Post-traumatic stress disorder and the law: critical review of the new frontier.
Since its debut in the psychiatric nomenclature in 1980, post-traumatic stress disorder (PTSD) has had a dramatic impact on criminal and civil jurisprudence. PTSD has created a cottage industry among both criminal and negligence attorneys and mental health practitioners. The diagnosis first achieved public notoriety when it was introduced as a new basis for the insanity defense. More recently "syndrome evidence" of the subtypes and variations of PTSD have encroached on the substantive criminal law of self-defense. In addition, the diagnosis may have an impact on such traditionally legal and factual determinations as the credibility of witnesses and may undermine conservative tort doctrine that attempts to cabin psychic injury. The emerging legal area of victims' rights has been strengthened and paradoxically divided by PTSD. Yet the newly defined disorder of PTSD has not borne such a heavy forensic burden easily. Indeed the diagnosis poses for psychiatry some of the very problems it supposedly solves for legal purposes, including the illusory objectivity of the causative traumatic event and the expert's dependence upon the victim's subjective and unverifiable reports of symptomatology for the diagnosis.


The effect of early motion on tibial tunnel widening after anterior cruciate ligament replacement using hamstring tendon grafts.
The purpose of this study was to evaluate the hypothesis that early motion increases tibial tunnel enlargement in patients who underwent anterior cruciate ligament (ACL) replacement with hamstring autograft. Cohort analytic study. All patients in this study had received a doubled semitendinous and gracilis graft. Grafts were secured in place with an implant-free technique. Two groups of patients were evaluated. Group A consisted of 35 patients who underwent isolated ACL replacement and whose rehabilitation protocol included early motion. Group B consisted of 20 patients who underwent combined arthroscopic meniscal repair and ACL replacement. Partial weight bearing and restriction of range of motion for 6 weeks was recommended for these patients. The only 2 variables between the groups were the meniscal repair and the postoperative rehabilitation. Patients were evaluated clinically and radiographically at 3, 6, and 12 months postoperatively. After correction for radiographic magnification, the tibial tunnel was measured at distal (T1), middle (T2), and proximal (T3) locations on both anteroposterior and lateral views. At 1-year follow-up evaluations, tunnel enlargement was significantly higher in the group with early motion, in both the anteroposterior and lateral views, in all but one location (anteroposterior, T1). The enlargement was greater in the mid-portion (T2) of the tunnel in both groups. The mean percentage was 45.92% for group A and 23.34% for group B ( P <.05) in the anteroposterior view, and 48.14% for group A and 24.47% for group B ( P <.05) in the lateral view. No correlation was found between tunnel enlargement and clinical results or between tunnel enlargement and joint laxity measured by a KT-1000 arthrometer. Our study confirms that early motion increases the amount of tibial tunnel enlargement after anterior cruciate ligament replacement with hamstring autograft. This may have an impact on future rehabilitation protocols. Level II.


Complete Genome Sequence of Akkermansia glycaniphila Strain PytT, a Mucin-Degrading Specialist of the Reticulated Python Gut.
Akkermansia glycaniphila is a novel Akkermansia species that was isolated from the intestine of the reticulated python and shares the capacity to degrade mucin with the human strain Akkermansia muciniphila MucT Here, we report the complete genome sequence of strain PytT of 3,074,121 bp. The genomic analysis reveals genes for mucin degradation and aerobic respiration.


Managing potato biodiversity to cope with frost risk in the high Andes: a modeling perspective.
Austral summer frosts in the Andean highlands are ubiquitous throughout the crop cycle, causing yield losses. In spite of the existing warming trend, climate change models forecast high variability, including freezing temperatures. As the potato center of origin, the region has a rich biodiversity which includes a set of frost resistant genotypes. Four contrasting potato genotypes--representing genetic variability--were considered in the present study: two species of frost resistant native potatoes (the bitter Solanum juzepczukii, var. Luki, and the non-bitter Solanum ajanhuiri, var. Ajanhuiri) and two commercial frost susceptible genotypes (Solanum tuberosum ssp. tuberosum var. Alpha and Solanum tuberosum ssp. andigenum var. Gendarme). The objective of the study was to conduct a comparative growth analysis of four genotypes and modeling their agronomic response under frost events. It included assessing their performance under Andean contrasting agroecological conditions. Independent subsets of data from four field experiments were used to parameterize, calibrate and validate a potato growth model. The validated model was used to ascertain the importance of biodiversity, represented by the four genotypes tested, as constituents of germplasm mixtures in single plots used by local farmers, a coping strategy in the face of climate variability. Also scenarios with a frost routine incorporated in the model were constructed. Luki and Ajanhuiri were the most frost resistant varieties whereas Alpha was the most susceptible. Luki and Ajanhuiri, as monoculture, outperformed the yield obtained with the mixtures under severe frosts. These results highlight the role played by local frost tolerant varieties, and featured the management importance--e.g. clean seed, strategic watering--to attain the yields reported in our experiments. The mixtures of local and introduced potatoes can thus not only provide the products demanded by the markets but also reduce the impact of frosts and thus the vulnerability of the system to abiotic stressors.


Ethical aspects of malaria control and research.
Malaria currently causes more harm to human beings than any other parasitic disease, and disproportionally affects low-income populations. The ethical issues raised by efforts to control or eliminate malaria have received little explicit analysis, in comparison with other major diseases of poverty. While some ethical issues associated with malaria are similar to those that have been the subject of debate in the context of other infectious diseases, malaria also raises distinct ethical issues in virtue of its unique history, epidemiology, and biology. This paper provides preliminary ethical analyses of the especially salient issues of: (i) global health justice, (ii) universal access to malaria control initiatives, (iii) multidrug resistance, including artemisinin-based combination therapy (ACT) resistance, (iv) mandatory screening, (v) mass drug administration, (vi) benefits and risks of primaquine, and (vii) malaria in the context of blood donation and transfusion. Several ethical issues are also raised by past, present and future malaria research initiatives, in particular: (i) controlled infection studies, (ii) human landing catches, (iii) transmission-blocking vaccines, and (iv) genetically-modified mosquitoes. This article maps the terrain of these major ethical issues surrounding malaria control and elimination. Its objective is to motivate further research and discussion of ethical issues associated with malaria--and to assist health workers, researchers, and policy makers in pursuit of ethically sound malaria control practice and policy.


Experiences of hearing voices: analysis of a novel phenomenological survey.
Auditory hallucinations--or voices--are a common feature of many psychiatric disorders and are also experienced by individuals with no psychiatric history. Understanding of the variation in subjective experiences of hallucination is central to psychiatry, yet systematic empirical research on the phenomenology of auditory hallucinations remains scarce. We aimed to record a detailed and diverse collection of experiences, in the words of the people who hear voices themselves. We made a 13 item questionnaire available online for 3 months. To elicit phenomenologically rich data, we designed a combination of open-ended and closed-ended questions, which drew on service-user perspectives and approaches from phenomenological psychiatry, psychology, and medical humanities. We invited people aged 16-84 years with experience of voice-hearing to take part via an advertisement circulated through clinical networks, hearing voices groups, and other mental health forums. We combined qualitative and quantitative methods, and used inductive thematic analysis to code the data and χ(2) tests to test additional associations of selected codes. Between Sept 9 and Nov 29, 2013, 153 participants completed the study. Most participants described hearing multiple voices (124 [81%] of 153 individuals) with characterful qualities (106 [69%] individuals). Less than half of the participants reported hearing literally auditory voices--70 (46%) individuals reported either thought-like or mixed experiences. 101 (66%) participants reported bodily sensations while they heard voices, and these sensations were significantly associated with experiences of abusive or violent voices (p=0·024). Although fear, anxiety, depression, and stress were often associated with voices, 48 (31%) participants reported positive emotions and 49 (32%) reported neutral emotions. Our statistical analysis showed that mixed voices were more likely to have changed over time (p=0·030), be internally located (p=0·010), and be conversational in nature (p=0·010). This study is, to our knowledge, the largest mixed-methods investigation of auditory hallucination phenomenology so far. Our survey was completed by a diverse sample of people who hear voices with various diagnoses and clinical histories. Our findings both overlap with past large-sample investigations of auditory hallucination and suggest potentially important new findings about the association between acoustic perception and thought, somatic and multisensorial features of auditory hallucinations, and the link between auditory hallucinations and characterological entities. Wellcome Trust.


Mapping the Spatiotemporal Distribution of Bovine Rabies in Colombia, 2005-2019.
Introduction: Rabies is caused by a virus belonging to the genus Lyssavirus and family Rhabdoviridae, which can infect any mammal including humans. Hematophagous, fructivorous, and insectivorous bats have become the main reservoir of sylvatic rabies in Latin America. In the sylvatic cycle, hematophagous bats are usually the main reservoir. In contrast, dogs and cats fulfil this critical role in the urban cycle. However, in rural areas, the most affected animals are bovines. They show clinical signs such as behavioural changes, hypersalivation, muscle tremors, spasms caused by extensive damage to the central nervous system, and death from respiratory paralysis. Objective: To describe the spatiotemporal distribution of bovine rabies in Colombia from 2005 to 2019. Methods: Retrospective cross-sectional descriptive observational study, based on the monthly reports of the Colombian Agricultural Institute (ICA) on the surveillance of bovine rabies in Colombia from 2005 to 2019, retrieved from its official website. The data were converted to databases in Microsoft Access 365®. Multiple epidemiological maps were developed with the GIS software Kosmo RC1® 3.0 coupled to the shape files (.shp) of all the country's municipalities. Results: During the study period, 4888 cases of rabies were confirmed in cattle, ranging from a peak of 542 cases (11.1%) in 2014 to 43 in 2019 (0.88%). From 2014 to 2019, there has been a significant reduction in the annual national number of cases (r2 = 0.9509, p < 0.05). In 2019, 32.6% of the cases occurred in January, and 48.8% occurred in the department of Sucre. In 2009, the maximum number of spatial clusters (13) occurred in the Orinoquia region, where other clusters were also identified in 2005, 2006 and 2008. In 2018, 98 outbreaks were identified that led to the death of cattle and other animals, 28.6% of them in the department of Sucre. In the first half of 2019, of 38 outbreaks, 55.2% were identified in Sucre. Conclusions: It is necessary to review the current national program for the prevention and control of rabies in cattle, incorporating concepts from the ecology of bats, as well as the prediction of contagion waves of geographical and temporal spread in the context of the OneHealth Approach. Sylvatic rabies remains a threat in Colombia that requires further study.


