Pre-exposure Prophylaxis Uptake, Adherence, and Persistence: A Narrative Review of Interventions in the U.S.
Since 2012, HIV pre-exposure prophylaxis (PrEP) has been available to prevent HIV transmission; yet, uptake, adherence, and persistence to PrEP have been suboptimal. This narrative review examines the latest interventions and programs to improve all 3 stages of PrEP adherence and reviews ongoing studies to promote effective PrEP use. From 2017 to 2020, a total of 20 studies analyzed different individual- and structural-level approaches to increase PrEP adherence, including behavior change interventions, technology-based interventions (e.g., short message service messages and mobile applications), and alternate delivery strategies (e.g., pharmacy-based PrEP, integration with other services, and home delivery). Most published interventions involved men who have sex with men, although 3 assessed women (2 transgender, 1 cisgender). Randomized, controlled data support 3 behavioral change interventions and 1 technology-based intervention. Alternate delivery strategies seem promising, although more robust study designs are generally needed. In addition, data on the alignment of ongoing HIV risk and PrEP persistence (i.e., prevention-effective adherence) were limited. The authors also identified 20 ongoing studies that are promoting PrEP adherence. Future work should be inclusive of all at-risk groups in the U.S., including African American and Latinx heterosexual populations and people who inject drugs. Proven and promising approaches may work well in combination and may also need to be adapted with the introduction of long-acting pre-exposure prophylaxis formulations. Collectively, this body of work indicates considerable progress toward understanding the role PrEP adherence will play in Ending the HIV Epidemic in the U.S. that will be bolstered by the outcomes of ongoing trials.


Daily Bicycling in Older Adults May be Effective to Reduce Fall Risks-A Case-Control Study.
Older adults gain many health benefits from riding bicycles regularly. We aimed to explore whether older persons who ride bicycles regularly have better balance than controls. Balance control and voluntary stepping were assessed in 20 older adults aged 65-85 years who live in an agricultural community village and who ride bicycles regularly, and 30 age- and gender-matched nonbicycle riders (NBR). Self-reported function and fear of fall were also assessed. Bicycle riders (BR) showed significantly better balance, faster voluntary stepping, and better self-reported advanced lower-extremity function compared with NBR. The results might suggest that bicycling regularly preserves balance control and speed of voluntary stepping in older adults because bicycling might maintain specific balance coordination patterns. The results should be treated with caution as bicycle riders were older adults who selected an active lifestyle (i.e., bicycling as well as living in an agricultural village) that may bias the results.


Induction of tyrosine 3-monooxygenase in adrenal medulla: role of protein kinase activation and translocation.
The transsynaptic induction of tyrosine 3-monooxygenase (TH) in rat adrenal medulla is preceded by an early increase in the ratio of cyclic adenosine monophosphate (AMP) to cyclic guanosine monophosphate, an activation of cytosol cyclic AMP-dependent protein kinase, and a subsequent translocation of protein kinase catalytic subunits from cytosol to subcellular particles. As a result of this translocation, nuclear protein kinase activity increases during the induction of TH. Transection of splanchnic nerve reverts these events and prevents the induction of TH. Thus, adrenal medulla activation and translocation of cyclic AMP-dependent protein kinase may act as a long-range messenger for the genetic regulation of TH synthesis.


A Network-Based Bioinformatics Approach to Identify Molecular Biomarkers for Type 2 Diabetes that Are Linked to the Progression of Neurological Diseases.
Neurological diseases (NDs) are progressive disorders, the progression of which can be significantly affected by a range of common diseases that present as comorbidities. Clinical studies, including epidemiological and neuropathological analyses, indicate that patients with type 2 diabetes (T2D) have worse progression of NDs, suggesting pathogenic links between NDs and T2D. However, finding causal or predisposing factors that link T2D and NDs remains challenging. To address these problems, we developed a high-throughput network-based quantitative pipeline using agnostic approaches to identify genes expressed abnormally in both T2D and NDs, to identify some of the shared molecular pathways that may underpin T2D and ND interaction. We employed gene expression transcriptomic datasets from control and disease-affected individuals and identified differentially expressed genes (DEGs) in tissues of patients with T2D and ND when compared to unaffected control individuals. One hundred and ninety seven DEGs (99 up-regulated and 98 down-regulated in affected individuals) that were common to both the T2D and the ND datasets were identified. Functional annotation of these identified DEGs revealed the involvement of significant cell signaling associated molecular pathways. The overlapping DEGs (i.e., seen in both T2D and ND datasets) were then used to extract the most significant GO terms. We performed validation of these results with gold benchmark databases and literature searching, which identified which genes and pathways had been previously linked to NDs or T2D and which are novel. Hub proteins in the pathways were identified (including DNM2, DNM1, MYH14, PACSIN2, TFRC, PDE4D, ENTPD1, PLK4, CDC20B, and CDC14A) using protein-protein interaction analysis which have not previously been described as playing a role in these diseases. To reveal the transcriptional and post-transcriptional regulators of the DEGs we used transcription factor (TF) interactions analysis and DEG-microRNAs (miRNAs) interaction analysis, respectively. We thus identified the following TFs as important in driving expression of our T2D/ND common genes: FOXC1, GATA2, FOXL1, YY1, E2F1, NFIC, NFYA, USF2, HINFP, MEF2A, SRF, NFKB1, USF2, HINFP, MEF2A, SRF, NFKB1, PDE4D, CREB1, SP1, HOXA5, SREBF1, TFAP2A, STAT3, POU2F2, TP53, PPARG, and JUN. MicroRNAs that affect expression of these genes include mir-335-5p, mir-16-5p, mir-93-5p, mir-17-5p, mir-124-3p. Thus, our transcriptomic data analysis identifies novel potential links between NDs and T2D pathologies that may underlie comorbidity interactions, links that may include potential targets for therapeutic intervention. In sum, our neighborhood-based benchmarking and multilayer network topology methods identified novel putative biomarkers that indicate how type 2 diabetes (T2D) and these neurological diseases interact and pathways that, in the future, may be targeted for treatment.


Parathyroid hormone-related protein in patients with primary breast cancer and eucalcemia.
Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in breast cancer and other malignancies. We studied circulating PTHrP levels with three different immunoassays directed against different parts of the PTHrP molecule in 48 patients with breast cancer and eucalcemia. The methods used were: (a) a RIA with antibodies directed toward the midregion (63-78); (b) an immunofluorometric assay with two antibodies against 1-34 and 38-67; and (c) an immunoradiometric assay with antibodies against 1-40 and 1-72. Although most patients had PTHrP levels indistinguishable from normal when measured by all three methods, four patients had increased serum levels in the IFMA. PTHrP was detected by immunohistochemistry in tumors from nearly all patients. One patient with elevated PTHrP in plasma measured by IFMA showed intense staining of tumor by immunohistochemistry; the tumor was histologically graded as III (severe) and was the largest of all tumors in this patient group. The IFMA can identify increased serum PTHrP in some patients with breast cancer who are not hypercalcemic. This assay may be especially useful in screening patients for this tumor during a relative early phase of the disease.


Apoptotic and proliferative indexes in esophageal cancer: Predictors of response to neoadjuvant therapy apoptosis and proliferation in esophageal cancer.
Altered expression of the genes that control apoptosis and proliferation may influence the response of cancer cells to cytotoxic agents. The primary aim of this study was to determine the role of the novel an-tiapoptotic and cell cycle gene, survivin, in apoptotsis and proliferation in esophageal cancer and to evaluate whether the survivin, p53, and bcl-2 status were able to predict a patient's response to neoadjuvant therapy. A total of 104 patients with esophageal tumors were studied. Tumor tissue was immunostained for survivin, p53, and bcl-2 proteins. Proliferative and apoptotic activity was measured using ki-67 immu-nohistochemical analysis and the TUNEL method, respectively. Forty-eight patients whose pretreat-ment biopsies were analyzed received neoadjuvant chemoradiation therapy or chemotherapy followed by surgery. Outcome was graded as a complete response, a partial response, or no response according to the results of histologic examination and CT imaging. Expression of survivin was found to correlate significantly with the proliferative index but not the apoptotic index. Patients who received neoadjuvant treatment were more likely to achieve a complete response if their tumors had high proliferative activity, and p53 positive tumors were more likely to contain residual tumor after treatment. In conclusion, survivin expression appears to foster proliferative activity in esophageal cancer, and tumors with a high proliferative index or a functioning p53 gene are more responsive to neoadjuvant chemoradiation therapy.


Alignment and mapping methodology influence transcript abundance estimation.
The accuracy of transcript quantification using RNA-seq data depends on many factors, such as the choice of alignment or mapping method and the quantification model being adopted. While the choice of quantification model has been shown to be important, considerably less attention has been given to comparing the effect of various read alignment approaches on quantification accuracy. We investigate the influence of mapping and alignment on the accuracy of transcript quantification in both simulated and experimental data, as well as the effect on subsequent differential expression analysis. We observe that, even when the quantification model itself is held fixed, the effect of choosing a different alignment methodology, or aligning reads using different parameters, on quantification estimates can sometimes be large and can affect downstream differential expression analyses as well. These effects can go unnoticed when assessment is focused too heavily on simulated data, where the alignment task is often simpler than in experimentally acquired samples. We also introduce a new alignment methodology, called selective alignment, to overcome the shortcomings of lightweight approaches without incurring the computational cost of traditional alignment. We observe that, on experimental datasets, the performance of lightweight mapping and alignment-based approaches varies significantly, and highlight some of the underlying factors. We show this variation both in terms of quantification and downstream differential expression analysis. In all comparisons, we also show the improved performance of our proposed selective alignment method and suggest best practices for performing RNA-seq quantification.


