Snoring as a risk factor for ischaemic heart disease and stroke in men.
The association of snoring with ischaemic heart disease and stroke was studied prospectively in 4388 men aged 40-69. The men were asked, in a questionnaire sent to them, whether they snored habitually, frequently, occasionally, or never. Hospital records and death certificates were checked for the next three years to establish how many of the men developed ischaemic heart disease or stroke: the numbers were 149 and 42, respectively. Three categories of snoring were used for analysis: habitual and frequent snorers (n = 1294), occasional snorers (n = 2614), and non-snorers (n = 480). The age adjusted relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.91 (p less than 0.01) and for ischaemic heart disease or stroke, or both, 2.38 (p less than 0.001). There were no cases of stroke among the non-snorers. Adjustment for age, body mass index, history of hypertension, smoking, and alcohol use did not significantly decrease the relative risks, which were 1.71 (p greater than 0.05) for ischaemic heart disease and 2.08 (p less than 0.01) for ischaemic heart disease and stroke combined. At the beginning of follow up in 1981, 462 men reported a history of angina pectoris or myocardial infarction. For them the relative risk of ischaemic heart disease between habitual plus frequent snorers and non-snorers was 1.30 (NS); for men without previous ischaemic heart disease 2.72 (p less than 0.05). Snoring seems to be a potential determinant of risk of ischaemic heart disease and stroke.


Two rare complications in a single patient of lung cancer: Radiation-induced spontaneous esophageal perforation and aortic rupture and their successful management.
Adjuvant radiotherapy is indicated in few operated cases of lung cancer for effective local control. Oesophageal perforation and aortic rupture are rare and lethal complications of postoperative adjuvant radiotherapy. Both of these complications happened in a 64 year male patient with squamous cell carcinoma of lung. Radiation induced oesophageal perforation occurred immediately after completion of radiotherapy. Endoscopic Self Expanding Radio Therapy (SEMS) was placed, thoracic cavity was debrided and window thoracostomy was performed. After few months of this episode, he had torrential bleeding from descending thoracic aorta. Thoracic Endo Vascular Aortic Repair (TEVAR) was done and bleeding was controlled. This case is unique because both these fatal events happened in a single patient. This report also highlights the use of above mentioned novel therapeutic methods for successful management of these complications in these frail patients.


Perceptions and attitudes regarding sexually transmitted infection and family planning among adolescents in Northern Madagascar.
The prevalence of sexually transmitted infections (STIs) and early pregnancy are high among adolescents in Madagascar. We applied a qualitative descriptive approach to evaluate perceptions, attitudes, and misconceptions regarding STIs and contraception among female and male adolescents ages 15-19 years (n = 43) in Northern Madagascar in 2014 using focus group discussions with open-ended questions. Data were coded and analyzed for major themes. Participants were in grades 6 to 12 in school; 53% were female. Despite high levels of awareness, significant stigma against and misconceptions about STIs, condom use, and sexual practices existed. Many participants did not know how to use condoms and felt uncomfortable suggesting condoms with regular partners, despite acknowledging infidelity as a frequent problem. Male participants were more willing to use condoms as contraception for unwanted pregnancy than for prevention of STIs. Most participants held misconceptions about side effects of contraceptives, including infertility, cancer, and preventing bad blood from leaving the woman's body. Systematic and community-wide health education and formal reproductive health curricula in schools may improve attitudes and stigma regarding STIs and family planning. These strategies need to be developed and employed via collaboration among faith-based, community, and non-governmental organizations, schools, and governmental health and social service agencies.


Pyrazolyl methyls prescribe the electronic properties of iron(II) tetra(pyrazolyl)lutidine chloride complexes.
A series of iron(II) chloride complexes of pentadentate ligands related to α,α,α',α'-tetra(pyrazolyl)-2,6-lutidine, pz(4)lut, has been prepared to evaluate whether pyrazolyl substitution has any systematic impact on the electronic properties of the complexes. For this purpose, the new tetrakis(3,4,5-trimethylpyrazolyl)lutidine ligand, pz**(4)lut, was prepared via a CoCl(2)-catalyzed rearrangement reaction. The equimolar combination of ligand and FeCl(2) in methanol gives the appropriate 1:1 complexes [FeCl(pz(R)(4)lut)]Cl that are each isolated in the solid state as a hygroscopic solvate. In solution, the iron(II) complexes have been fully characterized by several spectroscopic methods and cyclic voltammetry. In the solid state, the complexes have been characterized by X-ray diffraction, and, in some cases, by Mössbauer spectroscopy. The Mössbauer studies show that the complexes remain high spin to 4 K and exclude spin-state changes as the cause of the surprising solid-state thermochromic properties of the complexes. Non-intuitive results of spectroscopic and structural studies showed that methyl substitution at the 3- and 5- positions of the pyrazolyl rings reduces the ligand field strength through steric effects whereas methyl substitution at the 4-position of the pyrazolyl rings increases the ligand field strength through inductive effects.