Arsenic exposure and prevalence of type 2 diabetes in US adults.
High chronic exposure to inorganic arsenic in drinking water has been related to diabetes development, but the effect of exposure to low to moderate levels of inorganic arsenic on diabetes risk is unknown. In contrast, arsenobetaine, an organic arsenic compound derived from seafood intake, is considered nontoxic. To investigate the association of arsenic exposure, as measured in urine, with the prevalence of type 2 diabetes in a representative sample of US adults. Cross-sectional study in 788 adults aged 20 years or older who participated in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) and had urine arsenic determinations. Prevalence of type 2 diabetes across intake of arsenic. The median urine levels of total arsenic, dimethylarsinate, and arsenobetaine were 7.1, 3.0, and 0.9 mug/L, respectively. The prevalence of type 2 diabetes was 7.7%. After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic (95% confidence interval [CI], 2.0%-56.0%) and a nonsignificant 10% higher level of dimethylarsinate (95% CI, -8.0% to 33.0%) than participants without type 2 diabetes, and levels of arsenobetaine were similar to those of participants without type 2 diabetes. After similar adjustment, the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th percentiles were 3.58 for the level of total arsenic (95% CI, 1.18-10.83), 1.57 for dimethylarsinate (95% CI, 0.89-2.76), and 0.69 for arsenobetaine (95% CI, 0.33-1.48). After adjustment for biomarkers of seafood intake, total urine arsenic was associated with increased prevalence of type 2 diabetes. This finding supports the hypothesis that low levels of exposure to inorganic arsenic in drinking water, a widespread exposure worldwide, may play a role in diabetes prevalence. Prospective studies in populations exposed to a range of inorganic arsenic levels are needed to establish whether this association is causal.


The Use of Geometric Morphometric Techniques to Identify Sexual Dimorphism in Gait.
This study attempts to apply geometric morphometric techniques for the analysis of 3D kinematic marker-based gait data. As a test, we attempted to identify sexual dimorphism during the stance phase of the gait cycle. Two techniques were used to try to identify differences in the way males and females walk without the results being affected by individual differences in body shape and size. Twenty-eight kinematic markers were placed on the torso and legs of 6 male and 8 female subjects, and the 3D time varying coordinates of the kinematic markers were recorded. The gait cycle trials were time-normalized to 61 frames representing the stance phase of gait, and the change in the shape of the configuration of kinematic markers was analyzed using principal components analysis to produce 'gait signatures' that characterize the kinematics of each individual. The variation in the gait signatures was analyzed with a further principal components analysis. These methods were able to detect significant sexual dimorphism even after the effects of sexual body shape and size differences were factored out. We discuss insights gained from performing this study which may be of value to others attempting to apply geometric morphometric methods to motion analysis.


Down-regulation of K cell activity by neutrophils.
Human neutrophils, activated by phorbol-myristate acetate (PMA), (A-neutrophils), were found to suppress lymphocytic killer (K) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Resting (R) neutrophils, ie, PMA-untreated cells, were completely ineffective. Suppression was optimal when A-neutrophils were added at the beginning of the ADCC assay. Furthermore, A-neutrophils were found to cause an approximately 80% reduction in the number of Raji target cell-bound lymphocytes. These data indicate that A-neutrophils inhibit K cell activity by interfering with the target cell recognition. A-neutrophils were capable of reducing the percentage of Fc receptor (FcR)-bearing lymphocytes with a half-time of 7.2 minutes, through a process preventable by the serine-protease inhibitors tosyl-lysine-chloromethyl ketone (TLCK) and lima bean trypsin inhibitor (LBTI). Conversely, A-neutrophils caused a very slow decrease in the amount of Raji cell-bound antibodies, as detected by the complement-mediated lytic assay. Thus, only lymphocyte FcR structures seem to be highly susceptible to neutrophil-derived TLCK- and LBTI-inhibitable proteases. Furthermore, supernatants from A-neutrophils were found to inhibit K cell ADCC and lymphocyte binding to Raji target cells. In addition, LBTI prevented the A-neutrophil-dependent and the supernatant-dependent inhibition of both K cell ADCC activity and lymphocyte-target cell conjugate formation. Together these data suggest that A-neutrophils suppress K cell function through a protease-mediated impairment of the FcR binding capacity. The results provide evidence that human neutrophils are endowed with mechanisms to regulate K cell ADCC activity.


Gender-differences in disease distribution and outcome in hospitalized elderly: data from the REPOSI study.
Women live longer and outnumber men. On the other hand, older women develop more chronic diseases and conditions such as arthritis, osteoporosis and depression, leading to a greater number of years of living with disabilities. The aim of this study was to describe whether or not there are gender differences in the demographic profile, disease distribution and outcome in a population of hospitalized elderly people. Retrospective observational study including all patients recruited for the REPOSI study in the year 2010. Analyses are referred to the whole group and gender categorization was applied. A total of 1380 hospitalized elderly subjects, 50.5% women and 49.5% men, were considered. Women were older than men, more often widow and living alone or in nursing homes. Disease distribution showed that malignancy, diabetes, coronary artery disease, chronic kidney disease and chronic obstructive pulmonary disease were more frequent in men, but hypertension, osteoarthritis, anemia and depression were more frequent in women. Severity and comorbidity indexes according to the Cumulative Illness Rating Scale (CIRS-s and CIRS-c) were higher in men, while cognitive impairment evaluated by the Short Blessed Test (SBT), mood disorders by the Geriatric Depression Scale (GDS) and disability in daily life measured by Barthel Index (BI) were worse in women. In-hospital and 3-month mortality rates were higher in men. Our study showed a gender dimorphism in the demographic and morbidity profiles of hospitalized elderly people, emphasizing once more the need for a personalized process of healthcare.


mini-PAT (Peer Assessment Tool): a valid component of a national assessment programme in the UK?
To design, implement and evaluate a multisource feedback instrument to assess Foundation trainees across the UK. mini-PAT (Peer Assessment Tool) was modified from SPRAT (Sheffield Peer Review Assessment Tool), an established multisource feedback (360 degrees ) instrument to assess more senior doctors, as part of a blueprinting exercise of instruments suitable for assessment in Foundation programmes (first 2 years postgraduation). mini-PAT's content validity was assured by a mapping exercise against the Foundation Curriculum. Trainees' clinical performance was then assessed using 16 questions rated against a six-point scale on two occasions in the pilot period. Responses were analysed to determine internal structure, potential sources of bias and measurement characteristics. Six hundred and ninety-three mini-PAT assessments were undertaken for 553 trainees across 12 Deaneries in England, Wales and Northern Ireland. Two hundred and nineteen trainees were F1s or PRHOs and 334 were F2s. Trainees identified 5544 assessors of whom 67% responded. The mean score for F2 trainees was 4.61 (SD = 0.43) and for F1s was 4.44 (SD = 0.56). An independent t test showed that the mean scores of these 2 groups were significantly different (t = -4.59, df 390, p < 0.001). 43 F1s (19.6%) and 19 F2s (5.6%) were assessed as being below expectations for F2 completion. The factor analysis produced 2 main factors, one concerned clinical performance, the other humanistic qualities. Seventy-four percent of F2 trainees could have been assessed by as few as 8 assessors (95% CI +/-0.6) as they either scored an overall mean of 4.4 or above or 3.6 and below. Fifty-three percent of F1 trainees could have been assessed by as few as 8 assessors (95% CI +/-0.5) as they scored an overall mean of 4.5 or above or 3.5 and below. The hierarchical regression when controlling for the grade of trainee showed that bias related to the length of the working relationship, occupation of the assessor and the working environment explained 7% of the variation in mean scores when controlling for the year of the Foundation Programme (R squared change = 0.06, F change = 8.5, significant F change <0.001). As part of an assessment programme, mini-PAT appears to provide a valid way of collating colleague opinions to help reliably assess Foundation trainees.