Steady-state hydrodynamic instabilities of active liquid crystals: hybrid lattice Boltzmann simulations.
We report hybrid lattice Boltzmann (HLB) simulations of the hydrodynamics of an active nematic liquid crystal sandwiched between confining walls with various anchoring conditions. We confirm the existence of a transition between a passive phase and an active phase, in which there is spontaneous flow in the steady state. This transition is attained for sufficiently "extensile" rods, in the case of flow-aligning liquid crystals, and for sufficiently "contractile" ones for flow-tumbling materials. In a quasi-one-dimensional geometry, deep in the active phase of flow-aligning materials, our simulations give evidence of hysteresis and history-dependent steady states, as well as of spontaneous banded flow. Flow-tumbling materials, in contrast, rearrange themselves so that only the two boundary layers flow in steady state. Two-dimensional simulations, with periodic boundary conditions, show additional instabilities, with the spontaneous flow appearing as patterns made up of "convection rolls." These results demonstrate a remarkable richness (including dependence on anchoring conditions) in the steady-state phase behavior of active materials, even in the absence of external forcing; they have no counterpart for passive nematics. Our HLB methodology, which combines lattice Boltzmann for momentum transport with a finite difference scheme for the order parameter dynamics, offers a robust and efficient method for probing the complex hydrodynamic behavior of active nematics.


Incidence of tardive dyskinesia and tardive dystonia in African Caribbean patients on long-term antipsychotic treatment: the Curaçao extrapyramidal syndromes study V.
Tardive dyskinesia (TD) and tardive dystonia (TDt) syndromes represent severe side effects of first-generation antipsychotics (FGAs). Although second-generation antipsychotics (SGAs) confer a lower risk for tardive syndromes, many patients continue to use FGAs alone or in combination with SGAs. Some patients remain free of TD or TDt even after many years of antipsychotic treatment with predominantly FGAs. Do these patients remain at risk for TD or TDt and, consequently, should a switch to SGAs be considered? A longitudinal cohort study in patients on long-term antipsychotic treatment may answer this question. A 9-year cohort study (1992-2001) was conducted of the whole, mostly chronic, psychiatric inpatient population on the Caribbean island of Curaçao (N = 194). Almost all patients (95%) were of African Carribean origin. TD and TDt were assessed (1 baseline, 6 follow-ups) with the Abnormal Involuntary Movement Scale and the Fahn-Marsden rating scale, respectively. New cases of TD or TDt were diagnosed if they fulfilled the criteria at 2 successive follow-up visits. In patients with a mean antipsychotic use of approximately 18 years, the yearly incidence rates of TD and TDt were 10.2% (95% CI = 7.7 to 13.5) and 0.7% (95% CI = 0.4 to 1.5), respectively. The severity of TD was strongly associated with the severity of TDt (beta = 0.08, 95% CI = 0.03 to 0.14) and vice versa (beta = 0.10, 95% CI = 0.03 to 0.16). TD severity was positively associated with age and akathisia but negatively associated with parkinsonism. Patients who are free of TD after many years of antipsychotic treatment still have a considerable risk for TD. Switching to an SGA may be warranted. The risk for incident TDt in this group was very low.


A high-magnetic-field-induced density-wave state in graphite.
Whilst the realization of graphene, probably one of the best two-dimensional carrier systems to study, has attracted much research interest recently, graphite, which may be regarded as multi-layered graphene, has also been known to exhibit very interesting phenomena at high magnetic fields and low temperatures. The electron-hole system in the compensated semimetal graphite undergoes a magnetic-field-induced electronic phase transition and successive transitions, including a reentrant transition back to the normal phase, at higher magnetic fields. In this article, we review the physics of the high-magnetic-field phase of graphite and elaborate on our studies on this subject using pulsed high magnetic fields.


Isolation and characterization of an iridoid, Arbortristoside-C from Nyctanthes arbor-tristis Linn., a potential drug candidate for diabetes targeting α-glucosidase.
Many parts of the plant Nyctanthes arbor-tristis Linn. are widely investigated for their biological properties. Purified Arbortristosides from seeds are reported as anticancer, anti-leishmania, anti-inflammatory, anti-allergic, immunomodulatory and antiviral. The present study elaborates on the isolation, structural and functional characterization of Arbortristoside-C and its inhibition properties against alpha-glucosidase, an important target for diabetes mellitus. Arbortristoside-C is purified from seeds of N. arbor-tristis by extraction using polar fractionation and chromatographic techniques. Arbortristoside-C has been characterized using Ultra Violet (UV), Mass (MS), Infra-Red (IR) and Nuclear Magnetic Resonance (NMR). Inhibition kinetics and Isothermal Titration Calorimetry (ITC) were used for activity and binding characteristics of acarbose and Arbortristoside-C using in-house purified α-glucosidase from Bos taurus. Modeling, docking and structural comparison with acarbose bound structure revealing the similar binding characteristics of Arbortristoside-C which include interaction with catalytic acid/base Aspartic acid residue. Cytotoxicity assay revealed that 100 µg/ml is the maximum toxic-free concentration of Arbortristoside-C. The purified Arbortristoside-C showed inhibition against mammalian α-glucosidase, suggesting its potential to treat Diabetes mellitus.


The performance of SolarScan: an automated dermoscopy image analysis instrument for the diagnosis of primary melanoma.
To describe the diagnostic performance of SolarScan (Polartechnics Ltd, Sydney, Australia), an automated instrument for the diagnosis of primary melanoma. Images from a data set of 2430 lesions (382 were melanomas; median Breslow thickness, 0.36 mm) were divided into a training set and an independent test set at a ratio of approximately 2:1. A diagnostic algorithm (absolute diagnosis of melanoma vs benign lesion and estimated probability of melanoma) was developed and its performance described on the test set. High-quality clinical and dermoscopy images with a detailed patient history for 78 lesions (13 of which were melanomas) from the test set were given to various clinicians to compare their diagnostic accuracy with that of SolarScan. Seven specialist referral centers and 2 general practice skin cancer clinics from 3 continents. Comparison between clinician diagnosis and SolarScan diagnosis was by 3 dermoscopy experts, 4 dermatologists, 3 trainee dermatologists, and 3 general practitioners. Images of the melanocytic lesions were obtained from patients who required either excision or digital monitoring to exclude malignancy. Sensitivity, specificity, the area under the receiver operator characteristic curve, median probability for the diagnosis of melanoma, a direct comparison of SolarScan with diagnoses performed by humans, and interinstrument and intrainstrument reproducibility. The melanocytic-only diagnostic model was highly reproducible in the test set and gave a sensitivity of 91% (95% confidence interval [CI], 86%-96%) and specificity of 68% (95% CI, 64%-72%) for melanoma. SolarScan had comparable or superior sensitivity and specificity (85% vs 65%) compared with those of experts (90% vs 59%), dermatologists (81% vs 60%), trainees (85% vs 36%; P =.06), and general practitioners (62% vs 63%). The intraclass correlation coefficient of intrainstrument repeatability was 0.86 (95% CI, 0.83-0.88), indicating an excellent repeatability. There was no significant interinstrument variation (P = .80). SolarScan is a robust diagnostic instrument for pigmented or partially pigmented melanocytic lesions of the skin. Preliminary data suggest that its performance is comparable or superior to that of a range of clinician groups. However, these findings should be confirmed in a formal clinical trial.


Are there differences in factors influencing access and continued use of assistive products for people with intellectual disabilities living in group homes?
Background: The World Health Organization has launched a program to promote Global Cooperation on Assistive Technology (GATE) to implement those parts of the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) referring to assistive technology and products. A particular vulnerable group deeply affected by health inequity affecting access to assistive products are people with intellectual disabilities.Objective: The objective of this study is to understand the barriers and facilitators to effectively access and continuously use essential assistive products for people with intellectual disabilities.Materials and methods: Face-to-face interviews with 15 adults with a mild to profound intellectual disability and 15 providers of assistive products were conducted to gain insights about current use, needs, knowledge, awareness, access, customization, funding, follow-up, social inclusion, stigma and policies around assistive products and intellectual disability. The technique of constant comparative analysis was used to analyze the data.Results and conclusion: An overview of factors is presented that fit within seven domains for access and eight domains for continuous use of assistive products for people with intellectual disabilities. It illustrates that access and continuous use are influenced by different barriers and facilitators. These different influences should be taken into account in country policies and frameworks that seek to implement the UNCRPD through assistive technology.Implications for rehabilitationProactive assessment for assistive products by health professionals is rare and the vast majority of people with intellectual disabilities depend on carers to signal the need .A lack of education for carers around available assistive products and the benefits of assistive products for people with intellectual disabilities may lead to an underutilization for this group.The paternalistic attitude of care providers towards people with intellectual disabilities limits access and use to certain (high-tech) assistive products.The segmented and disjointed aspect of public funding to support assistive products found in this study is a key issue for policymakers who aspire to adhere to implementing the UNCRPD equally in all areas of their country.


Questing Dermacentor reticulatus harbouring Babesia canis DNA associated with outbreaks of canine babesiosis in the Swiss Midlands.
In 2011 and 2012, outbreaks of clinical canine babesiosis were observed in 2 areas of the Swiss Midlands that had no history of this disease so far. In one area, cases of canine babesiosis occurred over 2 consecutive tick seasons. The outbreaks involved 29 dogs, 4 of which died. All dogs were infected with large Babesia sp. as diagnosed in Giemsa-stained blood smears and/or PCR. These were identified as B. canis (formerly known as B. canis canis) by subsequent partial sequencing of the 18S rRNA gene of Babesia sp. Interestingly, the sequence indicated either a genotype with heterogeneity in the ssrRNA gene copies or double infection with different B. canis isolates. None of the dogs had a recent travel history, but one had frequently travelled to Hungary and had suffered twice from clinical babesiosis 18 and 24 months prior to the outbreak in autumn 2011. Retrospective sequencing of a stored blood DNA sample of this dog revealed B. canis, with an identical sequence to the Babesia involved in the outbreaks. For the first time in Switzerland, the partial 18S rRNA gene of B. canis could be amplified from DNA isolated from 19 out of 23 adult Dermacentor reticulatus ticks flagged in the same area. The sequence was identical to that found in the dogs. Furthermore, one affected dog carried a female D. reticulatus tick harbouring B. canis DNA. Our findings illustrate that, under favourable biogeographic and climatic conditions, the life-cycle of B. canis can relatively rapidly establish itself in previously non-endemic areas. Canine babesiosis should therefore always be a differential diagnosis when dogs with typical clinical signs are presented, regardless of known endemic areas.