Should male gender assignment be considered in the markedly virilized patient With 46,XX and congenital adrenal hyperplasia?
We assess the outcome in 46,XX men with congenital adrenal hyperplasia who were born with Prader 4 or 5 genitalia and assigned male gender at birth. After receiving institutional review board approval and subject consent we reviewed the medical records of 12 men 35 to 69 years old with 46,XX congenital adrenal hyperplasia, of whom 6 completed social and gender issue questionnaires. All subjects were assigned male gender at birth, were diagnosed with virilizing congenital adrenal hyperplasia at age greater than 3 years and indicated a male gender identity with sexual orientation to females. Ten of the 12 subjects had always lived as male and 2 who were reassigned to female gender in childhood subsequently self-reassigned as male. Nine of the 12 men had long-term female partners, including 7 married 12 years or more. The 3 subjects without a long-term female partner included 1 priest, 1 who was reassigned female gender, married, divorced and self-reassigned as male, and 1 with a girlfriend and sexual activity. All except the priest and the subject who was previously married when female indicated a strong libido and frequent orgasmic sexual activity. Responses to self-esteem, masculinity, body image, social adjustment and symptom questionnaires suggested adjustments related to the extent of familial and social support. Outcome data on severely masculinized 46,XX patients with congenital adrenal hyperplasia who were assigned male gender at birth indicate male gender identity in adulthood with satisfactory male sexual function in those retaining male genitalia. In men who completed questionnaires results were poorer in those lacking familial/social support. Male gender of rearing may be a viable option for parents whose children are born with congenital adrenal hyperplasia, a 46,XX karyotype and male genitalia, although positive parental and other support, and counseling are needed for adjustment.


Glucocorticoids induce specific ion-channel-mediated toxicity in human rotator cuff tendon: a mechanism underpinning the ultimately deleterious effect of steroid injection in tendinopathy?
Glucocorticoid injection (GCI) and surgical rotator cuff repair are two widely used treatments for rotator cuff tendinopathy. Little is known about the way in which medical and surgical treatments affect the human rotator cuff tendon in vivo. We assessed the histological and immunohistochemical effects of these common treatments on the rotator cuff tendon. Controlled laboratory study. Supraspinatus tendon biopsies were taken before and after treatment from 12 patients undergoing GCI and 8 patients undergoing surgical rotator cuff repair. All patients were symptomatic and none of the patients undergoing local GCI had full thickness tears of the rotator cuff. The tendon tissue was then analysed using histological techniques and immunohistochemistry. There was a significant increase in nuclei count and vascularity after rotator cuff repair and not after GCI (both p=0.008). Hypoxia inducible factor 1α (HIF-1α) and cell proliferation were only increased after rotator cuff repair (both p=0.03) and not GCI. The ionotropic N-methyl-d-aspartate receptor 1 (NMDAR1) glutamate receptor was only increased after GCI and not rotator cuff repair (p=0.016). An increase in glutamate was seen in both groups following treatment (both p=0.04), while an increase in the receptor metabotropic glutamate receptor 7 (mGluR7) was only seen after rotator cuff repair (p=0.016). The increases in cell proliferation, vascularity and HIF-1α after surgical rotator cuff repair appear consistent with a proliferative healing response, and these features are not seen after GCI. The increase in the glutamate receptor NMDAR1 after GCI raises concerns about the potential excitotoxic tendon damage that may result from this common treatment.