Impact of multiple firings and resin cement type on shear bond strength between zirconia and resin cements.
The aim of this study was to evaluate the effect of multiple firings on the bond strength between yttria-tetragonal zirconia polycrystals (Y-TZP) and 2 types of resin cements. Sixty 3Y-TZP specimens (LAVA Frame Multi) were divided into 3 groups depending on the following firing procedures: (1) 2-firing cycles, (2) 5-firing cycles, (3) 10-firing cycles. Two samples from each group were investigated by using SEM to determine the morphological changes. All specimens were treated with 125 µm airborne-particle abrasion and the surface roughness of each specimen was measured. The specimens from each firing group were then further divided into 2 subgroups (n = 9) to apply 2 types of resin cement (MDP-free resin cement: RelyX Unicem-RU, and MDP containing resin cement: Panavia F 2.0-PA). The shear bond strength (SBS) test was performed and failure types of all the debonded specimens were classified by using a stereomicroscope as adhesive, cohesive, and mixed. The statistical analysis of surface roughness and SBS data were performed by using 1-way ANOVA and 2-way ANOVA followed by Tukey-HSD tests (α=.05). Failure modes were calculated as a percentage for each group. The bond strength of RU and PA to the specimens obtained with 2 firings were not statistically different from each other (P=.1). However, the SBS values of PA were found to be significantly higher than RU for the specimens obtained with 5 and 10 firing cycles (P=.001 and P=.02, respectively). Surface roughness analysis revealed no statistical difference between groups (P=.2). The SEM analysis of samples fired 5- and 10- times showed irregularities and boundary loss in zirconia grains, and empty spaces between zirconia grains. The bond strength of PA cement was higher than that of RU to the zirconia subjected to repeated firings (5 and 10 firing cycles). When zirconia is subjected to multiple firings, using MDP-containing resin cement can be recommended.


Association Between Atopic Dermatitis and Autism Spectrum Disorders: A Systematic Review.
Atopic dermatitis (AD) is an allergic disorder caused by both immunological dysregulation and epidermal barrier defect. Several studies have investigated the association between AD and mental health disorders. Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions characterized by impairments in social communication and restricted, stereotyped interests and behaviors. The concurrent increased prevalence of AD and ASD in the last decades has led many scientists to investigate the relationship between the two diseases. The aim of this systematic review was to examine the association between AD and ASD. A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed and ScienceDirect were searched up to March 2015 for all reports examining the association between ASD and AD. Descriptive statistics of the studies are reported. The review included 18 studies assessing the association between ASD and AD. Of these studies, two focused on ASD in relation to AD alone, 14 discussed ASD in relation to both AD and other atopic disorders, and two evaluated AD in parents of children with ASD. Most of these studies found a positive association between the two disorders, although there were some studies going in the opposite direction. The entity of the association is somewhat inconsistent among the different studies given that the frequencies of AD in ASD compared with a control group ranged from 7 to 64.2%. In addition, odds ratios (ORs) or hazard ratios (HRs) gave different results as three studies found a weak association with an OR below 2 and a nonsignificant p value, and three other studies found a moderate or strong association with an OR ranging from 1.52 to 7.17 and a significant p value. When all atopic disorders were considered when evaluating the risk of ASD, the association was strong with an HR of 3.4 or an OR of 1.24 and p < 0.001. Overall, the results of this systematic review seem to reveal an association between ASD and AD, suggesting that subjects with ASD have an increased risk of presenting with AD compared with typically developing controls, and vice versa. This association is supported by clinical/epidemiological aspects, shared genetic background and common immunological and autoimmune processes. However, the variability in study population and design, and the presence of other risk factors acting as confounding factors, sometimes contribute to inconsistent results. Further studies are needed to clarify the underlying pathophysiologic mechanism explaining the association between ASD and AD and to explore the causal association between the two conditions.


The interplay of dietary nutrient level and varying calcium to phosphorus ratios on efficacy of a bacterial phytase: 2. Ileal and total tract nutrient utilization.
A 14-d broiler experiment was conducted to assess the effects of 2 dietary variables on efficacy of a bacterial 6-phytase from Citobacter braakii on nutrient and phytate P (PP) utilization. Diets were formulated with or without nutrient matrix values (matrix) for phytase as negative control (NC) or positive control (PC), respectively, and with 2 Ca:total P (tP) levels (2:1 or 2.5:1). The diets were supplemented with 0, 1,000, or 2,000 phytase units (FYT)/kg of diet, thus producing a 2 × 2 × 3 factorial arrangement. Excreta were collected on d 19 to 21 and ileal digesta on d 21. There was no 3-way interaction on digestibility of any nutrient. There was matrix × phytase (P < 0.01) interaction for Ca and DM digestibility and Ca:tP × phytase interaction (P < 0.05) for acid hydrolyzed fat and Ca and P digestibility. Prececal flow of Mn, Zn, and Na was greater (P < 0.05) in NC diets, whereas phytase increased (P < 0.05) prececal flow of Mg, Fe, Mn, and Zn but decreased (P < 0.05) prececal Na flow. Total tract PP disappearance and total tract Ca retention increased (P < 0.05) with phytase supplementation in diets with 2:1 Ca:tP, whereas there was no effect of phytase supplementation on PP disappearance or Ca retention in diets with 2.5:1 Ca:tP. Total P and Ca retention were reduced (P < 0.05) in PC and NC diets when Ca:tP increased to 2.5:1, but the depression was more pronounced in the NC diet. In addition, PP disappearance decreased (P < 0.05) with increasing Ca:tP in the PC diets, but there was no effect of widening Ca:tP on PP disappearance in NC diets. It was concluded from the current study that the effect of phytase supplementation on P utilization is reduced when diets contain adequate P as exemplified in the PC diets and that the negative impact of wide Ca:tP is more pronounced in diets with phytase matrix allowance as exemplified in the NC diets.


A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy.
We report the development of an all-fiber-optic scanning endomicroscope capable of high-resolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized double-clad fiber, a compact rapid two-dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of bench-top SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth.


Hospitalization Trends and Comorbidities Among People With HIV/AIDS Compared With the Overall Hospitalized Population, Illinois, 2008-2014.
To understand trends in health care use among people living with HIV/AIDS (PLWHA), this study compared trends in hospitalization rates, comorbidities, and hospital death rates of hospitalized PLWHA with the overall hospitalized population in Illinois during 2008-2014. This study identified principal hospitalizations (the principal discharge diagnosis coded with an HIV-related billing code) and secondary HIV hospitalizations (a non-principal discharge diagnosis coded with an HIV-related billing code) from 2008-2014 Illinois hospital discharge data. Hospitalization rates among PLWHA were calculated using prevalence data from the Illinois Electronic HIV/AIDS Registry; US Census population estimates were used to calculate overall Illinois hospitalization rates. Joinpoint regression analysis was used to assess trends overall and among demographic subgroups. Comorbidities and discharge status for all hospitalizations were identified. In 2014, the hospitalization rate was 2.2 times higher among PLWHA than among the overall Illinois hospitalized population. From 2008 to 2014, principal HIV hospitalization rates per 1000 PLWHA decreased by 48% (from 71 to 37) and secondary HIV hospitalization rates declined by 26% (from 296 to 218). The decline in the principal HIV hospitalization rate was steepest from 2008 to 2011 (annual percentage change = -16.0%; P = .003). Mood disorders, substance-related diagnoses, and schizophrenia accounted for 18% to 22% of principal hospitalizations among PLWHA compared with 7% to 8% of overall Illinois hospitalizations. Hepatitis as a comorbidity was more common among hospitalized PLWHA (18%-22%) than among the overall Illinois hospitalized population (1.4%-1.5%). Hospitalized PLWHA were 3 times more likely than the overall Illinois hospitalized population to die while hospitalized. HIV hospitalizations are largely preventable with appropriate treatment and adherence. Additional efforts to improve retention in HIV care that address comorbidities of PLWHA are needed.


A Spanish Consensus on the Use of Safinamide for Parkinson's Disease in Clinical Practice.
Safinamide is an approved drug for the treatment of fluctuations in Parkinson's disease (PD). Scarce data are available on its use in clinical practice. A group of Spanish movement disorders specialists was convened to review the use of safinamide across different clinical scenarios that may guide neurologists in clinical practice. Eight specialists with recognized expertise in PD management elaborated the statements based on available evidence in the literature and on their clinical experience. The RAND/UCLA method was carried, with final conclusions accepted after a 2-round modified Delphi process. Higher level of agreement between panellists was reached for the following statements. Safinamide significantly improves mean daily ON time without troublesome dyskinesias [corrected]. Adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD. The efficacy of safinamide on motor fluctuations is maintained at long-term, with no increase over time in dyskinesias severity. The clinical benefits of safinamide on pain and depression remain unclear. Safinamide presents a similar incidence of adverse events compared with placebo. The efficacy and safety of safinamide shown in the pivotal clinical trials are reproduced in clinical practice, with improvement of parkinsonian symptoms, decrease of daily OFF time, control of dyskinesias at the long term, and good tolerability and safety.


Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID.
Despite considerable effort, the genetic factors responsible for >90% of the antibody deficiency syndromes IgAD and CVID remain elusive. To produce a functionally diverse antibody repertoire B lymphocytes undergo class switch recombination. This process is initiated by AID-catalyzed deamination of cytidine to uridine in switch region DNA. Subsequently, these residues are recognized by the uracil excision enzyme UNG2 or the mismatch repair proteins MutSalpha (MSH2/MSH6) and MutLalpha (PMS2/MLH1). Further processing by ubiquitous DNA repair factors is thought to introduce DNA breaks, ultimately leading to class switch recombination and expression of a different antibody isotype. Defects in AID and UNG2 have been shown to result in the primary immunodeficiency hyper-IgM syndrome, leading us to hypothesize that additional, potentially more subtle, DNA repair gene variations may underlie the clinically related antibody deficiencies syndromes IgAD and CVID. In a survey of twenty-seven candidate DNA metabolism genes, markers in MSH2, RAD50, and RAD52 were associated with IgAD/CVID, prompting further investigation into these pathways. Resequencing identified four rare, non-synonymous alleles associated with IgAD/CVID, two in MLH1, one in RAD50, and one in NBS1. One IgAD patient carried heterozygous non-synonymous mutations in MLH1, MSH2, and NBS1. Functional studies revealed that one of the identified mutations, a premature RAD50 stop codon (Q372X), confers increased sensitivity to ionizing radiation. Our results are consistent with a class switch recombination model in which AID-catalyzed uridines are processed by multiple DNA repair pathways. Genetic defects in these DNA repair pathways may contribute to IgAD and CVID.