Regulation of renin release and renal hemodynamics during acute and chronic verapamil administration.
The effects of short- and long-term administration of the calcium-entry blocker verapamil on regulation of renal hemodynamics and renin release were analyzed in anesthetized dogs at controlled levels of renal perfusion pressure between 110 and 60 mmHg. The following three groups of dogs were studied: a control group, an acutely treated verapamil group (initial dose of 150 micrograms/kg followed by 4 micrograms.kg-1.min-1), and a chronically treated verapamil group (240 mg per os twice each day). At 110 mmHg the renal blood flow (RBF) in the acutely and chronically treated groups was 53% greater than (P less than 0.03) and 79% greater than (P less than 0.01) that of the control group. Glomerular filtration rate (GFR) in the acutely and chronically treated groups was 64 and 92%, respectively, greater than (P less than 0.01 for both) that of the control group. Autoregulation of RBF and GFR was extremely effective in the control group, whereas it was severely impaired by acute and long-term treatment with verapamil. Renin release at 110 mmHg in the control and the acutely treated groups were similar, 3.36 +/- 0.96 and 4.46 +/- 0.64 U.min-1.g-1, respectively, although in the chronically treated group the rate of release was 8.89 +/- 2.60 U.min-1.g-1 (P less than 0.03). As perfusion pressure was reduced, the rate of release from the acutely treated group rose to higher levels than that of the control group; at 70 mmHg release from the acutely treated group was 88% greater than that of the control group (P less than 0.01). Verapamil profoundly alters regulation of renal hemodynamics and renin release and the effect is prominent during both short- and long-term administration.


First Detection of West Nile Virus Lineage 2 in Mosquitoes in Switzerland, 2022.
West Nile virus (WNV) is one of the most widespread flaviviruses in the world, and in recent years, it has been frequently present in many Mediterranean and Eastern European countries. A combination of different conditions, such as a favourable climate and higher seasonal average temperatures, probably allowed its introduction and spread to new territories. In Switzerland, autochthonous cases of WNV have never been reported, and the virus was not detected in mosquito vectors until 2022, despite an entomological surveillance in place in Canton Ticino, southern Switzerland, since 2010. In 2022, 12 sites were monitored from July to October, using BOX gravid mosquito traps coupled with honey-baited FTA cards. For the first time, we could detect the presence of WNV in FTA cards and mosquitoes in 8 out of the 12 sampling sites monitored, indicating an unexpectedly widespread circulation of the virus throughout the territory. Positive findings were recorded from the beginning of August until mid-October 2022, and whole genome sequencing analysis identified a lineage 2 virus closely related to strains circulating in Northern Italy. The entomological surveillance has proved useful in identifying viral circulation in advance of possible cases of WNV infection in humans or horses.


Palatal morphology predicts the paleobiology of early salamanders.
Ecological preferences and life history strategies have enormous impacts on the evolution and phenotypic diversity of salamanders, but the yet established reliable ecological indicators from bony skeletons hinder investigations into the paleobiology of early salamanders. Here, we statistically demonstrate by using time-calibrated cladograms and geometric morphometric analysis on 71 specimens in 36 species, that both the shape of the palate and many non-shape covariates particularly associated with vomerine teeth are ecologically informative in early stem- and basal crown-group salamanders. Disparity patterns within the morphospace of the palate in ecological preferences, life history strategies, and taxonomic affiliations were analyzed in detail, and evolutionary rates and ancestral states of the palate were reconstructed. Our results show that the palate is heavily impacted by convergence constrained by feeding mechanisms and also exhibits clear stepwise evolutionary patterns with alternative phenotypic configurations to cope with similar functional demand. Salamanders are diversified ecologically before the Middle Jurassic and achieved all their present ecological preferences in the Early Cretaceous. Our results reveal that the last common ancestor of all salamanders share with other modern amphibians a unified biphasic ecological preference, and metamorphosis is significant in the expansion of ecomorphospace of the palate in early salamanders.


Hospitalized lithium overdose cases reported to the California Poison Control System.
Lithium overdose primarily results in neurologic toxicity; however, cardiac effects have also been reported. Our aim was to describe a large cohort of hospitalized lithium overdose patients. Specifically we were interested in reported cardiac complications, frequency of hemodialysis (HD), and mortality. This is a retrospective, observational case series of admitted isolated lithium exposure cases reported to the California Poison Control System (CPCS) from 2003 through 2007. Reported lithium exposure cases were identified by a search of our CPCS database. Only those cases resulting in hospital admission were included in this study. Cases with concomitant toxic exposures were excluded. Primary outcome variables were reported cardiac complications (defined as bradycardia with a heart rate < or =50 bpm, atrioventricular (AV) block, ventricular tachycardia, and ventricular fibrillation), administration of cardiovascular intervention (resuscitation, vasopressor medications, or cardiac pacing), and death. In the 5-year-study period 629 lithium cases were reported to the CPCS and 502 hospitalized cases were included in this study. There were 44 [8.8%; 95% confidence intervals (CI) 6.3, 11.2] cases of acute lithium exposure, 124 (24.7%; 95% CI 20.9, 28.5) cases of acute on chronic (AC) overdose, and 282 (56.2%; 95% CI 51.8, 60.5) cases of chronic overdose. Sixty-nine patients received hemodialysis. This includes 6 (13.6%) acute, 12 (9.7%) AC, and 45 (16.0%) chronic cases. There were four deaths (0.8%, 95% CI 0.2, 1.6). Cardiac complications were reported in 29 cases (5.7%, 95% CI 3.7, 7.7%) with 18 of these cases (18/29; 62%) being isolated bradycardias (without hypotension). Only seven patients with reported cardiac complication (7/29; 24.1%; 95% CI = 8.6, 39.7) required cardiovascular intervention and all of these were cases of chronic lithium toxicity. Two bradycardic arrests occurred in chronic lithium exposure cases, including one who died. In this cohort of hospitalized lithium exposure patients, death was rare. Reported cardiac complications were unusual with instances requiring cardiovascular intervention occurring only in cases of chronic lithium overdose. The majority of lithium toxicity cases were managed without HD.


Assessment of sediment toxicity in the Lagoon of Venice (Italy) using a multi-species set of bioassays.
Within the framework of a Weight of Evidence (WoE) approach, a set of four toxicity bioassays involving the amphipod Corophium volutator (10 d lethality test on whole sediment), the sea urchin Paracentrotus lividus (fertilization and embryo toxicity tests on elutriate) and the pacific oyster Crassostrea gigas (embryo toxicity test on elutriate) was applied to sediments from 10 sampling sites of the Venice Lagoon (Italy). Sediments were collected during three campaigns carried out in May 2004 (spring campaign), October 2004 (autumn campaign) and February 2005 (winter campaign). Toxicity tests were performed on all sediment samples. Sediment grain-size and chemistry were measured during spring and autumn campaigns. This research investigated (i) the ability of toxicity tests in discriminating among sites with different contamination level, (ii) the occurrence of a gradient of effect among sampling sites, (iii) the possible correlation among toxicity tests, sediment chemistry, grain size and organic carbon, and (iv) the possible occurrence of toxicity seasonal variability. Sediment contamination levels were from low to moderate. No acute toxicity toward amphipods was observed, while sea urchin fertilization was affected only in few sites in just a single campaign. Short-term effects on larval development of sea urchin and oyster evidenced a clear spatial trend among sites, with increasing effects along the axis connecting the sea-inlets with the industrial area. The set of bioassays allowed the identification of a spatial gradient of effect, with decreasing toxicity from the industrial area toward the sea-inlets. Multivariate data analysis showed that the malformations of oyster embryos were significantly correlated to the industrial contamination (metals, polynuclear aromatic hydrocarbons, hexachlorobenzene and polychlorinated biphenyls), while sea urchin development to sediment concentrations of As, Cr and organic carbon. Both embryo toxicity tests were significantly affected by high ammonia concentrations found in the elutriates extracted from some mudflat and industrial sediments. No significant temporal variation of the toxicity was observed within the experimental period. Amendments to the set of bioassays, with inclusion of chronic tests, can certainly provide more reliability and consistency to the characterization of the (possible) toxic effects.


Mechanisms of reproductive suppression in female pine voles (Microtus pinetorum).
In co-operatively breeding birds and mammals, philopatric females are often reproductively suppressed. Many studies have focused on the functional significance of reproductive suppression, but further investigation of the mechanisms involved is required for a complete understanding of this process. This study investigated whether reproductive suppression in non-reproductive female pine voles (Microtus pinetorum) occurs as a result of lack of gamete maturation or lack of increase in LH. The behaviour of male pine voles was also examined to determine whether they show a preference for the mother versus her daughter, as lack of male stimulation may inhibit an increase of LH in daughter pine voles. Ovarian development and circulating LH concentrations were investigated in females housed with a prospective mate in the presence or absence of a parent. Maturation of gametes was not affected by the presence of a parent. In the presence of the mother, there was no increase in LH, as was observed in females housed with or exposed to a novel male. Males spent more time with mothers and possibly showed a preference for mating with the mother. These results are consistent with the contention that ovulation does not occur in female pine voles housed in the presence of their mother; however, it is not clear whether the lack of ovulation is caused by lack of stimulation from the male or suppression by the mother.


