addition, tau-containing lesions were detected throughout the brain. Epidemiological data suggested a close association of the disease with the regular consumption of soursop, a tropical annonaceous plant. Experimental studies performed in midbrain cell cultures identified annonacin, a selective mitochondrial complex I inhibitor contained in the fruit and leaves of soursop, as a probable etiological factor. Consistent with this view, chronic administration of annonacin to rats through Alzet osmotic minipumps showed that annonacin was able to reproduce the brain lesions characteristic of the human disease.


[Classification of neurotic and psychopathic states].
On the basis of a general clinical assessment of 204 patients they were divided into 2 groups: with neurosis (80 cases) and psychopathy (124 cases). In a classification with the aid of a computer, the most informative differential signs appeared to be not the genetical, but situational and clinical: incomplete homes, neurotical and psychopathical traits in childhood and in the premorbid personality, explosive and hyposocial traits in the mental state. Treatment with tranquillizers increased the mistake in an automatical classification.


Octreotide modulates the expression of somatostatin receptor subtypes in inflamed rat jejunum induced by Cryptosporidium parvum.
Somatostatins are proteins that are involved in gastrointestinal function. However, little is known with regard to somatostatin receptor subtype (SSTR) expression changes that occur in the jejunum during low-grade inflammation and during subsequent octreotide treatment. The aim of the present study was to investigate the expression of SSTRs in the jejunums of Cryptosporidium parvum (C. parvum)-infected rats by immunohistochemisty, reverse transcription (RT) PCR and quantitative real-time RT-PCR assays. Five-day-old suckling Sprague-Dawley rats (n = 15 for each group) were orally gavaged with 105 Nouzilly isolate (NoI) oocysts. Rats then received 50 μg/kg/day of octreotide by intraperitoneal injection from day 10 to day 17 post-infection. Animals were sacrificed on days 7 and 14 post-infection for immunohistochemical analysis and on days 14, 35 and 50 for mRNA expression analysis of SSTR subtypes. Histological analysis of jejunum tissues demonstrated infection of C. parvum along the villus brush border on day 7 post-infection and infection clearance by day 14 post-infection. Real-time PCR analysis indicated that in the inflamed jejunum, a significant increase in SSTR1 and SSTR2 expression was observed on day 14 post-infection. Octreotide therapy down-regulated the expression of SSTR2 on day 37 post-infection but significantly increased expression of SSTR1, SSTR2 and SSTR3 on day 50 post-infection. The results indicate that specific SSTRs may regulate the inflammatory pathway in the rat intestinal inflammation model.


Electrophysiological response and attraction of emerald ash borer to green leaf volatiles (GLVs) emitted by host foliage.
Green leaf volatiles (GLVs) function as host attractants, pheromone synergists, or sexual kairomones for a number of coleopteran folivores. Hence, we focused on host GLVs to determine if they were attractive to adults of the emerald ash borer, Agrilus planipennis (Coleoptera: Buprestidae), which feeds on ash (Fraxinus) foliage. Eight GLVs were identified by chromatography-electroantennogram (GC) and GC-mass spectrometry in foliar headspace volatiles collected in traps containing Super-Q from white ash, Fraxinus americana, and green ash, Fraxinus pennsylvanica, trees. GLVs in the aeration extracts elicited antennal responses from both male and female adults in gas chromatography-electroantennogram detection bioassays. Male antennae were more responsive than female antennae and showed the strongest response to (Z)-3-hexenol. Six field experiments were conducted in Canada and the USA from 2004 to 2006 to evaluate the attractiveness of candidate GLVs, in various lure combinations and dosages. Field experiments demonstrated that lures containing (Z)-3-hexenol were the most effective in increasing trap catch when placed on purple traps in open areas or along the edges of woodlots containing ash. Lures with (Z)-3-hexenol were more attractive to males than females, and dosage may be a factor determining its effectiveness.