Skin irritation and histopathologic alterations in rats exposed to lightstick contents, UV radiation and seawater.
Lightsticks are fishing gadgets that provide fluorescent lighting when two organic solutions are mixed. In NE Brazil, low-income coastal residents ignore their conventional use and collect lightsticks stranded on beaches. The lightstick solution is then used for various purposes, including direct human skin exposure. We assessed the reactions and possible cell damages on the skin of Wistar rats. Animals were exposed to lightstick contents, UV radiation and/or seawater. Lightstick exposure led to erythemas, oedemas and vesicles. Histopathologic alterations included proliferation of the epidermis and inflammatory infiltrates. In spite of the short time of experimentation (4 days), the rats exposed to the lightstick content alone and together with UV radiation and/or seawater provided evidence of irritation/alteration reactions that may evolve into skin cancer. Our results demonstrated a few of the potential problems associated with lightstick dumping into the ocean and highlight the need for further investigations about this new type of marine pollutant.


Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement.
Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement. We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain. We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups. Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.


Structural and electronic properties of polyacetylene and polyyne from hybrid and Coulomb-attenuated density functionals.
The bond length alternation (BLA), the highest-occupied-lowest-unoccupied (HO-LU) orbital energy gap, and the corresponding excitation energy are determined for trans-polyacetylene (PA) and polyyne (PY) using density functional theory. Results from the Coulomb-attenuated CAM-B3LYP functional are compared with those from the conventional BHHLYP and B3LYP hybrid functionals. BLA values and HO-LU gaps are determined using both finite oligomer and infinite chain calculations, subject to periodic boundary conditions. TDDFT excitation energies are determined for the oligomers. The oligomer excitation energies and HO-LU gaps are then used, in conjunction with the infinite chain HO-LU gap, to estimate the infinite chain excitation energy. Overall, BHHLYP and CAM-B3LYP give BLA values and excitation energies that are larger and more accurate than those obtained using B3LYP. The results highlight the degree to which excitation energies can be approximated using the HO-LU gaps-at the infinite limit, this approximation works well for B3LYP, but not for the other functionals, where the HO-LU gap is significantly larger. The study provides further evidence for the high-quality theoretical predictions that can be obtained from the CAM-B3LYP functional.


Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration.
Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.


Immune control of oncogenic γ-herpesviruses.
Human γ-herpesviruses contain Epstein Barr virus (EBV), the first human tumor virus that was identified in man, and Kaposi Sarcoma associated herpesvirus (KSHV), one of the most recently identified human oncogenic pathogens. Both of these have co-evolved with humans to cause tumors only in a minority of infected individuals, despite their exquisite ability to establish persistent infections. In this review we will summarize the fine-tuned balance between immune responses, immune escape and cellular transformation by these viruses, which results in life-long persistent, but asymptomatic infection with immune control in most virus carriers. A detailed understanding of this balance is required to immunotherapeutically reinstall it in patients that suffer from EBV and KSHV associated malignancies.


Placental Infection Associated with SARS-CoV-2 Wildtype Variant and Variants of Concern.
The original SARS-CoV-2 lineages have been replaced by successive variants of concern (VOCs) over time. The aim of this study was to perform an assessment of the placental infection by SARS-CoV-2 according to the predominant variant at the moment of COVID-19 diagnosis. This was a prospective study of SARS-CoV-2-positive pregnant women between March 2020 and March 2022. The population was divided into pregnancies affected by COVID-19 disease during 2020 (Pre-VOC group) and pregnancies affected after December 2020 by SARS-CoV-2 variants of concern (VOC group). The presence of virus was assessed by RT-PCR, and the viral variant was determined by whole genome sequencing. A total of 104 placentas were examined, among which 54 cases belonged to the Pre-VOC group and 50 cases belonged to the VOC group. Sixteen positive placental RT-PCR tests for SARS-CoV-2 were reported. The NGS analysis confirmed the SARS-CoV-2 lineage in placenta tissue. All samples corresponded to the Pre-VOC group, whereas no placental presence of SARS-CoV-2 was detected in the VOC group (16, 29.6% vs. 0, 0.0% p = 0.000). Preterm birth (9, 16.7% vs. 2, 4%; p = 0.036) and hypertensive disorders of pregnancy (14, 25.9% vs. 3, 6%; p = 0.003) were more frequent in the Pre-VOC group than in the VOC group. Finally, the VOC group was composed of 23 unvaccinated and 27 vaccinated pregnant women; no differences were observed in the sub-analysis focused on vaccination status. In summary, SARS-CoV-2-positive placentas were observed only in pregnancies infected by SARS-CoV-2 wildtype. Thus, placental SARS-CoV-2 presence could be influenced by SARS-CoV-2 variants, infection timing, or vaccination status. According to our data, the current risk of SARS-CoV-2 placental infection after maternal COVID disease during pregnancy should be updated.


A profile on HIV prevalence and risk behaviors among injecting drug users in Nigeria: should we be alarmed?
Injecting drug use is now recognized as a significant risk factor for HIV in sub-Saharan Africa. We evaluated prevalence and correlates of HIV among injecting drug users (IDUs) in Nigeria. A cross sectional design using respondent driven sampling was conducted in six states in 2010. Weighted HIV prevalence and injecting risk behaviors calculated using RDS analytic tool. Logistic regression was used to determine correlates of HIV infection, stratified by state. Total numbers of IDUs ranged from 197 in Lagos to 273 in Cross River and Oyo states. HIV prevalence was highest in Federal Capital Territory (FCT) at 9.3%, Kaduna 5.8%, Oyo 5.1%, Kano 4.9%, CR 3.3% and Lagos 3.0%. Although >90% of participants were male, females had higher HIV prevalence in all states surveyed except FCT (range: 7.4% in CR to 37.7% in Kano). Logistic regression showed that females were significantly more likely to be HIV positive in Kano [OR=33.2, 95% CI: 6.8-160.4], Oyo [AOR=15.9, 95% CI: 3.69-68.51], Lagos [OR=15.5, 95% CI: 2.41-99.5] and Kaduna states [AOR=19.6, 95% CI: 4.4-87.6]. For injecting risk behavior, only receptive sharing was associated with HIV [AOR=7.6, 95% CI: 1.2-48.7] and [AOR=0.2, 95% CI: 0.04-0.92] in Oyo and Kaduna states respectively. Considerable heterogeneity in the prevalence of HIV and associated risk behaviors exist among IDUs across Nigeria. Females had higher HIV prevalence among IDUs in five of six states, suggesting a need for targeted interventions for this hidden subgroup. Further research is needed to understand HIV transmission dynamics of IDUs in Nigeria. Community-based opioid substitution therapy and needle exchange programs should be implemented without delay.


Application of the Random Forest method to analyse epidemiological and phenotypic characteristics of Salmonella 4,[5],12:i:- and Salmonella Typhimurium strains.
Salmonella enterica 4,[5],12:i:- is a monophasic variant of S. Typhimurium. In the last decade, its prevalence rose sharply. Although S. 4,[5],12:i:- and S. Typhimurium are known to pose a considerable public health risk, there is no detailed information on the circulation of these serovars in Italy, particularly as far as veterinary isolates are concerned. For this reason, a data set of 877 strains isolated in the north-east of Italy from foodstuffs, animals and environment was analysed during 2005-2010. The Random Forests (RF) method was used to identify the most important epidemiological and phenotypic variables to show the difference between the two serovars. Both descriptive analysis and RF revealed that S. 4,[5],12:i:- is less heterogeneous than S. Typhimurium. RF highlighted that phage type was the most important variable to differentiate the two serovars. The most common phage types identified for S. 4,[5],12:i:- were DT20a, U311 and DT193. The same phage types were also found in S. Typhimurium isolates, although with a much lower prevalence. DT7 and DT120 were ascribed to the two serovars at comparable levels. DT104, DT2 and DT99 were ascribed exclusively to S. Typhimurium, and almost all the other phage types identified were more related to the latter serovar. Such data confirm that phage typing can provide an indication of the biphasic or monophasic state of the strains investigated and could therefore support serotyping results. However, phage typing cannot be used as the definitive method to differentiate the two serovars, as part of the phage types were detected for both serovars and, in particular, all phage types found for S. 4,[5],12:i- were found also for S. Typhimurium.