[Inhibition of enteropathogens by Clostridium butyricum MIYAIRI 588].
The inhibitory effect of Clostridium butyricum MIYAIRI 588 against various enteropathogens was investigated in mixed cultures. It was observed that C. butyricum M588 inhibited the growth of Vibrio cholerae O1, V. cholerae non-O1, Aeromonas hydrophila, and Shigella flexneri. Considering that the interaction between C. butyricum and Shigella is especially important because of their proliferation site in the lower intestine, further examinations were carried out on Shigella in particular. Results were as follows: 1) In BHI broth culture of Shigella, the pH of culture fluid went down to 5.2, but the growth of Shigella was not inhibited. 2) In the mixed culture of Shigella and C. butyricum, the growth of Shigella was inhibited, nevertheless the pH of the culture fluid was 5.6. 3) In the mixed culture with phosphate buffered BHI maintaining the pH higher than 6.0, the growth of Shigella was inhibited. 4) In case of pure culture of C. butyricum in BHI broth, the pH of culture fluid indicated 5.5, and Shigella failed to grow in the cell free culture supernatant. 5) The growth of Shigella was not inhibited in the culture supernatant when the pH was adjusted at 7.2. These results suggested that the inhibition of Shigella in the mixed culture with C. butyricum was not due to a single factor such as pH or fatty acid etc. but due to multifactors including live cells of C. butyricum.


Allergic Dermatitis After Total Knee Arthroplasty Using the Prineo Wound-Closure Device: A Report of Three Cases.
Three patients who underwent uncomplicated total knee arthroplasty with use of the Prineo (Ethicon) wound-closure system had development of allergic contact dermatitis. All patients were started on Keflex (cephalexin), and two were started on topical corticosteroid. In all patients, the reaction resolved within weeks. To our knowledge, the present report describes the first case series of patients in whom allergic contact dermatitis developed in association with the use of the Prineo wound-closure system during orthopaedic procedures. The presentation can range from blistering to erythematous papules and vesicles to crusted plaques that resolve with Keflex and topical corticosteroid cream.


Variable promoter region CpG island methylation of the putative tumor suppressor gene Connexin 26 in breast cancer.
Intercellular communication via gap junctions is a mechanism for tumor suppression. Connexin 26 (Cx26) is a structural component of gap junctions expressed by breast epithelial cells. Expression levels of Cx26 are reduced in many breast tumors. Methylation-sensitive single-stranded conformation analysis showed variable methylation in the promoter region CpG island in 11 out of 20 (55%) breast cancer patients. Heterogeneity in methylation patterns was observed both between and within tumors. The degree of methylation ranged from a few CpG dinucleotides to almost all the CpG dinucleotides in the analyzed region. The most frequently methylated CpG was in an Sp1 site known to be important for Cx26 gene expression. One of eight breast cancer cell lines (MD-MBA-453) was methylated in the promoter region and did not express Cx26. Treatment of MDA-MB-453 with 5-aza-2'-deoxycytidine resulted in the re-expression of Cx26 mRNA. Methylation of the promoter region is likely to be an important mechanism in modulating the expression of Cx26 in breast cancer.


Oxytocin/alpha(2)-Adrenoceptor interactions in feeding responses.
The modulation of alpha(2)-adrenoceptor-induced food intake by oxytocin has been evaluated in studies on food intake and by quantitative receptor autoradiography in the hypothalamus and the amygdala of the rat. The effects of lateral intracerebroventricular administration of clonidine and oxytocin were evaluated on food intake in satiated animals. Food consumption was measured at 30, 90, 240 min and 22 h (1,320 min) after injection. The coinjection of oxytocin and clonidine was found to counteract the increase in food intake produced by clonidine (p < 0.001) in satiated rats. Receptor autoradiographic experiments showed that oxytocin significantly increased the K(d) values of [(3)H]p-aminoclonidine alpha(2)-agonist-binding sites in the hypothalamus. Effective oxytocin concentrations ranged between 0.3 and 1 nM (p < 0.05) with a maximal action of 250% at 1 nM. The B(max) value was significantly increased (p < 0.05) for all concentrations of oxytocin. In the amygdala, oxytocin also increased both the K(d) of [(3)H]p-aminoclonidine-binding sites by about 190% at 1 nM and the B(max) values at 1 and 3 nM (p < 0.05). Oxytocin (1 nM) also significantly and substantially (p < 0.01) increased the K(d) and B(max) values of the [(3)H]UK 14.304 alpha(2)-agonist-binding sites in the hypothalamus and amygdala in agreement with the results obtained with the other agonist of the alpha(2)-adrenoceptor [(3)H]p-aminoclonidine. This effect was partially blocked by the presence of the specific oxytocin receptor antagonist, CAP. These findings suggest the existence of an antagonistic oxytocin/alpha(2)-receptor interaction in the hypothalamus and amygdala that may be of relevance for the demonstrated modulation of alpha(2)-adrenoceptor-induced feeding responses by oxytocin.


Sin3a Associated Protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.
Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa ( Sap130 ), a protein in the chromatin modifying SIN3A/HDAC1 complex, as a gene contributing to the digenic etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cell communication were dysregulated in sap130a , but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a , in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.


[IDENTIFICATION OF LEPTOSPIRA SEROVARS BY MALDI-TOF MASS-SPEC- TROMETRY].
An attempt to use MALDI-TOF mass-spectrometry method for identification of lep- tospiral isolates on the serovar level. 8 reference Leptospira spp. and 11 leptospira strains isolated from leptospiral patients and infected animals in the North-Western region of Russia were included into the study. Mass-spectra of all the studied strains were obtained by direct profiling of cell extracts. The created main spectral profiles (MSP) of reference strains were used for identification of isolates. Evaluation of identification was carried out by calculating coefficients of matching rate of separate spectra of each isolate with MSP of all the reference strains. Results of identification have shown the similarity of spectra of isolates belonging to Pomona, Icterohaemorrhagiae and Canicola serogroups, with MSP of saprophyte strain L. biflexa Patoc I. It is assumed that spectra of the studied strains contained peaks of polysaccha- ride Ο-antigens. Wherein maximum mean values of matching rate coefficients between spectra of isolates and MSP of pathogenic reference strains of leptospira correctly matched serovar type of the isolate. Further extended studies may form the base of development of a simple and rapid method oftyping of leptospirosis causative agents on the level of serovars using MALDITOF mass-spectrometry.


Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial.
Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures. The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant-Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group's 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI -7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded. This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial. ClinicalTrials.gov NCT01246167.


Severity and susceptibility: measuring the perceived effectiveness and believability of tobacco health warnings.
Pictorial tobacco health warning labels (HWLs) have been shown to be more effective than text-only HWLs in changing smoking attitudes and intentions. However, there is contradictory evidence regarding how the severity of the content of HWLs influences responses to them. We examined the perceived believability and effectiveness of HWLs in an online study using a convenience sample of non-smokers (N = 437) and smokers (N = 436). HWLs were in one of three presentation formats: (text-only, a moderately severe image or highly severe image) and focussed on three disease outcomes (lung cancer, blindness or tooth and gum disease). Participants rated the effectiveness and believability of each HWL and also rated their perceived susceptibility to each disease. A 2 (smoking status) × 3 (presentation format) × 3 (disease outcome) ANOVA was run for both believability and effectiveness ratings. The most severe pictorial HWLs received the highest believability and effectiveness ratings and as expected, the text-only HWLs received the lowest. Lung cancer HWLs were rated most believable and effective, with the blindness HWLs receiving the lowest scores. A 2 (smoking status) × 3 (disease outcome) ANOVA was conducted on the ratings of perceived susceptibility to the three diseases. Smokers considered themselves to be more susceptible to all three diseases, and among smokers, perceived susceptibility to the diseases was positively correlated with effectiveness and believability ratings of the HWLs. Our findings support previous evidence that pictorial HWLs are rated as more effective and believable than text-only warnings, and provide some support for the use of severe or 'grotesque' HWLs on tobacco products. Our data also suggest that HWLs should aim to increase perceived susceptibility to disease, as this was positively related to perceived message effectiveness and believability.


The impact of verbal feedback about blushing on social discomfort and facial blood flow during embarrassing tasks.
To investigate whether verbal feedback about blushing influences subsequent social discomfort or blushing itself, changes in facial blood flow and ratings of blushing and embarrassment were investigated in high (N=28) and low scorers (N=28) on the Blushing Propensity scale while singing and reading aloud, and while listening to audiotapes of their performance. After each task half of the participants were told that they had blushed, and the rest were told that they had not blushed. Blood flow increased progressively in participants with high blushing propensity scores who were given "blushing" feedback, but not in the other participants. This finding suggests that expecting to blush may become a self-fulfilling prophecy. Verbal feedback about blushing strongly influenced subsequent social discomfort, and mimicked the effects of blushing propensity on ratings of embarrassment and blushing intensity. In sum, the findings support the view that preconceptions about blushing propensity are shaped by past learning experiences, that concern about blushing is a major source of discomfort in embarrassing situations, and that these concerns are often unrelated to the actual intensity of blushing.