Vaccination with intestinal tract antigens does not induce protective immunity in a permissive model of filariasis.
Antigens obtained from the intestinal tract of filarial nematodes have been proposed as potential safe and effective vaccine candidates. Because they may be 'hidden' from the immune response during natural infection, yet accessible by antibodies induced by vaccination, intestinal antigens may have a low potential for eliciting allergic responses when vaccinating previously infected individuals. Despite prior promising data, vaccination with intestinal antigens has yet to be tested in a permissive model of filariasis. In this study we investigated the efficacy of vaccination with filarial intestinal antigens in the permissive Litomosoides sigmodontis BALB/c model of filariasis, and we evaluated the extent to which these antigens are recognized by the immune system during and after infection. Infected BALB/c mice developed lower IgG antibody responses to soluble intestinal antigens (GutAg) than to soluble antigens of whole worms (LsAg). Similarly, GutAg induced less proliferation and less production of IL-4 and IFNγ from splenocytes of infected mice than LsAg. In contrast to these differences, active infection resulted in equivalent levels of circulating GutAg-specific IgE and LsAg-specific IgE levels. Consistent with this, basophil activation, as assessed by flow cytometric staining of intracellular basophil IL-4 expression, was equivalent in response to GutAg and LsAg. Vaccination with GutAg adsorbed to CpG/alum induced GutAg specific IgG1 and IgG2A production, with GutAg specific IgG titers greater than 5-fold higher than those measured in previously infected animals. Despite this response to GutAg vaccination, vaccinated mice harbored similar parasite burdens 8 weeks post infection when compared to non-vaccinated controls. These studies demonstrate that soluble antigens obtained from the intestinal tracts of L. sigmodontis have some qualities of 'hidden' antigens, but they still sensitize mice to allergic reactions and fail to protect against future infection when given as a vaccine adsorbed to alum/CPG.


RP4::Mu3A-mediated in vivo cloning and transfer of a chlorobiphenyl catabolic pathway.
Chromosomal DNA fragments encoding the ability to utilize biphenyl as sole carbon source (Bph+) were mobilized by means of plasmid RP4::Mu3A from strain JB1 (tentatively identified as Burkholderia sp.) to Alcaligenes eutrophus CH34 at a frequency of 10(-3) per transferred plasmid. The mobilized DNA integrated into the recipient chromosome or was recovered as catabolic prime plasmids. Three Bph+ prime plasmids were transferred from A. eutrophus to Escherichia coli and back to A. eutrophus without modification of the phenotype. The transferred Bph+ DNA segments allowed metabolism of biphenyl, 2-, 3- and 4-chlorobiphenyl, and diphenylmethane. Genes involved in biphenyl degradation were identified on the prime plasmids by DNA-DNA hybridization and by gene cloning. Bph+ prime plasmids were transferred to Burkholderia cepacia, Pseudomonas aeruginosa, Comamonas testosteroni and A. eutrophus and the catabolic genes were expressed in those hosts. Transfer of the plasmid to the 3-chlorobenzoate-degrading bacterium Pseudomonas sp. B13 allowed the recipient to mineralize 3-chlorobiphenyl. Other catabolic prime plasmids were obtained from JB1 by selection on m-hydroxybenzoate and tyrosine as carbon sources. 16S rRNA sequence data demonstrated that the in vivo transfer of bph was achieved between bacteria belonging to two different branches of the beta-Proteobacteria.


Antibiotics Knowledge, Attitudes and Behaviours among the Population Living in Greece and Turkey.
Antimicrobial resistance is one of the largest threats to public health worldwide. As the inappropriate use of antibiotics is one of the leading causes of antibiotic resistance, it is important to have an understanding of the public's knowledge, attitudes and behaviours towards antibiotics and antimicrobial resistance. The present study investigated the knowledge, attitudes and behaviours towards antibiotics among the public living in Greece and Turkey using an online cross-sectional survey, with social media advertising (e.g., Facebook) and snowball sampling. In total, 709 individuals completed the survey (Greece n = 309, Turkey n = 400), with an average age of 34.2 (SD = 13.1) and 40.5 (SD = 14.7), respectively. In Greece, 49.4% of the participants were female, and in Turkey, this figure was 62.4%. The Greek respondents reported that obtaining antibiotics without a prescription was easier (52.6% reported "easy or very easy") than the Turkish (35.6% reported "easy or very easy") respondents did. This study reveals that Greek citizens were more educated and knowledgeable about antibiotics (58.5% of Greeks and 44.2% of Turks identified antibiotics correctly), their effects (20.9% of Greeks and 26.3% of Turks agreed with wrong statements about antibiotics) and the risks of antibiotic resistance, compared to those from Turkey. On the other hand, the Greek respondents were more prone to use leftover antibiotics or to give them to someone else later (p < 0.001). The findings of this study indicate that Greece and Turkey, both countries with high rates of antibiotic usage, exhibit distinct variations in their knowledge, attitudes, and perceptions concerning antibiotic use and antibiotic resistance. Effective countermeasures such as public campaigns should be targeted according to the population and those areas of knowledge, attitudes and behaviours in which the main shortcomings lie.