Acetylcholinesterase 1 in populations of organophosphate-resistant North American strains of the cattle tick, Rhipicephalus microplus (Acari: Ixodidae).
Rhipicephalus microplus, the cattle fever tick, is a global economic problem to the cattle industry due to direct infestation of cattle and pathogens transmitted during feeding. Cattle fever tick outbreaks continue to occur along the Mexico-US border even though the tick has been eradicated from the USA. The organophosphate (OP) coumaphos targets acetylcholinesterase (AChE) and is the approved acaricide for eradicating cattle fever tick outbreaks. There is evidence for coumaphos resistance developing in cattle ticks in Mexico, and OP-resistant R. microplus ticks were discovered in outbreak populations of Texas in 2005. The molecular basis of coumaphos resistance is not known, and our study was established to gather further information on whether AChE1 is involved in the resistance mechanism. We also sought information on allele diversity in tick populations with different levels of coumaphos resistance. The overarching project goal was to define OP resistance-associated gene mutations such that a DNA-based diagnostic assay could be developed to assist the management of resistance. Three different AChE transcripts have been reported in R. microplus, and supporting genomic and transcriptomic data are available at CattleTickBase. Here, we report the complete R. microplus AChE1 gene ascertained by sequencing a bacterial artificial chromosome clone containing the entire coding region and the flanking 5' and 3' regions. We also report AChE1 sequences of larval ticks from R. microplus strains having different sensitivities to OP. To accomplish this, we sequenced a 669-bp region of the AChE1 gene corresponding to a 223 amino acid region of exon 2 to assess alleles in seven strains of R. microplus with varying OP resistance phenotypes. We identified 72 AChE1 sequence variants, 2 of which are strongly associated with OP-resistant phenotypes. Esterase-like sequences from the R. microplus transcriptome RmiTr Version 1.0 were compared to the available sequence databases to identify other transcripts with similarity to AChE1.


Nonclonal hemopoietic progenitor cells detected in long-term marrow cultures from a Turner syndrome mosaic with chronic myeloid leukemia.
We have investigated the clonality of Ph1-negative hemopoietic progenitor cells appearing in long-term marrow cultures established with cells from a mosaic Turner syndrome patient (46,XX/45,X) with Ph1-positive chronic myeloid leukemia (CML). The Ph1-positive clone had been shown previously to have arisen from a cell of the 45,X lineage. At the time of the present study, the patient was five years post-diagnosis and had been off chemotherapy for two months following a year of treatment for lymphoid blast crisis. All analyzed unstimulated marrow metaphases and each of 23 individually analyzed erythroid and granulocyte colonies produced in assays of the starting marrow were 45,X,Ph1. Pooled granulocyte colonies from the same assays yielded four metaphases that were 45,X,Ph1 and one that was 46,XX. Very few hemopoietic progenitors were detected in long-term cultures at any time; however, all of four individually analyzed large granulocyte colonies and a pooled granulocyte colony preparation obtained from assays of 4- to 6-week-old adherent layers yielded exclusively 46,XX metaphases. These results provide evidence that non-clonal progenitors can persist in patients with CML, even after the onset and treatment of blast crisis, and that the long-term marrow culture system provides a sensitive method for detecting such cells.


Online Nonlinear AUC Maximization for Imbalanced Data Sets.
Classifying binary imbalanced streaming data is a significant task in both machine learning and data mining. Previously, online area under the receiver operating characteristic (ROC) curve (AUC) maximization has been proposed to seek a linear classifier. However, it is not well suited for handling nonlinearity and heterogeneity of the data. In this paper, we propose the kernelized online imbalanced learning (KOIL) algorithm, which produces a nonlinear classifier for the data by maximizing the AUC score while minimizing a functional regularizer. We address four major challenges that arise from our approach. First, to control the number of support vectors without sacrificing the model performance, we introduce two buffers with fixed budgets to capture the global information on the decision boundary by storing the corresponding learned support vectors. Second, to restrict the fluctuation of the learned decision function and achieve smooth updating, we confine the influence on a new support vector to its -nearest opposite support vectors. Third, to avoid information loss, we propose an effective compensation scheme after the replacement is conducted when either buffer is full. With such a compensation scheme, the performance of the learned model is comparable to the one learned with infinite budgets. Fourth, to determine good kernels for data similarity representation, we exploit the multiple kernel learning framework to automatically learn a set of kernels. Extensive experiments on both synthetic and real-world benchmark data sets demonstrate the efficacy of our proposed approach.


Foam granulation: new developments in pharmaceutical solid oral dosage forms using twin screw extrusion machinery.
This paper investigates foam granulation in a twin screw extruder as a new continuous wet granulation technique for pharmaceutical powder drug formulations. Foamed aqueous binder has a reportedly lower soak-to-spread ratio than drop or spray liquid addition in batch granulation. This work demonstrates a twin screw extruder configuration for foam granulation and subsequently compares the new approach against liquid injection in the granulation of α-lactose monohydrate with a methylcellulose binder. Trials were conducted at high powder output rates (20-40 kg/h) and high screw speeds (220-320 RPM) with two screw configurations. Process stability improved with the new technique allowing granulation with less binder. The extruded mass maintained a low exit temperature, being insensitive to operating conditions unlike the liquid injection approach, where temperatures rose significantly as flow rate increased. The particle size distribution by foam granulation reflected a more uniformly wetted mass with larger granule growth noted even for conditions where dry powder exited by liquid injection. Other factors were found similar between the two binder delivery methods such as consumed mechanical energy, as well as fracture strength and compressibility of produced granules.


Determination of mechanical stiffness of bone by pQCT measurements: correlation with non-destructive mechanical four-point bending test data.
Mechanical tests of bone provide valuable information about material and structural properties important for understanding bone pathology in both clinical and research settings, but no previous studies have produced applicable non-invasive, quantitative estimates of bending stiffness. The goal of this study was to evaluate the effectiveness of using peripheral quantitative computed tomography (pQCT) data to accurately compute the bending stiffness of bone. Normal rabbit humeri (N=8) were scanned at their mid-diaphyses using pQCT. The average bone mineral densities and the cross-sectional moments of inertia were computed from the pQCT cross-sections. Bending stiffness was determined as a function of the elastic modulus of compact bone (based on the local bone mineral density), cross-sectional moment of inertia, and simulated quasistatic strain rate. The actual bending stiffness of the bones was determined using four-point bending tests. Comparison of the bending stiffness estimated from the pQCT data and the mechanical bending stiffness revealed excellent correlation (R2=0.96). The bending stiffness from the pQCT data was on average 103% of that obtained from the four-point bending tests. The results indicate that pQCT data can be used to accurately determine the bending stiffness of normal bone. Possible applications include temporal quantification of fracture healing and risk management of osteoporosis or other bone pathologies.


Naltrexone: A Pan-Addiction Treatment?
Addiction is a major public health problem with few efficacious and safe treatments. The goal of this review is to provide an evidence-based assessment of the therapeutic role of the opioid antagonist naltrexone across the addiction spectrum-substance-based and behavioral. The PubMed database was searched for randomized, placebo-controlled clinical trials that investigated the oral or intramuscular long-acting formulation of naltrexone in substance use disorders or behavioral addictions such as pathological gambling, kleptomania, and trichotillomania. Thirty-nine efficacy studies were retrieved, covering alcohol use disorder (n = 22), opioid use disorder (n = 6), nicotine use disorder (n = 5), stimulant use disorder (n = 2), gambling disorder (n = 2), trichotillomania (n = 1), and kleptomania (n = 1). Despite the very different presentations within and between both addiction categories, the data, as a whole, show consistency in favor of naltrexone's relative efficacy and safety. Given the potential benefit and good tolerability revealed in the studies, the high morbidity associated with addiction, and the dearth of alternate treatments, naltrexone would seem like an underutilized treatment option. Further, naltrexone's seemingly broad anti-addiction efficacy supports a shared role for brain opioid pathways in the pathophysiology of addiction, broadly defined. More studies investigating the efficacy and tolerability of naltrexone and other opioid modulators are warranted. Studies should also further examine the effect of combining psychotherapy with naltrexone, as well as the potential role of naltrexone in treating comorbid addictions.


Podokinetic stimulation causes shifts in perception of straight ahead.
Podokinetic after-rotation (PKAR) is a phenomenon in which subjects inadvertently rotate when instructed to step in place after a period of walking on a rotating treadmill. PKAR has been shown to transfer between different forms of locomotion, but has not been tested in a non-locomotor task. We conducted two experiments to assess effects of PKAR on perception of subjective straight ahead and on quiet standing posture. Twenty-one healthy young right-handed subjects pointed to what they perceived as their subjective straight ahead with a laser pointer while they were recorded by a motion capture system both before and after a training period on the rotating treadmill. Subjects performed the pointing task while standing, sitting on a chair without a back, and a chair with a back. After the training period, subjects demonstrated a significant shift in subjective straight ahead, pointing an average of 29.1 ± 10.6° off of center. The effect was direction-specific, depending on whether subjects had trained in the clockwise or counter-clockwise direction. Postures that limited subjects' ability to rotate the body in space resulted in reduction, but not elimination, of the effect. The effect was present in quiet standing and even in sitting postures where locomotion was not possible. The robust transfer of PKAR to non-locomotor tasks, and across locomotor forms as demonstrated previously, is in contrast to split-belt adaptations that show limited transfer. We propose that, unlike split-belt adaptations, podokinetic adaptations are mediated at supraspinal, spatial orientation areas that influences spinal-level circuits for locomotion.