Investigating trajectories of change in psychological distress amongst patients with depression and generalised anxiety disorder treated with internet cognitive behavioural therapy.
Internet based cognitive behavioural therapy (CBT) is efficacious for the treatment of anxiety and depression. The current study aimed to examine the effectiveness of internet based CBT prescribed by primary care clinicians for the treatment of depression and generalised anxiety disorder. Psychological distress data from 302 patients who completed an online CBT course for depression and 361 patients who completed an online CBT course for generalised anxiety disorder were subjected to growth mixture analysis. For both disorders psychological distress decreased across each lesson in a quadratic trend. Two classes of individuals were identified with different trajectories of change: a large group of individuals who responded well to the courses and a smaller group of individuals with a lower response. Both groups were similar with respect to socio-demographic characteristics however the Low Responders tended to have higher levels of symptom severity and psychological distress at baseline in comparison to the responders. For the majority of patients (75-80%) the internet CBT courses for depression and generalised anxiety disorder were effective. Further research is required to identify and effectively treat the smaller proportion of patients who did not improve during internet CBT.


Delta 3, delta 2-enoyl-CoA isomerase is the protein that copurifies with human glutathione S-transferases from S-hexylglutathione affinity matrices.
An unidentified 30 kDa protein frequently copurifies with human glutathione S-transferases from S-hexyl-glutathione affinity matrices. Application of two-step sequential affinity chromatographic methods yielded a homogeneous preparation of that protein from human liver specimens. The protein was digested with Achromobacter protease I, and sequences of peptides resolved by h.p.l.c. showed a high degree of identity with those of rat mitochondrial delta 3, delta 2-enoyl-CoA isomerase. The human protein also exhibited catalytic activity with delta 3-cis-octenyl CoA as a substrate. Thus it is identified as liver delta 3, delta 2-enoyl-CoA isomerase.


Primary sequence and domain structure of chicken vinculin.
We have determined the complete sequence of chick vinculin from two overlapping cDNA clones. The vinculin mRNA consists of 262 bp of 5' untranslated sequence, an open reading frame of 3195 bp (excluding the initiation codon) and a long 3' untranslated sequence (greater than 2 kb). Chick vinculin contains 1066 amino acid residues, and has a deduced molecular mass of 116,933 Da. Analysis of the domain structure of vinculin shows that the molecule can be cleaved by V8 proteinase into a 90 kDa globular head and a 32 kDa tail region, the latter of which could further be cleaved into a 27 kDa polypeptide. The 90 kDa globular head contains the N-terminus of vinculin, three 112-residue repeats (residues 259-589), and extends to approximately residue 850. Gel overlay experiments show that it also contains a binding site for the cytoskeletal protein talin. The talin-binding domain was further localized to the N-terminal 398 amino acid residues of the protein by expression in vitro of this region from a vinculin cDNA cloned into the Bluescript SK+ vector. The head and tail domains are apparently separated by a proline-rich region that contains V8-proteinase-cleavage sites and a candidate tyrosine (822)-phosphorylation site. Secondary-structure prediction suggests that the head and tail domains contain alpha-helical regions separated by short stretches of turn/coil. Comparison of the chick with a partial human sequence reveals that vinculin is a highly conserved protein. In chickens Southern-blot analysis is consistent with a single vinculin gene, and it is therefore likely that vinculin, and its higher-molecular-mass isoform termed metavinculin, arise through alternative splicing.


On the factors that promote the diversity of herbivorous insects and plants in tropical forests.
Some of the most fascinating and challenging questions in ecology are why biodiversity is highest in tropical forests and whether the factors involved are unique to these habitats. I did a worldwide test of the hypotheses that plant community divergence in antiherbivore traits results in higher insect herbivore diversity, and that predominant attack by specialized herbivores promotes plant richness. I found strong correlative support for both ideas. Butterfly diversity was greatest in regions where the community average species-pairwise dissimilarity in antiherbivore traits among plant species was highest. There was also a strong positive relationship between specialized (insect) vs. generalized (mammal) herbivores and plant richness. Regions where herbivory impact by mammals was higher than that of insects tended to have lower plant diversities. In contrast, regions in which insects are the main consumers, particularly in the Central and South American tropics, had the highest plant richness. Latitude did not explain any residual variance in insect or plant richness. The strong connections found between insect specialization, plant defense divergence, and plant and insect diversities suggest that increasing our understanding of the ecology of biological communities can aid in considerations of how to preserve biodiversity in the future.


The identification and expression analysis of candidate chemosensory genes in the bird cherry-oat aphid Rhopalosiphum padi (L.).
The bird cherry-oat aphid Rhopalosiphum padi (L.) is one of the most important wheat pests with polyphagia and autumn migrants. And, chemosensory genes were thought to play a key role in insect searching their hosts, food and mate. However, a systematic identification of the chemosensory genes in this pest has not been reported. Thus, in this study, we identified 14 odorant-binding proteins, nine chemosensory proteins, one sensory neuron membrane protein, 15 odorant receptors, 19 gustatory receptors and 16 ionotropic receptors from R. padi transcriptomes with a significantly similarity (E-value < 10-5) to known chemosensory genes in Acyrthosiphon pisum and Aphis gossypii. In addition, real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the expression profiles of obtained genes. Among these obtained genes, we selected 23 chemosensory genes to analyze their expression patterns in different tissues, wing morphs and host plants. We found that except RpOBP1, RpOBP3, RpOBP4 and RpOBP5, the rest of the selected genes were highly expressed in the head with antennae compared with body without head and antennae. Besides that, the stimulation and depression of chemosensory genes by plant switch indicated that chemosensory genes might be involved in the plant suitability assessment. These results not only provide insights for the potential roles of chemosensory genes in plant search and perception of R. padi but also provide initial background information for the further research on the molecular mechanism of the polyphagia and autumn migrants of it. Furthermore, these chemosensory genes are also the candidate targets for pest management control in future.


Personal protective equipment in health care: can online infection control courses transfer knowledge and improve proper selection and use?
We used observational evaluation to assess the ability of an online learning course to effectively transfer knowledge on personal protective equipment (PPE) selection and removal. During orientations for new hospital staff, 117 participants applied either airborne, droplet, or contact precautions in mock scenarios. Postcourse, all 3 scenarios demonstrated improvement in PPE sequence scores (P = .001); moreover, hand hygiene also was more frequent during both donning and doffing of PPE (P < .001).


Adjuvant effect of bacterial LPS and/or alum precipitation in responses to polysaccharide and protein antigens.
A conjugate of a hapten (NIP) and a strongly antigenic protein chicken gamma globulin (CGG), when injected in soluble form into mice, induced weak primary responses, as weak as responses induced by conjugates of NIP (or other haptens) to polysaccharides Ficoll or alpha (-1-6) dextran. Mean concentrations of anti-hapten antibodies on day 14 varied within the range of 37-105 micrograms/ml (C57BL mice) or 14-38 micrograms/ml (CBA mice). The NIP-protein conjugate administered in alum-precipitated form induced 100 times higher primary antibody responses. Alum-precipitation of NIP-Ficoll made it a modestly stronger antigen than soluble NIP-Ficoll. When lipopolysaccharide (LPS) was injected together with any of the soluble antigens, the mice produced plenty of anti-hapten antibodies regardless of whether the antigen was hapten-polysaccharide or hapten-protein conjugate. Concentrations on day 14 varied from around 400 micrograms/ml to approximately 1600 micrograms/ml. LPS had a similar adjuvant effect on antidextran responses. LPS alone induced a polyclonal immunoglobulin production, and the immunoglobulin produced included 'anti-NIP' or 'anti-dextran' detectable in the solid phase antibody assay. These 'antibodies' induced by LPS alone were almost totally mercapto-ethanol-sensitive and poorly detectable by Farr assay or the bacteriophage assay. The response to the LPS+antigen combination was specific for the antigen and included both mercapto-ethanol-sensitive and resistant antibodies.


Stable Defects in Semiconductor Nanowires.
Semiconductor nanowires are commonly described as being defect-free due to their ability to expel mobile defects with long-range strain fields. Here, we describe previously undiscovered topologically protected line defects with null Burgers vector that, unlike dislocations, are stable in nanoscale crystals. We analyze the defects present in semiconductor nanowires in regions of imperfect crystal growth, i.e., at the nanowire tip formed during consumption of the droplet in self-catalyzed vapor-liquid-solid growth and subsequent vapor-solid shell growth. We use a form of the Burgers circuit method that can be applied to multiply twinned material without difficulty. Our observations show that the nanowire microstructure is very different from bulk material, with line defects either (a) trapped by locks or other defects, (b) arranged as dipoles or groups with a zero total Burgers vector, or (c) have a zero Burgers vector. We find two new line defects with a null Burgers vector, formed from the combination of partial dislocations in twinned material. The most common defect is the three-monolayer high twin facet with a zero Burgers vector. Studies of individual nanowires using cathodoluminescence show that optical emission is quenched in defective regions, showing that they act as strong nonradiative recombination centers.


Primitive duplicate Hox clusters in the European eel's genome.
The enigmatic life cycle and elongated body of the European eel (Anguilla anguilla L., 1758) have long motivated scientific enquiry. Recently, eel research has gained in urgency, as the population has dwindled to the point of critical endangerment. We have assembled a draft genome in order to facilitate advances in all provinces of eel biology. Here, we use the genome to investigate the eel's complement of the Hox developmental transcription factors. We show that unlike any other teleost fish, the eel retains fully populated, duplicate Hox clusters, which originated at the teleost-specific genome duplication. Using mRNA-sequencing and in situ hybridizations, we demonstrate that all copies are expressed in early embryos. Theories of vertebrate evolution predict that the retention of functional, duplicate Hox genes can give rise to additional developmental complexity, which is not immediately apparent in the adult. However, the key morphological innovation elsewhere in the eel's life history coincides with the evolutionary origin of its Hox repertoire.