Decreased citrate improves iron availability from infant formula: application of an in vitro digestion/Caco-2 cell culture model.
We have applied an in vitro digestion/Caco-2 cell culture model to the assessment of iron availability from human milk and a generic cow's milk-based infant formula. Experiments were designed to determine the availability of iron from human milk relative to infant formula and whether known promoters of iron absorption would increase Caco-2 cell iron uptake and availability from the infant formula. In addition, we sought to determine if decreasing the citrate concentration in the infant formula would increase the iron uptake. Although approximately twice as much iron was in solution from digests of the infant formula relative to that of human milk, smaller or equal amounts of iron were taken up from the infant formula relative to the human milk digest. These results are qualitatively similar to in vivo studies. Addition of known iron uptake promoters to infant formula did not enhance Caco-2 cell iron uptake from the infant formula digest, indicating that the iron in the infant formula existed predominantly in a tightly bound unavailable form(s). Enzymatic pretreatment of the infant formula with citrate lyase and oxalacetate decarboxylase decreased the citrate concentration by 67% and resulted in a 64% increase of iron in solution, which corresponded to a 46% increase in the cell iron uptake. Iron uptake from the "low citrate" formula plus cysteine was 102% greater relative to the nontreated formula. The results indicate that too much citrate can reduce iron uptake, particularly if it is present at concentrations greater than promoters such as ascorbic acid and cysteine.


Long-term patterns of axon regeneration in the sciatic nerve and its tributaries.
The present study determines the numbers of axons that regenerate after sciatic nerve transection in the rat. The transections are done by removing either 4 mm or 8 mm of the nerve. The axons are counted in the gap and distal stump of the sciatic nerve and in 5 of its tributaries. Survival time is 9 months which we define as long-term to allow comparison with short-term data obtained after a much shorter survival. The first findings is that the numbers of axons in the gap and distal stump are different in the 2 transection paradigms. For the 4 mm paradigm, more axons than normal appear in the gap and only a fraction of these pass into the distal stump. For the 8 mm paradigm, the numbers of axons in the gap are normal and the numbers in the distal stump do not deviate far from these. Thus by changing only the length of the segment of removed nerve, one causes major differences in the numbers of axons that regenerate. Second the numbers of axons that regenerate in tributary nerves that innervate muscle have a different pattern than the numbers that regenerate into cutaneous nerves. Thus the factors control axonal numbers must be different in the 2 types of nerves. Finally, axons that regenerate into tributary nerves do not, by and large, regenerate in concert with those in the distal stump of the parent nerve. Thus the factors that control axonal numbers in the tributary nerves must be different from those that control the numbers in the distal stump of the parent nerve.


Thumbsucking and falling asleep.
A review of the studies on the etiology of habitual thumbsucking reveals either contradictory or inconclusive results. In this study carried out in Turkey, 50 thumbsuckers, 50 non-thumbsuckers, 250 school children and 312 'problem' children were investigated through interviews, questionnaires and other clinical techniques with their mothers. Among variables studied, were aspects of feeding, onset and incidence of thumbsucking, strength of the sucking drive, sex distribution, educational level and occupation of mothers, parental attitudes toward physical contact with children, mother-child relationships, and particular forms of falling asleep. It was found that thumbsucking was etiologically more related to ways of falling asleep than to other factors. An attempt was made to explain the social, psychological and physiological basis of the etiological significance of the falling asleep stage in habitual thumbsucking.


Polarization dependence of quantum-confined Stark effect in Ge/SiGe quantum well planar waveguides.
We report room-temperature quantum-confined Stark effect in Ge/SiGe multiple quantum wells (MQWs) with light propagating parallel to the plane of the Ge/SiGe MQWs for applications in integrated photonics. Planar waveguides embedded in a p-i-n diode are fabricated in order to investigate the absorption spectra at different reverse bias voltages from optical transmission measurements for both TE and TM polarizations. Polarization dependence of the absorption spectra of the Ge/SiGe MQWs is clearly observed. The planar waveguides exhibit a high extinction ratio and low insertion loss over a wide spectral range for TE polarization.


Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma.
To test a new clinical staging system in patients with metastatic cutaneous squamous cell carcinoma involving the parotid gland or lymph nodes of the neck. Retrospective analysis of clinicopathological data from patients with a minimum of 2 years' follow-up. Multidisciplinary head and neck unit in a tertiary referral center. Between 1987 and 1999, 126 patients (104 men and 22 women; median age, 69 years) were treated for metastatic cutaneous squamous cell carcinoma involving the parotid and/or neck. Locoregional recurrence and disease-specific survival. Of the 126 patients, disease involved the parotid gland in 81 patients, of whom 14 also had clinical neck disease, while 45 patients had neck involvement only. Parotid stages were as follows: P0, 45 patients; P1, 55; P2, 20; and P3, 6. Neck stages were: N0, 67 patients; N1, 31; and N2, 28. Treatment involved combined surgery and radiotherapy in 93 patients, surgery alone in 12, and radiotherapy alone in 18. Three patients received palliative treatment only. There were 47 therapeutic and 40 elective neck dissections. Pathologic evaluation demonstrated parotid involvement in 70 patients and neck involvement in 51, representing 44 therapeutic and 7 elective neck dissections. Disease involved both the parotid and neck in 19 patients. The 5-year local (parotid) control rate was 80% and this varied statistically significantly with P stage. Parotid stages 2 and 3 were independent risk factors for a decrease in local control rate using multivariate analysis. The 5-year disease-specific survival rate for the entire group was 68% and P stage significantly influenced survival: P0, 60%; P1, 81%; P2, 51%; and P3, 33% (P<.001). Pathological involvement of neck nodes did not worsen survival of patients with parotid disease. Overall multivariate analysis demonstrated that single-modality therapy, P3 stage, and presence of immunosuppression independently predicted a decrease in survival. These results confirm that the extent of metastatic disease in the parotid gland significantly influences outcome and suggests that staging the parotid separately in metastatic cutaneous squamous cell carcinoma may be useful. Further evaluation of the recommended staging changes with a larger patient cohort will be required to clarify the influence of neck node involvement.


Long-term effects of exercise and physical therapy in people with Parkinson disease.
Parkinson disease (PD) is a progressive, neurodegenerative movement disorder with symptoms reflecting various impairments and functional limitations, such as postural instability, gait disturbance, immobility and falls. In addition to pharmacological and surgical management of PD, exercise and physical therapy interventions are also being actively researched. This Review provides an overview of the effects of PD on physical activity - including muscle weakness, reduced aerobic capacity, gait impairment, balance disorders and falls. Previously published reviews have discussed only the short-term benefits of exercises and physical therapy for people with PD. However, owing to the progressive nature of PD, the present Review focuses on the long-term effects of such interventions. We also discuss exercise-induced neuroplasticity, present data on the possible risks and adverse effects of exercise training, make recommendations for clinical practice, and describe new treatment approaches. Evidence suggests that a minimum of 4 weeks of gait training or 8 weeks of balance training can have positive effects that persist for 3-12 months after treatment completion. Sustained strength training, aerobic training, tai chi or dance therapy lasting at least 12 weeks can produce long-term beneficial effects. Further studies are needed to verify disease-modifying effects of these interventions.


Canine and Feline Patients Referred Exclusively for Acupuncture and Herbs: A Two-Year Retrospective Analysis.
Acupuncture and the administration of herbal supplements are increasingly used in veterinary practice, but no retrospective studies have examined patient characteristics and treatment interventions in a population of dogs and cats presenting exclusively for such therapies. This two-year retrospective analysis of 161 referrals to an integrative medicine service at an academic teaching hospital found that dogs were more frequently treated than cats (91.9% vs. 8.1%, respectively) and that small animal patients most frequently were presented for musculoskeletal (26.7%), neurologic (16.8%), oncologic (14.9%), and dermatologic (10.6%) conditions. Cats were older than treated dogs (12.7 ± 3.7 vs. 9.5 ± 4.3 years) and more likely to be treated for oncologic complaints (odds ratio = 5.6). Patients received acupuncture (95.4%), herbal supplements (76.4%), acupuncture with percutaneous electrical nerve stimulation (electroacupuncture, 26.1%), and/or cyanocobalamin injections in acupuncture points (pharmacopuncture, 23.6%). Some differences were detected between treatment groups. This retrospective analysis provides a foundation for designing future prospective studies using acupuncture and herbs in dogs and cats.