Safety and feasibility of intra-arterial nicardipine for the treatment of subarachnoid hemorrhage-associated vasospasm: initial clinical experience with high-dose infusions.
Delayed cerebral ischemia from vasospasm is a major complication after aneurysmal subarachnoid hemorrhage (SAH), but complications and/or low efficacy are associated with current therapy. We report our initial experience with intra-arterial use of a calcium channel blocker, nicardipine. A retrospective review of a consecutive series of patients with clinical and angiographic vasospasm treated with intra-arterial nicardipine was performed. Standard criteria for definition of significant, intractable vasospasm after aneurysmal SAH were used. After catheter angiographic confirmation of vasospasm, arteries showing severe narrowing were targeted for superselective catheterization. Nicardipine was infused at a high dose rate (0.415-0.81 mg/min). Contrast injections were performed at 2-5-mg intervals to assess effective response (a 60% increase in arterial diameter of the most severely decreased in caliber vessel compared with the very first angiographic run). Eleven consecutive patients underwent a total of 20 procedures; most had SAH with high Hunt and Hess grades (III or IV). All had depressed level of consciousness; others had paresis (7/20, 35%), aphasia (1/20, 5%), and facial nerve palsy (1/20, 5%). Between 10 and 40 mg of nicardipine was used. A 60% increase in diameter of the main affected artery compared with the initial diameter measured in the initial angiographic run was achieved in all procedures. Clinical improvement (resolved focal symptoms or increased Glasgow Coma Score) occurred in 10 of 11 patients (91%). One patient died from complications of the initial hemorrhage. No complications occurred after 16 of 20 procedures (80%); minor complications without sequelae occurred after the remaining procedures. Follow-up of at least 2 months in 10 survivors revealed minor or no deficits in most patients with a Glasgow Outcome Score of 1 or 2 in 9 of 10 patients (90%). In this small series, high-dose intra-arterial nicardipine infusion to treat SAH-associated vasospasm seems to be safe and effective.


Non-cytotoxic cobra cardiotoxin A5 binds to alpha(v)beta3 integrin and inhibits bone resorption. Identification of cardiotoxins as non-RGD integrin-binding proteins of the Ly-6 family.
Severe tissue necrosis with a retarded wound healing process is a major symptom of a cobra snakebite. Cardiotoxins (CTXs) are major components of cobra venoms that belong to the Ly-6 protein family and are implicated in tissue damage. The interaction of the major CTX from Taiwan cobra, i.e. CTX A3, with sulfatides in the cell membrane has recently been shown to induce pore formation and cell internalization and to be responsible for cytotoxicity in cardiomyocytes (Wang, C.-H., Liu, J.-H., Lee, S.-C., Hsiao, C.-D., and Wu, W.-g. (2006) J. Biol. Chem. 281, 656-667). We show here that one of the non-cytotoxic CTXs, i.e. CTX A5 or cardiotoxin-like basic polypeptide, from Taiwan cobra specifically bound to alpha(v)beta3 integrin and inhibited bone resorption activity. We found that both membrane-bound and recombinant soluble alpha(v)beta3 integrins bound specifically to CTX A5 in a dose-dependent manner. Surface plasmon resonance analysis showed that human soluble alpha(v)beta3 bound to CTX A5 with an apparent affinity of approximately 0.3 microM. Calf pulmonary artery endothelial cells, which constitutively express alpha(v)beta3, showed a CTX A5 binding profile similar to that of membrane-bound and soluble alpha(v)beta3 integrins, suggesting that endothelial cells are a potential target for CTX action. We tested whether CTX A5 inhibits osteoclast differentiation and bone resorption, a process known to be involved in alpha(v)beta3 binding and inhibited by RGD-containing peptides. We demonstrate that CTX A5 inhibited both activities at a micromolar range by binding to murine alpha(v)beta3 integrin in osteoclasts and that CTX A5 co-localized with beta3 integrin. Finally, after comparing the integrin binding affinity among CTX homologs, we propose that the amino acid residues near the two loops of CTX A5 are involved in integrin binding. These results identify CTX A5 as a non-RGD integrin-binding protein with therapeutic potential as an integrin antagonist.


Chromenones as Multineurotargeting Inhibitors of Human Enzymes.
The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).


The Cost of Long Catalytic Loops in Folding and Stability of the ALS-Associated Protein SOD1.
A conspicuous feature of the amyotrophic lateral sclerosis (ALS)-associated protein SOD1 is that its maturation into a functional enzyme relies on local folding of two disordered loops into a catalytic subdomain. To drive the disorder-to-order transition, the protein employs a single Zn2+ ion. The question is then if the entropic penalty of maintaining such disordered loops in the immature apoSOD1 monomer is large enough to explain its unusually low stability, slow folding, and pathological aggregation in ALS. To find out, we determined the effects of systematically altering the SOD1-loop lengths by protein redesign. The results show that the loops destabilize the apoSOD1 monomer by ∼3 kcal/mol, rendering the protein marginally stable and accounting for its aggregation behavior. Yet the effect on the global folding kinetics remains much smaller with a transition-state destabilization of <1 kcal/mol. Notably, this 1/3 transition-state to folded-state stability ratio provides a clear-cut example of the enigmatic disagreement between the Leffler α value from loop-length alterations (typically 1/3) and the "standard" reaction coordinates based on solvent perturbations (typically >2/3). Reconciling the issue, we demonstrate that the disagreement disappears when accounting for the progressive loop shortening that occurs along the folding pathway. The approach assumes a consistent Flory loop entropy scaling factor of c = 1.48 for both equilibrium and kinetic data and has the added benefit of verifying the tertiary interactions of the folding nucleus as determined by phi-value analysis. Thus, SOD1 not only represents a case where evolution of key catalytic function has come with the drawback of a destabilized apo state but also stands out as a well-suited model system for exploring the physicochemical details of protein self-organization.


Meta-analysis of the prevalence of tooth wear in primary dentition.
To conduct a meta-analysis of all the studies published in literature over the past three decades on the prevalence of dental erosion in preschool children. The Pubmed data base revealed only one systematic review on the prevalence of tooth wear in children up to 5 years old. The search included works published from January 1982 to September 2012, using the following combinations of keywords: 1) "dental erosion" AND "children"; 2) "dental erosion in primary dentition"; 3) "dental" AND "attrition" AND "prevalence". The inclusion criteria for papers on tooth wear were the deciduous dentition observed only on the palatal and buccal sides with the distinction of erosion, attrition and abrasion. We took into consideration only randomized control trials. We excluded articles not written in English, case reports, historical and forensic studies, in vitro and in vivo studies. In case of doubt and/or when an abstract was not available, the full text copy of the article was examined. The first search on Pubmed revealed 29 articles, the same found in the study of Kreulen [2010], however we selected only multicentric studies focused on children of age below 5 years old, in which only the primary dentition (D) and only anterior teeth (incisors) were considered. Both forest plot and scatter plot showed the prevalence of dental erosion in primary dentition, and that older children had a more severe dental erosion. Dental erosion should be considered a paediatric dentistry pathological entity as well as dental caries, and it can be related to more severe systemic diseases such as Gastroesophageal reflux disease. In addition, taking care of these little patients is important because they might suffer persentiveness, and also pulpal pathology caused by the typical structure of deciduous teeth, where the pulp cavity is wide and close to the dentine and the enamel.


Challenges associated with current and future TB treatment.
Current tuberculosis (TB) treatment is based on a combination of drugs that were developed mostly in the central decades of the last century. Cure rates are high for drug sensitive strains of Mycobacterium tuberculosis (M. tb) when the recommended complex and lengthy treatment protocols are adhered to. However the difficulty in correctly prescribing and adhering to these protocols, the emergence of M tb strains resistant to multiple drugs, and drug-drug interactions that interfere with optimal treatment of HIV and TB coinfected patients have generated a pressing need for improved TB therapies. Together with the ominous global burden of TB, these shortcomings of current treatment have contributed to a renewed interest in the development of improved drugs and protocols for the treatment of tuberculosis. This article highlights hurdles related to the optimized use of existing drugs and challenges related to the development of novel, improved products, focusing in particular on aspects inherent in TB drug clinical development. Concluding comments propose processes for more efficient development of new TB therapies.


Overweight and poor? On the relationship between income and the body mass index.
Contrary to conventional wisdom, NHANES data indicate that the poor have never had a statistically significant higher prevalence of overweight status at any time in the last 35 years. Despite this empirical evidence, the view that the poor are less healthy in terms of excess accumulation of fat persists. This paper provides evidence that conventional wisdom is reflecting important differences in the relationship between income and the body mass index. The first finding is based on distribution-sensitive measures of overweight which indicates that the severity of overweight has been higher for the poor than the nonpoor throughout the last 35 years. The second finding is from a newly introduced estimator, unconditional quantile regression (UQR), which provides a measure of the income-gradient in BMI at different points on the unconditional BMI distribution. The UQR estimator indicates that the strongest relationship between income and BMI is observed at the tails of the distribution. There is a statistically significant negative income gradient in BMI at the obesity threshold and some evidence of a positive gradient at the underweight threshold. Both of these UQR estimates imply that for those at the tails of the BMI distribution, increases in income are correlated with healthier BMI values.


Cytoprotective effect of eckol against oxidative stress-induced mitochondrial dysfunction: involvement of the FoxO3a/AMPK pathway.
This study investigated the cytoprotective effect of Ecklonia cava-derived eckol against H2O2-induced mitochondrial dysfunction in Chang liver cells. While H2O2 augmented levels of mitochondrial reactive oxygen species (ROS), eckol decreased it. Eckol also attenuated high intracellular Ca(2+) levels stimulated by H2O2 and recovered H2O2-diminished ATP levels and succinate dehydrogenase activity. Eckol time-dependently increased the expression of manganese superoxide dismutase (Mn SOD), a mitochondrial antioxidant enzyme with cytoprotective effect against oxidative stress. Eckol recovered Mn SOD expression and activity that were decreased by H2O2. Finally, eckol induced Mn SOD through phosphorylated AMP-activated protein kinase (AMPK) and forkhead box O3a (FoxO3a). Specific silencing RNAs (siRNAs) against FoxO3a and AMPK reduced eckol-stimulated Mn SOD expression, and diethyldithiocarbamate (Mn SOD inhibitor) and siRNA against Mn SOD reduced the cytoprotective effect of eckol against H2O2-provoked cell death. These results demonstrate that eckol protects cells from mitochondrial oxidative stress by activating AMPK/FoxO3a-mediated induction of Mn SOD.