Female assortative mate choice functionally validates synthesized male odours of evolving stickleback river-lake ecotypes.
During mate choice decisions, females of many vertebrates use male olfactory cues to achieve immunogenetic optimality of their offspring. Three-spined sticklebacks ( Gasterosteus aculeatus) populating habitats that differ in their parasite communities evolve locally adapted combinations of genetic variants encoded at the major histocompatibility complex (MHC). Such adaptation confers optimal resistance to the local parasite fauna. Immunogenetic signatures co-evolved with local parasites favour population-specific assortative mate choice behaviour. Previous studies have shown that female sticklebacks evaluate male MHC-associated olfactory cues during the process of mate choice, but how habitat-specific information is exchanged between males and females has remained elusive. Here, we directly demonstrate the molecular nature of the olfactory cue providing habitat-specific information. Under controlled laboratory conditions, females that are ready to mate prefer mixtures of synthetic MHC peptide ligands mimicking the optimal allele number of their original population. These results imply that female sticklebacks can determine the number of MHC alleles of their prospective mates, compare it to their own immunogenetic status, and, if optimal with respect to the immunogenetic complementarity, accept the male as mate. Our results suggest a potentially common mechanism of ecological speciation in vertebrates that is based on the olfactory assessment of habitat-specific immunogenetic diversity.


Evaluation of point-of-care thumb-size bispectral electroencephalography device to quantify delirium severity and predict mortality.
We have developed the bispectral electroencephalography (BSEEG) method for detection of delirium and prediction of poor outcomes. To improve the BSEEG method by introducing a new EEG device. In a prospective cohort study, EEG data were obtained and BSEEG scores were calculated. BSEEG scores were filtered on the basis of standard deviation (s.d.) values to exclude signals with high noise. Both non-filtered and s.d.-filtered BSEEG scores were analysed. BSEEG scores were compared with the results of three delirium screening scales: the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Delirium Rating Scale-Revised-98 (DRS) and the Delirium Observation Screening Scale (DOSS). Additionally, the 365-day mortalities and the length of stay (LOS) in the hospital were analysed. We enrolled 279 elderly participants and obtained 620 BSEEG recordings; 142 participants were categorised as BSEEG-positive, reflecting slower EEG activity. BSEEG scores were higher in the CAM-ICU-positive group than in the CAM-ICU-negative group. There were significant correlations between BSEEG scores and scores on the DRS and the DOSS. The mortality rate of the BSEEG-positive group was significantly higher than that of the BSEEG-negative group. The LOS of the BSEEG-positive group was longer compared with that of the BSEEG-negative group. BSEEG scores after s.d. filtering showed stronger correlations with delirium screening scores and more significant prediction of mortality. We confirmed the usefulness of the BSEEG method for detection of delirium and of delirium severity, and prediction of patient outcomes with a new EEG device.


Immunonutrition in surgical and critically ill patients.
Surgery, trauma, burns and injury induce an inflammatory response that can become excessive and damaging in some patients. This hyperinflammation can be followed by an immunosuppressed state which increases susceptibility to infection. The resulting septic syndromes are associated with significant morbidity and mortality. A range of nutrients are able to modulate inflammation (and the associated oxidative stress) and to maintain or improve immune function. These include several amino acids, antioxidant vitamins and minerals, long-chain n-3 fatty acids and nucleotides. Experimental studies support a role for each of these nutrients in surgical, injured or critically ill patients. There is good evidence that glutamine influences immune function in such patients and that this is associated with clinical improvement. Evidence is also mounting for the use of long-chain n-3 fatty acids in surgical and septic patients, but more evidence of clinical efficacy is required. Mixtures of antioxidant vitamins and minerals are also clinically effective, especially if they include selenium. Their action appears not to involve improved immune function, although an anti-inflammatory mode of action has not been ruled out. Enteral immunonutrient mixtures, usually including arginine, nucleotides and long-chain n-3 fatty acids, have been used widely in surgical and critically ill patients. Evidence of efficacy is good in surgical patients. However whether these same mixtures are beneficial, or should even be used, in critically ill patients remains controversial, since some studies show increased mortality with such mixtures. There is a view that this is due to a high arginine content driving nitric oxide production.


Assisted dying around the world: a status quaestionis.
Assisted dying practices, which include euthanasia and physician-assisted suicide (PAS), have expanded significantly around the world over the past 20 years. Euthanasia refers to the act of intentionally ending the life of a patient by a health care practitioner through medical means at that patient's explicit request while PAS involves the provision or prescribing of drugs by a health care practitioner for a patient to end their own life. The growing global aging population accompanied by higher levels of chronic disease and protracted illnesses have sharpened the focus on end of life issues and societal and legislative debates continue to address related moral and ethical complexities. Assisted dying practices are now legal in 18 jurisdictions, increasing the number of people with access to euthanasia and/or physician-assisted suicide (PAS) to over 200 million. New legislation is being crafted or considered in Portugal, Spain and 16 US states. Germany has recently overturned a ban on assisted dying services and New Zealand will put legalization of euthanasia to a vote in 2020. Assisted dying practice characteristics differ and there is also considerable variation in the terminology and labels used for assisted dying, which can add to the confusion and controversy around the practices. Frequency of use also varies greatly by jurisdiction, though a consistent increase has been seen in European countries including Belgium, the Netherlands and Switzerland as well as some jurisdictions with long-standing physician assisted dying laws, such as Oregon and Washington. All assisted dying legislation includes substantive and procedural requirements, such as minimum age, waiting period, health condition, physician consultation and reporting procedure, however, some are extensive and detailed while others are more limited. As access to assisted dying expands in new and existing jurisdictions, research must also expand to diligently examine the impact on patients, specifically among vulnerable populations, as well as on health care practitioners, health care systems and communities. This article will provide a thorough investigation, or 'status quaestionis' of the terminology, evolution and current legislative picture of assisted dying practices around the globe and contribute to the ongoing ethical, regulatory and practice debate, which have become increasingly important considerations for medical practice, end-of-life care and public health.


Neuropsychologically informed strategic psychotherapy in teenagers and adults with ADHD.
Stimulants are the primary treatment for ADHD. Psychotherapy may augment pharmacologic treatment. In this article, we discuss strategies psychotherapists may use in working with teenagers and adults, including individuals who reject medications or take them suboptimally. Individuals with ADHD often have other psychiatric issues, including affective or cognitive comorbidities. Having ADHD does not protect people from the difficulties of life, and psychotherapy can help to disentangle "ADHD" from other issues. A psychotherapist knowledgeable about ADHD assessment can improve diagnostic precision. Psychotherapy can integrate forms of treatment in which the central goal is increasing mastery and competence of the individual.


On delay adjustment for dynamic load balancing in distributed virtual environments.
Distributed virtual environments (DVEs) are becoming very popular in recent years, due to the rapid growing of applications, such as massive multiplayer online games (MMOGs). As the number of concurrent users increases, scalability becomes one of the major challenges in designing an interactive DVE system. One solution to address this scalability problem is to adopt a multi-server architecture. While some methods focus on the quality of partitioning the load among the servers, others focus on the efficiency of the partitioning process itself. However, all these methods neglect the effect of network delay among the servers on the accuracy of the load balancing solutions. As we show in this paper, the change in the load of the servers due to network delay would affect the performance of the load balancing algorithm. In this work, we conduct a formal analysis of this problem and discuss two efficient delay adjustment schemes to address the problem. Our experimental results show that our proposed schemes can significantly improve the performance of the load balancing algorithm with neglectable computation overhead.


Macropis fulvipes Venom component Macropin Exerts its Antibacterial and Anti-Biofilm Properties by Damaging the Plasma Membranes of Drug Resistant Bacteria.
The abuse of antibiotics for disease treatment has led to the emergence of multidrug resistant bacteria. Antimicrobial peptides, found naturally in various organisms, have received increasing interest as alternatives to conventional antibiotics because of their broad spectrum antimicrobial activity and low cytotoxicity. In a previous report, Macropin, isolated from bee venom, exhibited antimicrobial activity against both gram-positive and negative bacteria. In the present study, Macropin was synthesized and its antibacterial and anti-biofilm activities were tested against bacterial strains, including gram-positive and negative bacteria, and drug resistant bacteria. Moreover, Macropin did not exhibit hemolytic activity and cytotoxicity to keratinocytes, whereas Melittin, as a positive control, showed very high toxicity. Circular dichroism assays showed that Macropin has an α-helical structure in membrane mimic environments. Macropin binds to peptidoglycan and lipopolysaccharide and kills the bacteria by disrupting their membranes. Moreover, the fractional inhibitory concentration index indicated that Macropin has additive and partially synergistic effects with conventional antibiotics against drug resistant bacteria. Thus, our study suggested that Macropin has potential for use of an antimicrobial agent for infectious bacteria, including drug resistant bacteria.


Alpha-phenyl-N-tert-butylnitrone prevents oxidative stress in a haloperidol-induced animal model of tardive dyskinesia: investigating the behavioural and biochemical changes.
Haloperidol (HP) is a widely prescribed antipsychotic drug used for the treatment of mental disorders. However, while providing therapeutic benefits, this drug also causes serious extrapyramidal side effects, such as tardive dyskinesia (TD). Upon chronic administration, HP causes behavioural supersensitivity to dopamine D2 receptor agonists, as well as the development of vacuous chewing movements (VCMs), in an animal model of human TD. Currently, a prevailing hypothesis to account for these behavioural abnormalities implicates oxidative stress. This study was undertaken to examine whether the free radical trapping agent, α-phenyl-N-tert-butylnitrone (PBN), can prevent the development of behavioural supersensitivity to dopamine D2 receptor agonists and the development of VCMs. Additionally, the study examined whether increased synthesis of apoptosis inducing factor (AIF) can result from HP-induced oxidative stress. Male Sprague-Dawley rats were treated with HP in conjunction with PBN, or its vehicle, for 4weeks. After a 24-hour washout period, behavioural observations were recorded along with the estimation of lipid peroxidation and antioxidant enzyme activities. The free radical trapping agent, PBN, prevented the development of behavioural supersensitivity, reduced lipid peroxidation and prevented the reduction of antioxidant enzyme activities. AIF concentrations at the mRNA and protein levels remained unchanged; therefore increased AIF gene expression is unlikely to be involved in HP-induced oxidative stress. The findings of the present study suggest the involvement of striatal free radicals in the development of behavioural supersensitivity, and free radical trapping agents, such as PBN, as possible options for the treatment of extrapyramidal side effects in humans.