Drosophila TRPA channel painless inhibits male-male courtship behavior through modulating olfactory sensation.
The Drosophila melanogaster TRPA family member painless, expressed in a subset of multidendritic neurons embeding in the larval epidermis, is necessary for larval nociception of noxious heat or mechanical stimuli. However, the function of painless in adult flies remains largely unknown. Here we report that mutation of painless leads to a defect in male-male courtship behavior and alteration in olfaction sensitivity in adult flies. Specific downregulation of the expression of the Painless protein in the olfactory projection neurons (PNs) of the antennal lobes (ALs) resulted in a phenotype resembling that found in painless mutant flies, whereas overexpression of Painless in PNs of painless mutant males suppressed male-male courtship behavior. The downregulation of Painless exclusively during adulthood also resulted in male-male courtship behavior. In addition, mutation of the painless gene in flies caused changes in olfaction, suggesting a role for this gene in olfactory processing. These results indicate that functions of painless in the adult central nervous system of Drosophila include modulation of olfactory processing and inhibition of male-male courtship behavior.


OncoCis: annotation of cis-regulatory mutations in cancer.
Whole genome sequencing has enabled the identification of thousands of somatic mutations within non-coding genomic regions of individual cancer samples. However, identification of mutations that potentially alter gene regulation remains a major challenge. Here we present OncoCis, a new method that enables identification of potential cis-regulatory mutations using cell type-specific genome and epigenome-wide datasets along with matching gene expression data. We demonstrate that the use of cell type-specific information and gene expression can significantly reduce the number of candidate cis-regulatory mutations compared with existing tools designed for the annotation of cis-regulatory SNPs. The OncoCis webserver is freely accessible at https://powcs.med.unsw.edu.au/OncoCis/.


Magnetic Resonance Imaging as a Major Milestone in Multiple Sclerosis Diagnosis and Treatment.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Magnetic resonance imaging (MRI) has played a unique role in the diagnosis and management of patients with MS. In recent years, there have been considerable changes in the diagnostic criteria for MS as MRI-based studies have demonstrated their power in the earlier and more accurate diagnosis of the disease. Moreover, MRI metrics have become key supportive outcome measures for evaluating the efficacy of experimental treatments in randomized controlled trials. MRI can also be used as a prognostic tool in patients with clinically isolated syndrome (CIS). Conventional MR techniques including proton density, T1/T2-weighted images, and FLAIR sequences are now accepted in standard protocols for diagnostic and treatment outcome measures in clinical trials for MS. Radiological features may show a similarity between radiologically isolated syndrome and MS. Approximately two-thirds of individuals with RIS exhibit radiological progression and one-third develop neurological symptoms during mean follow-up times of up to five years. However, a current challenge in the global application of established criteria for RIS involves the accurate classification of subjects with incidentally identified anomalies that are highly characteristic of MS, in comparison to those categorized in medical parlance as possessing "unidentified bright objects" or nonspecific T2-hyperintensities, which are commonly identified in patients with migraine headache who fulfill the spatial dissemination requirements for MS. The need for systematically acquired data for improvements in the classification of radiologically isolated syndrome (RIS) and the generation of risk algorithms are critically important, providing a basis for scientifically supported management and most importantly, minimizing the number of improperly classified subjects exposed to unnecessary medical testing, MS treatments, and psychological harm. In addition, brain atrophy is a common finding that can now be quantitatively assessed by MR volumetric measures. Further, integrated strategies that combine MRI and clinical markers in scoring systems have provided a potentially useful approach for the management of patients with MS.