Theoretical examination of solvent and R group dependence in gold thiolate nanoparticle synthesis.
The growth of gold thiolate nanoparticles can be affected by the solvent and the R group on the ligand. In this work, the difference between methanol and benzene solvents as well as the effect of alkyl (methyl) and aromatic (phenyl) thiols on the reaction energies and barrier heights is investigated theoretically. Density functional theory (DFT) calculations using the BP86 functional and a triple ζ polarized basis set show that the overall reaction favors methylthiol over phenylthiol with reaction energies of -0.54 and -0.39 eV in methanol, respectively. At the same level of theory, the methanol solvent is favored over the benzene solvent for reactions forming ions; in benzene, the overall reaction energies for methylthiol and phenylthiol reacting with AuCl4(-) to form Au(HSR)2(+) are 0.37 eV and 0.44 eV, respectively. Methylthiol in methanol also has the lowest barrier heights at about 0.3 eV, whereas phenylthiol has barrier heights around 0.4 eV. Barrier heights in benzene are significantly larger than those in methanol.


Early component changes in corticomotor evoked potentials following experimental stroke.
Corticomotor evoked potentials have recently been used in experimental animals and patients as a measure of neurologic function after stroke. However, little is known about the fundamental electrophysiologic properties contributing to the formation of these potentials. To define some of these properties, corticomotor evoked potentials were recorded from the contralateral hindlimb in response to transcortical stimulation in cats anesthetized with halothane. These potentials were obtained hourly for 6 hours after middle cerebral artery occlusion. Four major identifiable components were recorded in control responses. Immediately after infarction, all component amplitudes were significantly attenuated. However, after approximately 5 hours, the early latency components exceeded control values; late latency components were also increased. Corresponding somatosensory evoked potentials were abolished and did not return throughout the recording session. Based on classic neurophysiologic studies, the amplitude increment can be explained as combined activation of low-threshold brainstem facilitatory centers and/or direct activation of subcortical axonal pathways. With further study, corticomotor evoked potentials may be a valuable adjunct to current electrophysiologic monitoring techniques, particularly with regard to defining the extent and location of an infarct, as well as to assessing functional recovery.


The structure of schizotypal personality traits: a cross-national study.
Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.


Hypoxia tolerance in animals: biology and application.
Many invertebrates and ectothermic vertebrates successfully cope with a fluctuating supply of ambient oxygen-and consequently, a highly variable tissue oxygenation-through increasing their antioxidant barriers. During chronic deprivation of oxygen, however, the hypometabolic defense mode of the fruit fly Drosophila, the hypoxia-induced behavioral hypothermia of the crayfish Pacifastacus leniusculus, and the production of ethanol during anoxia by the crucian carp Carassius carassius all indicate that these animals are also capable of utilizing a suite of genetic and physiological defenses to survive otherwise lethal reductions in tissue oxygenation. Normally, much of an organism's gene response to hypoxia is orchestrated via the hypoxia-inducible transcription factor HIF. Recent developments expand our view of HIF function even further by highlighting regulatory roles for HIF in the hypometabolism of insects, in the molting and the normoxic immune response of crustaceans, and in the control-via the downstream effector gene erythropoietin-of the hypoxic ventilatory response and pulmonary hypertension in mammals. These and related topics were collectively presented by the authors in a symposium of the 2008 ICA-CBP conference at Mara National Reserve, Kenya, Africa. This synthesis article communicates the essence of the symposium presentations to the wider community.


Structure of the monotopic membrane protein (S)-mandelate dehydrogenase at 2.2 Å resolution.
The x-ray structure of the monotopic membrane protein (S)-mandelate dehydrogenase (MDH) from Pseudomonas putida reveals an inherent flexibility of its membrane binding segment that might be important for its biological activity. The surface of MDH exhibits a concentration of the positive charges on one side and the negative charges on the other side. The putative membrane binding surface of MDH has a concentric circular ridge, formed by positively charged residues, which projects away from the protein surface by ∼4 Å; this is an unique structural feature and not observed in other monotopic membrane proteins to our knowledge. There are three α-helixes in the membrane binding region. Based on the structure of MDH, it is possible to propose that the interaction of MDH with the membrane is stabilized by coplanar electrostatic interactions, between the positively charged concentric circular ridge and the negatively charged head-groups of the phospholipid bilayer, along with three α-helixes that provide additional stability by inserting into the membrane. The structure reveals the possible orientation of these helixes along with possible roles for the individual residues which form those helixes. These α-helixes may play a role in the enzyme's mobility. A detergent molecule, N-Dodecyl-β-maltoside, is inserted between the membrane binding region and rest of the molecule and may provide structural stability to intra-protein regions by forming hydrogen bonds and close contacts. From the average B-factor of the MDH structure, it is likely that MDH is highly mobile, which might be essential for its interaction in membrane and non-membrane environments, as its substrate (S)-mandelate, is from the cytoplasm, while its electron acceptor is a component of the membrane electron transport chain.


Reproductive phenology across the lunar cycle: parental decisions, offspring responses, and consequences for reef fish.
Most organisms reproduce in a dynamic environment, and life-history theory predicts that this can favor the evolution of strategies that capitalize on good times and avoid bad times. When offspring experience these environmental changes, fitness can depend strongly upon environmental conditions at birth and at later life stages. Consequently, fitness will be influenced by the reproductive decisions of parents (i.e., birth date effects) and developmental decisions (e.g., adaptive plasticity) of their offspring. We explored the consequences of these decisions using a highly iteroparous coral reef fish (the sixbar wrasse, Thalassoma hardwicke) and in a system where both parental and offspring environments vary with the lunar cycle. We tested the hypotheses that (1) reproductive patterns and offspring survival vary across the lunar cycle and (2) offspring exhibit adaptive plasticity in development time. We evaluated temporal variation in egg production from February to June 2017, and corresponding larval developmental histories (inferred from otolith microstructure) of successful settlers and surviving juveniles that were spawned during that same period. We documented lunar-cyclic variation in egg production (most eggs were spawned at the new moon). This pattern was at odds with the distribution of birth dates of settlers and surviving juveniles-most individuals that successfully survived to settlement and older stages were born during the full moon. Consequently, the probability of survival across the larval stage was greatest for offspring born close to the full moon, when egg production was at its lowest. Offspring also exhibited plasticity in developmental duration, adjusting their age at settlement to settle during darker portions of the lunar cycle than expected given their birth date. Offspring born near the new moon tended to be older and larger at settlement, and these traits conveyed a strong fitness advantage (i.e., a carryover effect) through to adulthood. We speculate that these effects (1) are shaped by a dynamic landscape of risk and reward determined by moonlight, which differentially influences adults and offspring, and (2) can explain the evolution of extreme iteroparity in sixbars.


Exposure to silver impairs learning and social behaviors in adult zebrafish.
Silver and silver nanoparticles are used in several consumer products, particularly sterilizing agents. Ag+ released from the particles causes physiological damages of aquatic organisms. However, the effects of silver on neural and behavioral functions of fish remain unclear. Here, we used zebrafish as a model to investigate the impacts of silver on social, learning and memory behaviors in teleost. Adult zebrafish showed mortality rates of 12.875% and 100% on 72 h exposure to 30 and ≥ 50 ppb of silver nitrate, respectively. Silver accumulation in the brain increased on exposure to 10 and 30 ppb of AgNO3. The physical fitness of the zebrafish, measured by novel tank diving test and swimming performance, decreased after 72 h incubation in 30 ppb of AgNO3. Exposure to 10 ppb of AgNO3 impaired social preference, social recognition, learning, and memory, but did not affect anxiety level, aggressiveness, and shoaling behavior. In situ hybridization of c-fos mRNA showed that AgNO3 treatment decreased neural activity in the brain areas crucial for learning, memory, and social behaviors, including the medial and dorsal zones of the dorsal telencephalic area. In conclusion, 72 h exposure to AgNO3 in a sublethal level impaired learning and social behaviors, indicating neurotoxicity in adult zebrafish.


HbA1c, fasting and 2 h plasma glucose in current, ex- and never-smokers: a meta-analysis.
The relationships between smoking and glycaemic variables have not been well explored. We compared HbA1c, fasting plasma glucose (FPG) and 2 h plasma glucose (2H-PG) in current, ex- and never-smokers. This meta-analysis used individual data from 16,886 men and 18,539 women without known diabetes in 12 DETECT-2 consortium studies and in the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) and Telecom studies. Means of three glycaemic variables in current, ex- and never-smokers were modelled by linear regression, with study as a random factor. The I (2) statistic was used to evaluate heterogeneity among studies. HbA1c was 0.10% (95% CI 0.08, 0.12) (1.1 mmol/mol [0.9, 1.3]) higher in current smokers and 0.03% (0.01, 0.05) (0.3 mmol/mol [0.1, 0.5]) higher in ex-smokers, compared with never-smokers. For FPG, there was no significant difference between current and never-smokers (-0.004 mmol/l [-0.03, 0.02]) but FPG was higher in ex-smokers (0.12 mmol/l [0.09, 0.14]). In comparison with never-smokers, 2H-PG was lower (-0.44 mmol/l [-0.52, -0.37]) in current smokers, with no difference for ex-smokers (0.02 mmol/l [-0.06, 0.09]). There was a large and unexplained heterogeneity among studies, with I (2) always above 50%; I (2) was little changed after stratification by sex and adjustment for age and BMI. In this study population, current smokers had a prevalence of diabetes that was 1.30% higher as screened by HbA1c and 0.52% lower as screened by 2H-PG, in comparison with never-smokers. Across this heterogeneous group of studies, current smokers had a higher HbA1c and lower 2H-PG than never-smokers. This will affect the chances of smokers being diagnosed with diabetes.