Texture Analysis to Differentiate Malignant Renal Tumors in Children Using Gray-Scale Ultrasonography Images.
We assessed the feasibility of texture analysis to differentiate Wilms tumor, clear cell sarcoma and rhabdoid tumor of the kidney in children using gray-scale ultrasonography images. Children who had pre-operative renal ultrasonography images of the three tumors from January 2002 to February 2017 were retrospectively included as the test set, and children with the same criteria from March 2017 to December 2018 were included as the validation set. From histogram and second-order statistics, features were compared between the tumors, and diagnostic performances were assessed. Among a total of 32 children (24 children with Wilms tumors, five children with clear cell sarcomas and three children with rhabdoid tumors) from the test set, features from the second-order statistics showed an area under the curve greater than 0.89 for differentiating Wilms tumor from the others. These features aided in the differentiation of tumor type in the two children with Wilms tumors in the validation set. Therefore, texture analysis from gray-scale ultrasonography images can be used to differentiate Wilms tumors from clear cell sarcomas and rhabdoid tumors in children.


Feasibility of a Conditional Knockout System for Chlamydia Based on CRISPR Interference.
Chlamydia is an obligate intracellular bacterium and, as such, has significantly reduced its genome size and content. Although recent advances have allowed for transformation of C. trachomatis with an exogenous plasmid, genetic manipulation of Chlamydia remains challenging. In particular, the ability to create conditional knockouts has not been developed. This is particularly important given the likelihood that most genes within the small genome of Chlamydia may be essential. Here, I describe the feasibility of using CRISPR interference (CRISPRi) based on the catalytically inactive Cas9 variant (dCas9) of Staphylococcus aureus to inducibly, and reversibly, repress gene expression in C. trachomatis. CRISPRi has been developed and used successfully in a variety of bacterial organisms including E. coli and Mycobacterium tuberculosis. I first describe the creation of a single plasmid system for CRISPRi in Chlamydia, targeted to a non-essential gene, incA, that expresses a dispensable inclusion membrane protein. Control transformations of C. trachomatis serovar L2 with plasmids encoding only the dCas9, under the control of an inducible promoter, or only the guide RNA (gRNA) targeted to the 5' UTR of incA, expressed constitutively, failed to prevent expression of IncA. Importantly, expression of dCas9 alone did not have a deleterious effect on chlamydiae. Transformation of C. trachomatis with a plasmid combining the dCas9 and a gRNA targeting incA and induction of expression of the dCas9 resulted in the reversible inhibition of IncA expression. Consequently, conditional knockout mediated by CRISPRi is feasible in Chlamydia. Potential improvements and experimental concerns in using the system are also discussed.


Influence of tooth age and etching time on the microtensile bond strengths of adhesive systems to dentin.
1. To evaluate the effect of tooth age on the microtensile bond strengths (µTBS) of various adhesive systems to dentin; 2. To evaluate the effect of different etching times on the microtensile bond strengths of different adhesive systems to young vs mature dentin. One hundred twenty intact human teeth were mechanically ground to expose midcoronal dentin and were randomly assigned to three groups (n = 40) according to subjects' age in years: 15 to 25, 35 to 45, and >= 55. Within each group, specimens were further randomized into 8 subgroups according to adhesive (etch-and-rinse 3- and 2-step; self-etching 2- and 1-step) and etching time (manufacturer instructions vs extended). Resin composite was applied to the treated surfaces, and after 24 h, all specimens were processed for microtensile bond strength testing. Data were analyzed by factorial ANOVA and Tukey's test (p = 0.05). µTBS values ranged from 10.9 MPa (2-step self-etching, extended etching time, age group 15 to 25) to 50.7 MPa (1-step self-etching, extended etching time, age group >= 55). With only one exception, tooth age and etching time had no significant effect on the bond strengths of the adhesives to dentin. The 2-step self-etching system had lower bond strengths than the other systems, regardless of etching time or tooth age. Tooth age and etching time did not affect the dentin bond strengths of the adhesives tested.


Vascular lesions of the maxillofacial region: a case report and review of the literature.
There is frequently lack of understanding and apprehension among dental practitioners treating patients with vascular lesions of the oral and maxillofacial region. Arteriovenous malformations are rare lesions which can easily be misdiagnosed yet produce the very dramatic clinical presentation of severe life threatening oral bleeding. Much of this apprehension likely stems from a lack of understanding of these anomalies, including lesion behavior/ characteristics, clinical work-up, and treatment paradigms. A comprehensive, in depth review of the full spectrum of vascular lesions of the maxillofacial complex is beyond the scope of this review. The purpose of this article is to provide a comprehensive review of the diagnosis, treatment, and risks associated with these complex vascular anomalies and provide a case report. In 1982, Mulliken and Glowacki published a landmark article proposing characterization of vascular defects based on biologic and pathologic differences. Their work differentiated between two major categories of vascular lesions: hemangiomas and vascular malformations. Different categories, names, and treatment options have been advocated over the years with multiple outcomes. They can occur in various areas throughout the body, with 60 percent being located in the head and neck. The true mechanism of pathogenesis of vascular anomalies is still unclear. Embolization and surgery is often combined for extended cases to improve their facial contour and oral function. We present the case of a 29-year-old female that is 36 weeks pregnant and presented to University Hospital after having significant bleeding from her oral cavity. She was found to have a gingival lesion associated with a radiolucency in the right posterior mandible. During her stay she had an episode of acute bleeding that required an emergent exploration, embolization, and resection secondary to an Arteriovenous Malformation associated with the Inferior Alveolar Artery. We will discuss the presentation, treatment provided, and outcome of this patient. We will also cover the diverse group of congenital vascular malformations, and their pathologic, clinical, and radiologic diagnosis and management.


Development of local-global preference in vision and haptics.
We aimed to advance our understanding of local-global preference by exploring its developmental path within and across sensory modalities: vision and haptics. Neurotypical individuals from six years of age through adulthood completed a similarity judgement task with hierarchical haptic or visual stimuli made of local elements (squares or triangles) forming a global shape (a square or a triangle). Participants chose which of two probes was more similar to a target: the one sharing the global shape (but different local shapes) or the one with the same local shapes (but different global shape). Across trials, we independently varied the size of the local elements and that of the global configuration-the latter was varied by manipulating local element density while keeping their numerosity constant. We found that the size of local elements (but not global size) modulates the effects of age and modality. For stimuli with smaller local elements, the proportion of global responses increased with age and was similar for visual and haptic stimuli. However, for stimuli made of our largest local elements, the global preference was reduced or absent, particularly in haptics, regardless of age. These results suggest that vision and haptics progressively converge toward similar global preference with age, but residual differences across modalities and across individuals may be observed, depending on the characteristics of the stimuli.


Reproducibility of protein x-ray diffuse scattering and potential utility for modeling atomic displacement parameters.
Protein structure and dynamics can be probed using x-ray crystallography. Whereas the Bragg peaks are only sensitive to the average unit-cell electron density, the signal between the Bragg peaks-diffuse scattering-is sensitive to spatial correlations in electron-density variations. Although diffuse scattering contains valuable information about protein dynamics, the diffuse signal is more difficult to isolate from the background compared to the Bragg signal, and the reproducibility of diffuse signal is not yet well understood. We present a systematic study of the reproducibility of diffuse scattering from isocyanide hydratase in three different protein forms. Both replicate diffuse datasets and datasets obtained from different mutants were similar in pairwise comparisons (Pearson correlation coefficient ≥0.8). The data were processed in a manner inspired by previously published methods using custom software with modular design, enabling us to perform an analysis of various data processing choices to determine how to obtain the highest quality data as assessed using unbiased measures of symmetry and reproducibility. The diffuse data were then used to characterize atomic mobility using a liquid-like motions (LLM) model. This characterization was able to discriminate between distinct anisotropic atomic displacement parameter (ADP) models arising from different anisotropic scaling choices that agreed comparably with the Bragg data. Our results emphasize the importance of data reproducibility as a model-free measure of diffuse data quality, illustrate the ability of LLM analysis of diffuse scattering to select among alternative ADP models, and offer insights into the design of successful diffuse scattering experiments.


Reduced functional integration of the sensorimotor and language network in rolandic epilepsy.
Over the last years, evidence has accumulated that rolandic epilepsy (RE) is associated with serious cognitive comorbidities, including language impairment. However, the cerebral mechanism through which epileptiform activity in the rolandic (sensorimotor) areas may affect the language system is unknown. To investigate this, the connectivity between rolandic areas and regions involved in language processing is studied using functional MRI (fMRI). fMRI data was acquired from 22 children with rolandic epilepsy and 22 age-matched controls (age range: 8-14 years), both at rest and using word-generation and reading tasks. Activation map analysis revealed no group differences (FWE-corrected, p < 0.05) and was therefore used to define regions of interest for pooled (patients and controls combined) language activation. Independent component analysis with dual regression was used to identify the sensorimotor resting-state network in all subjects. The associated functional connectivity maps were compared between groups at the regions of interest for language activation identified from the task data. In addition, neuropsychological language testing (Clinical Evaluation of Language Fundamentals, 4th edition) was performed. Functional connectivity with the sensorimotor network was reduced in patients compared to controls (p = 0.011) in the left inferior frontal gyrus, i.e. Broca's area as identified by the word-generation task. No aberrant functional connectivity values were found in the other regions of interest, nor were any associations found between functional connectivity and language performance. Neuropsychological testing confirmed language impairment in patients relative to controls (reductions in core language score, p = 0.03; language content index, p = 0.01; receptive language index, p = 0.005). Reduced functional connectivity was demonstrated between the sensorimotor network and the left inferior frontal gyrus (Broca's area) in children with RE, which might link epileptiform activity/seizures originating from the sensorimotor cortex to language impairment, and is in line with the identified neuropsychological profile of anterior language dysfunction.