In vitro measurements of precision of fit of implant-supported frameworks. A comparison between "virtual" and "physical" assessments of fit using two different techniques of measurements.
Comparisons between different techniques measuring fit of implant-supported frameworks are few. The purpose of this study was to compare data on precision of fit from two highly accurate measuring techniques and, also, to compare results using software programs for fit assessments considering both a "virtual" as well as a "physical" (i.e., more clinical) situation. Five computer numerical control-milled titanium frameworks (Procera Implant Bridge, Nobel Biocare AB, Göteborg, Sweden) were fabricated from individual model/pattern measurements, simulating a clinical situation. Measurements of fit between frameworks and models were performed by means of a coordinate measuring machine (CMM; Zeiss Prismo Vast, Carl Zeiss Industrielle Messtechnik GmbH, Oberkochen, Germany) linked to a computer and an optical, high-resolution, three-dimensional scanner (Atos 4M SO, GOM International AG, Widen, Switzerland). Collected data on distortions between frameworks and models were analyzed and compared between the two measurement techniques. A comparison between "virtual" and "physical" fit assessments was also performed, based on data from the three-dimensional scanner. When using "virtual" fit assessment programs, overall mean three-dimensional distortion between implant and framework center points in absolute figures was 37 (SD 22) and 14 µm (SD 8) for the CMM and three-dimensional scanning measurements, respectively. Corresponding mean three-dimensional distortion when using a "physical" fit assessment program in the scanner was 43 µm (SD 24) (p < 0.001). Mean horizontal (x-axis) measurements of the distance between the two terminal implants of the models and the frameworks were 33.772 and 33.834 mm for the CMM technique. Corresponding measurements for the three-dimensional scanner was 33.798 and 33.806 mm, respectively. Horizontal distances from the three-dimensional scanner were, for most measurements, greater than for the CMM measurements. Measurements of fit between frameworks and models may vary depending on what technique is used and how fit assessments regarding "virtual" or "physical" fit is approached.


Whack-a-mole strategy for multifocal ground glass opacities of the lung.
Ground glass opacity (GGO) is a good prognostic indicator for lung cancer and is useful for physicians to predict prognosis. Due to recent advances in computed tomography (CT), the chance to encounter GGO is rapidly increasing in clinical practice. Based on the studies on radiological pathological correlation, GGO represents pathological lepidic growth and consolidation on CT represents pathologically invasive components. Thus, consolidation tumor ratio 0.5 or less means pathological less invasiveness for lung cancer. Not a few studies have shown that sublobar resection is equivalent to lobectomy for radiological early lung cancers. Additionally, observation of GGO is one of the options for physicians. Indication of surgical intervention remains unclear. Physician observing GGO in practice should know the natural history of GGO to reach an optimal treatment decision. For multifocal GGO lesions clinical management is surely challenging. Whack-a-mole strategy, which means sublobar resection for radiological invasive cancer is one of the most promising strategies for such lesions.


Association of newly discovered IS elements with the dichloromethane utilization genes of methylotrophic bacteria.
Dichloromethane (DCM) dehalogenases enable facultative methylotrophic bacteria to utilize DCM as sole carbon and energy source. DCM-degrading aerobic methylotrophic bacteria expressing a type A DCM dehalogenase were previously shown to share a conserved 4.2 kb BamHI DNA fragment containing the dehalogenase structural gene, dcmA, and dcmR, the gene encoding a putative regulatory protein. Sequence analysis of a 10 kb DNA fragment including this region led to the identification of three types of insertion sequences identified as IS1354, IS1355 and IS1357, and also two ORFs, orf353 and orf192, of unknown function. Two identical copies of element IS1354 flank the conserved 4.2 kb fragment as a direct repeat. The occurrence of these newly identified IS elements was shown to be limited to DCM-utilizing methylotrophs containing a type A DCM dehalogenase. The organization of the corresponding dcm regions in 12 DCM-utilizing strains was examined by hybridization analysis using IS-specific probes. Six different groups could be defined on the basis of the occurrence, position and copy number of IS sequences. All groups shared a conserved 5.6 kb core region with dcmA, dcmR, orf353 and orf192 as well as IS1357. One group of strains including Pseudomonas sp. DM1 contained two copies of this conserved core region. The high degree of sequence conservation observed within the genomic region responsible for DCM utilization and the occurrence of clusters of insertion sequences in the vicinity of the dcm genes suggest that a transposon is involved in the horizontal transfer of the DCM-utilization character among methylotrophic bacteria.