Retinoic acid increases glucocorticoid receptor phosphorylation via cyclin-dependent kinase 5.
Glucocorticoid receptor (GR) function is modulated by phosphorylation. As retinoic acid (RA) can activate some cytoplasmic kinases able to phosphorylate GR, we investigated whether RA could modulate GR phosphorylation in neuronal cells in a context of long-term glucocorticoid exposure. A 4-day treatment of dexamethasone (Dex) plus RA, showed that RA potentiated the (Dex)-induced phosphorylation on GR Serine 220 (pSer220GR) in the nucleus of a hippocampal HT22 cell line. This treatment increased the cytoplasmic ratio of p35/p25 proteins, which are major CDK5 cofactors. Roscovitine, a pharmacological CDK5 inhibitor, or a siRNA against CDK5 prevented RA potentiation of GR phosphorylation. Furthermore, roscovitine counter-acted the effect of RA on GR sensitive target proteins such as BDNF or tissue-transglutaminase. These data help understanding the interaction between RA- and glucocorticoid-signalling pathways, both of which have strong influences on the adult brain.


Bone transport with an external fixator and a locking plate for segmental tibial defects.
Although gradual bone transport may permit the restoration of large-diameter bones, complications are common owing to the long duration of external fixation. In order to reduce such complications, a new technique of bone transport involving the use of an external fixator and a locking plate was devised for segmental tibial bone defects. A total of ten patients (nine men, one woman) with a mean age at operation of 40.4 years (16 to 64) underwent distraction osteogenesis with a locking plate to treat previously infected post-traumatic segmental tibial defects. The locking plate was fixed percutaneously to bridge proximal and distal segments, and was followed by external fixation. After docking, percutaneous screws were fixed at the transported segment through plate holes. At the same time, bone grafting was performed at the docking site with the external fixator removed. The mean defect size was 5.9 cm (3.8 to 9.3) and mean external fixation index was 13.4 days/cm (11.8 to 19.5). In all cases, primary union of the docking site and distraction callus was achieved, with an excellent bony result. There was no recurrence of deep infection or osteomyelitis, and with the exception of one patient with a pre-existing peroneal nerve injury, all achieved an excellent or good functional result. With short external fixation times and low complication rates, bone transport with a locking plate could be recommended for patients with segmental tibial defects.


Diffraction in crystalline colloidal-array photonic crystals.
We characterized the diffraction and crystal structure of a crystalline colloidal array (CCA) photonic crystal composed of 270 nm diameter polystyrene spheres which have a nearest neighbor spacing of approximately 540 nm. This CCA diffracts light in first order at approximately 1200 nm and shows strong diffraction in the visible spectral region from higher order planes. We quantitatively examined the relative diffraction intensities of the putative fcc (111), (200), (220), and (311) planes. Comparing these intensities to those calculated theoretically we find that the crystal structure is fcc with significant stacking faults. Essentially, no light transmits at the Bragg angle for the fcc (111) planes even through thin approximately 40 microm thick CCA. However, much of this light is diffusely scattered about the Bragg angle due to crystal imperfections. Significant transmission occurs from thin samples oriented at the Bragg condition for the fcc (200), (220), and (311) planes. We also observe moderately intense two-dimensional diffraction from the first few layers at the crystal surfaces. We also examined the sample thickness dependence of diffraction from CCA photonic crystals prepared from approximately 120 nm polystyrene spheres whose fcc (111) planes diffract in the visible spectral region. These experimental observations, aided by calculations based upon a simple but flexible model of light scattering from an arbitrary collection of colloidal spheres, make clear that fabrication of three-dimensional photonic band gap crystals will be challenged by crystal imperfections.


Accreditation and ISO certification: do they explain differences in quality management in European hospitals?
Hospital accreditation and International Standardisation Organisation (ISO) certification offer alternative mechanisms for improving safety and quality, or as a mark of achievement. There is little published evidence on their relative merits. To identify systematic differences in quality management between hospitals that were accredited, or certificated, or neither. Research design of compliance with measures of quality in 89 hospitals in six countries, as assessed by external auditors using a standardized tool, as part of the EC-funded of Assessing Response to Quality Improvement Strategies project. Compliance scores in six dimensions of each hospital-grouped according to the achievement of accreditation, certification or neither. Of the 89 hospitals selected for external audit, 34 were accredited (without ISO certification), 10 were certificated under ISO 9001 (without accreditation) and 27 had neither accreditation nor certification. Overall percentage scores for 229 criteria of quality and safety were 66.9, 60.0 and 51.2, respectively. Analysis confirmed statistically significant differences comparing mean scores by the type of external assessment (accreditation, certification or neither); however, it did not substantially differentiate between accreditation and certification only. Some of these associations with external assessments were confounded by the country in which the sample hospitals were located. It appears that quality and safety structures and procedures are more evident in hospitals with either the type of external assessment and suggest that some differences exist between accredited versus certified hospitals. Interpretation of these results, however, is limited by the sample size and confounded by variations in the application of accreditation and certification within and between countries.


The impact of obesity on receipt of adjuvant chemotherapy for breast cancer in the National Comprehensive Cancer Network (NCCN) centers.
Disparities in the receipt of adjuvant chemotherapy for early stage breast cancer is an important factor influencing mortality. We investigated whether greater body mass index (BMI) decreases receipt of adjuvant chemotherapy among women with operable breast cancer. In the NCCN breast cancer outcomes database, we identified women aged ≤ 70 with newly diagnosed stage I, II, or III breast cancer between 1997 and 2007, for whom use of adjuvant chemotherapy was classified as either standard-of-care or discretionary based on their clinical characteristics. Body mass index was assessed in categories (<18.5 kg/m(2) [underweight], 18.5 to <25 kg/m(2) [normal], 25 to <30 kg/m(2) [overweight], 30-39 kg/m(2) [obese], ≥ 40 kg/m(2) [extreme obese]). Multivariable logistic regression analysis was used to examine the association between BMI and receipt of chemotherapy in each classification group. 9,527 women were eligible for the study; 40% normal weight or less; 31% overweight; 24% obese; and 5% extremely obese. In multivariable analysis, there was no significant association between BMI and receipt of chemotherapy in either classification group. Among women for whom chemotherapy would be considered standard-of-care, older age (P < 0.001), comorbidity (P < 0.001), and non-Hispanic black ethnicity (P = 0.002) were associated with a lower likelihood of receipt of chemotherapy; however, the effect of ethnicity was not modified by obesity. Among women treated for operable breast cancer in the NCCN centers, BMI had no impact on receipt of adjuvant chemotherapy and did not modify the lower likelihood of chemotherapy among non-Hispanic black patients. Further investigation is needed into other factors that contribute to patient disparities in the receipt of chemotherapy in major academic centers.


A disintegrin and metalloproteinase 17 (ADAM17) and epidermal growth factor receptor (EGFR) signaling drive the epithelial response to Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1).
Staphylococcal superantigens (SAgs), such as toxic shock syndrome toxin-1 (TSST-1), are the main cause of toxic shock syndrome (TSS). SAgs deregulate the host immune system after penetrating epithelial barriers such as the vaginal mucosa. In response to TSST-1, human vaginal epithelial cells (HVECs) produce cytokines and undergo morphological changes. The epithelial signaling mechanisms employed by SAgs remain largely unknown and are the focus of the work presented here. Analysis of published microarray data identified a network of genes up-regulated by HVECs in response to TSST-1 that includes the sheddase, a disintegrin and metalloproteinase 17 (ADAM17). Investigation revealed that the ADAM17 proteolytic targets, amphiregulin (AREG), transforming growth factor α (TGFα), syndecan-1 (SDC1), and tumor necrosis factor receptor 1 (TNFR1), are shed from HVECs in response to TSST-1. TAPI-1 (an ADAM inhibitor) completely abrogates all observed shedding and the production of the cytokine interleukin-8 (IL-8). Knock-down studies show that ADAM17, but not the closely related ADAM10, is required for AREG, TGFα, and TNFR1 shedding. Both ADAM10 and ADAM17 contribute to SDC1 shedding and IL-8 production by HVECs in response to TSST-1. EGFR signaling is critical for up-regulation of IL-8 at the transcriptional level in response to TSST-1 and is also necessary for AREG, TGFα, and TNFR1 shedding. A model is proposed describing the interactions of TSST-1, ADAMs, and the EGFR that lead to establishment of a proinflammatory positive feedback loop in epithelial cells and demonstrate a role for SAgs in the initial stages of disease.


Mortality Among Hardmetal Production Workers: UK Cohort and Nested Case-Control Studies.
The aim of this study was to characterize the mortality at two hardmetal production factories in the United Kingdom as part of an international study. Standardized mortality ratios (SMRs) were calculated on the basis of mortality rates for England and Wales, and local rates. A nested case-control study of lung cancer was undertaken. The cohort comprised 1538 workers, with tracing complete for 94.4%. All-cause mortality was statistically significantly low for all cancers and nonmalignant respiratory disease, and for lung cancer was nonsignificantly low. The SMR for lung cancer for maintenance workers was elevated, based on only six deaths. The odds ratio for lung cancer per year of exposure to hardmetal was 0.93 (0.76 to 1.13). In this small study, there is no evidence to support that working in the UK hardmetal manufacturing industry increased mortality from any cause including lung cancer.