Molecular imaging, biodistribution and efficacy of mesenchymal bone marrow cell therapy in a mouse model of Chagas disease.
Chagasic cardiomyopathy, resulting from infection with the parasite Trypanosoma cruzi, was discovered more than a century ago and remains an incurable disease. Due to the unique properties of mesenchymal stem cells (MSC) we hypothesized that these cells could have therapeutic potential for chagasic cardiomyopathy. Recently, our group pioneered use of nanoparticle-labeled MSC to correlate migration with its effect in an acute Chagas disease model. We expanded our investigation into a chronic model and performed more comprehensive assays. Infected mice were treated with nanoparticle-labeled MSC and their migration was correlated with alterations in heart morphology, metalloproteinase activity, and expression of several proteins. The vast majority of labeled MSC migrated to liver, lungs and spleen whereas a small number of cells migrated to chagasic hearts. Magnetic resonance imaging demonstrated that MSC therapy reduced heart dilatation. Additionally metalloproteinase activity was higher in heart and other organs of infected mice. Protein expression analyses revealed that connexin 43, laminin γ1, IL-10 and INF-γ were affected by the disease and recovered after cell therapy. Interestingly, MSC therapy led to upregulation of SDF-1 and c-kit in the hearts. The beneficial effect of MSC therapy in Chagas disease is likely due to an indirect action of the cells of the heart, rather than the incorporation of large numbers of stem cells into working myocardium.


Effects of Alkylthio and Alkoxy Side Chains in Polymer Donor Materials for Organic Solar Cells.
Side chains play a considerable role not only in improving the solubility of polymers for solution-processed device fabrication, but also in affecting the molecular packing, electron affinity and thus the device performance. In particular, electron-donating side chains show unique properties when employed to tune the electronic character of conjugated polymers in many cases. Therefore, rational electron-donating side chain engineering can improve the photovoltaic properties of the resulting polymer donors to some extent. Here, a survey of some representative examples which use electron-donating alkylthio and alkoxy side chains in conjugated organic polymers for polymer solar cell applications will be presented. It is envisioned that an analysis of the effect of such electron-donating side chains in polymer donors would contribute to a better understanding of this kind of side chain behavior in solution-processed conjugated organic polymers for polymer solar cells.


Functional role of the "aromatic cage" in human monoamine oxidase B: structures and catalytic properties of Tyr435 mutant proteins.
Current structural results of several flavin-dependent amine oxidizing enzymes including human monoamine oxidases A and B (MAO A and MAO B) show aromatic amino acid residues oriented approximately perpendicular to the flavin ring, suggesting a functional role in catalysis. In the case of human MAO B, two tyrosyl residues (Y398 and Y435) are found in the substrate binding site on the re face of the covalent flavin ring [Binda et al. (2002) J. Biol. Chem. 277, 23973-23976]. To probe the functional significance of this structure, Tyr435 in MAO B was mutated with the amino acids Phe, His, Leu, or Trp, the mutant proteins expressed in Pichia pastoris, and purified to homogeneity. Each mutant protein contains covalent FAD and exhibits a high level of catalytic functionality. No major alterations in active site structures are detected on comparison of their respective crystal structures with that of WT enzyme. The relative k(cat)/K(m) values for each mutant enzyme show Y435 > Y435F = Y435L = Y435H > Y435W. A similar behavior is also observed with the membrane-bound forms of MAO A and MAO B (MAO A Y444 mutant enzymes are found to be unstable on membrane extraction). p-Nitrobenzylamine is found to be a poor substrate while p-nitrophenethylamine is found to be a good substrate for all WT and mutant forms of MAO B. Analysis of these kinetic and structural data suggests the function of the "aromatic cage" in MAO to include a steric role in substrate binding and access to the flavin coenzyme and to increase the nucleophilicity of the substrate amine moiety. These results are consistent with a proposed polar nucleophilic mechanism for catalytic amine oxidation.


Neurobiology of feeding and energy expenditure.
Significant advancements have been made in the past century regarding the neuronal control of feeding behavior and energy expenditure. The effects and mechanisms of action of various peripheral metabolic signals on the brain have become clearer. Molecular and genetic tools for visualizing and manipulating individual components of brain homeostatic systems in combination with neuroanatomical, electrophysiological, behavioral, and pharmacological techniques have begun to elucidate the molecular and neuronal mechanisms of complex feeding behavior and energy expenditure. This review highlights some of these advancements that have led to the current understanding of the brain's involvement in the acute and chronic regulation of energy homeostasis.


Dual-label STED nanoscopy of living cells using photochromism.
We demonstrate live-cell STED microscopy of two protein species using photochromic green fluorescent proteins as markers. The reversible photoswitching of two markers is implemented so that they can be discerned with a single excitation and STED wavelength and a single detection channel. Dual-label STED microscopy is shown in living mammalian cells.


[Subcutaneous granuloma annulare: a case report].
Granuloma annulare is a benign and self-limited cutaneous disease. Subcutaneous granuloma annulare is an uncommon variant seen almost exclusively in young children, characterized by firm nodules appearing more frequently in lower extremities, buttocks, hands and scalp. To report a case of subcutaneous granuloma annulare and review its differential diagnoses and treatments. A 4 year-old male patient. Since 2 and a half years of age he presented asymptomatic firm subcutaneous nodules on the back of the left middle finger and later on the back of the left hand, right big toe, left frontal area and scalp. Excisional biopsy of some lesions from the scalp was consistent with subcutaneous granuloma annulare. Clobetasol 0,05% cream twice a day for 1 month was prescribed without response. Subcutaneous granuloma annulare must be considered within the differential diagnosis of subcutaneous nodules in children. In most of the cases a biopsy and histopathology of the lesions will be required to confirm the diagnosis. Due to its tendency to spontaneous resolution, treatment often is not necessary and periodic evaluation is recommended.


A mucoprotein derived from human urine which reacts with influenza, mumps, and Newcastle disease viruses.
A mucoprotein, present in normal human urine, has been isolated and obtained in a state of a high degree of purity. A number of the biological, chemical, and physicochemical properties of the substance have been studied. From the results obtained in the present investigation and those reported in succeeding papers (34, 35) it appears that the mucoprotein has a high molecular weight, i.e., of the order of 7.0 x 10(6), consists of thread-like molecules which have axial ratios of approximately 100, and is specifically antigenic. This substance, which appears to be free of contaminating material, possesses in extraordinary degree the capacity to react with influenza, mumps, and Newcastle disease viruses. At equilibrium, with influenza virus, the minimal amount of the substance capable of giving a demonstrable reaction with one hemagglutinating unit of virus appears to be about 0.0003 microg. The mucoprotein is altered by preparations of influenza viruses and its capacity to react with these agents or others is lost. The kinetics of the inactivation process brought about by influenza viruses is in accord with those of well known enzyme-substrate systems. With the exception of the capacity to react with viruses, altered mucoprotein did not differ from the native substance relative to any of the properties examined in the present study. That certain physicochemical properties of the altered mucoprotein are different from those of the native substance is demonstrated in succeeding papers (34, 35).


Some changes in immunity and blood in relation to clinical states of dengue hemorrhagic fever patients in Vietnam.
The role of immunological factors in the pathogenesis of Dengue Hemorrhagic Fever (DHF), particularly Dengue Shock Syndrome (DSS) was studied. The complement activity, circulating immune complex (IC), histamine level, platelets and leucocytes were determined in the blood of 30 patients and 43 healthy persons. The results showed a significant decrease in complement activity, platelet and neutrophil counts, an increase of histamine level (P less than 0.001), and the presence of circulating IC in 80 per cent of our patients. Furthermore, a marked correlation was found between the changes of the above parameters and the clinical stages of the disease. These parameters can be used in the prognostics of the pre-shock and shock syndrome of DHF.


Epidemiological and clinical aspects of human Brucella suis infection in Polynesia.
High brucellosis seroprevalence rates in domestic swine herds have been reported in Wallis and Futuna Islands and are associated with a significant burden of human infection by Brucella suis, a species that is rarely incriminated in human disease. Between 2003 and 2010, seven patients had a positive blood culture for B. suis biovar 1, 11 symptomatic patients had a positive Rose Bengal test (RBT) and a positive serum agglutination test (SAT) and three asymptomatic cases were found to be positive for RBT, SAT or ELISA IgM (after systematic screening of 52 family members of 15 index cases). Overall, Brucella infection was diagnosed in 21 people, corresponding to a mean annual incidence of 19 cases/100 000 inhabitants. Compared to series of patients infected with other more commonly encountered Brucella spp. such as B. melitensis and B. abortus, clinical presentation and percentage and distribution of complications were similar, apart from a marked observation of significantly increased median alanine aminotransferase levels, 20 times greater than upper normal rates, but not accompanied by any particular hepatic pathology. Wallis and Futuna, where people live in close proximity to animals and where the cultural significance of pig-raising precludes the implementation of adequate veterinary preventive measures, thus represents one of the few known B. suis foci worldwide and allows for evaluation of the peculiarities of this infection.