Child and adolescent internalizing and externalizing problems 12 months postburn: the potential role of preburn functioning, parental posttraumatic stress, and informant bias.
Adjustment after pediatric burn injury may be a challenge for children as well as their parents. This prospective study examined associations of internalizing and externalizing problems in children and adolescents 12 months postburn with preburn functioning, and parental acute and chronic posttraumatic stress symptoms (PTSS) from different perspectives. Child, mother, and father reports of 90 children (9-18 years), collected within the first month and 12 months postburn, were analyzed. Results indicated that overall, child and parental appraisals of pre- and postburn behavioral problems were not significantly different from reference data. Rates of (sub)clinical postburn behavioral problems ranged from 6 to 17 %, depending on the informant. Pre- and postburn behavioral problems were significantly related, but only from the parents' perspective. Path models showed an association between parental PTSS 12 months postburn and parental reports of child internalizing problems, as well as a significant indirect relationship from parental acute stress symptoms via PTSS 12 months postburn. Notably, no associations between parental PTSS and child reports of postburn behavioral problems were found. In conclusion, parental observations of child externalizing problems appear to be influenced by their perspectives on the child's preburn functioning, while parental observations of internalizing problems are also related to long-term parental PTSS. However, these factors seem of no great value in predicting behavioral problems from the child's perspective, suggesting substantial informant deviations. To optimize adjustment, clinical burn practice is recommended to adopt a family perspective including parent perception of preburn functioning and parental PTSS in assessment and intervention.


Experimental mixture design as a tool for the synthesis of antimicrobial selective molecularly imprinted monodisperse microbeads.
The effect of the cross-linker on the shape and size of molecular imprinted polymer (MIP) beads prepared by precipitation polymerization has been evaluated using a chemometric approach. Molecularly imprinted microspheres for the selective recognition of fluoroquinolone antimicrobials were prepared in a one-step precipitation polymerization procedure using enrofloxacin (ENR) as the template molecule, methacrylic acid as functional monomer, 2-hydroxyethyl methacrylate as hydrophilic comonomer, and acetonitrile as the porogen. The type and amount of cross-linker, namely ethylene glycol dimethacrylate, divinylbenzene or trimethylolpropane trimethacrylate, to obtain monodispersed MIP spherical beads in the micrometer range was optimized using a simplex lattice design. Particle size and morphology were assessed by scanning electron microscopy, dynamic light scattering, and nitrogen adsorption measurements. Electron paramagnetic resonance spectroscopy in conjunction with a nitroxide as spin probe revealed information about the microviscosity and polarity of the binding sites in imprinted and nonimprinted polymer beads.


Should dexamethasone be standard in the prophylaxis of pain flare after palliative radiotherapy for bone metastases?-a debate.
Pain flare is a well-recognized side-effect of palliative radiotherapy for the treatment of painful bone metastases, with recent randomized data showing incidence rates up to 35%. The impact of pain flare has been associated with worsening immobility, anxiety, depression and quality of life. The use of dexamethasone has recently been supported as an effective option in reducing radiation-induced pain flare based on the NCIC Clinical Trials Group (NCIC CTG) Symptom Control 23 (SC.23) randomized double-blind placebo-controlled trial. Despite this, conflicting opinions exist, and standard clinical use of dexamethasone to prevent pain flare continues to be debated among clinicians. Given this controversy, two sides of the debate are presented. Although consensus has not been achieved, the choice to use dexamethasone in the prophylactic setting to reduce pain flare incidence should be a shared decision between the oncologist and patient. Factors including symptom burden, comorbidities, performance status, quality of life and radiation dose and fractionation should be taken into account on an individualized level.


What's in a Friendship? Partner Visibility Supports Cognitive Collaboration between Friends.
Not all cognitive collaborations are equally effective. We tested whether friendship and communication influenced collaborative efficiency by randomly assigning participants to complete a cognitive task with a friend or non-friend, while visible to their partner or separated by a partition. Collaborative efficiency was indexed by comparing each pair's performance to an optimal individual performance model of the same two people. The outcome was a strong interaction between friendship and partner visibility. Friends collaborated more efficiently than non-friends when visible to one another, but a partition that prevented pair members from seeing one another reduced the collaborative efficiency of friends and non-friends to a similar lower level. Secondary measures suggested that verbal communication differences, but not psychophysiological arousal, contributed to these effects. Analysis of covariance indicated that females contributed more than males to overall levels of collaboration, but that the interaction of friendship and visibility was independent of that effect. These findings highlight the critical role of partner visibility in the collaborative success of friends.


Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study.
To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS). RMC is a rare and aggressive malignancy that afflicts young patients with sickle cell trait; there are limited data on management to date. This is a study of patients with RMC who were treated in 2000-2015 at eight academic institutions in North America and France. The Kaplan-Meier method was used to estimate OS, measured from initial RMC diagnosis to date of death. Cox regression analysis was used to determine predictors of OS. In all, 52 patients (37 males) were identified. The median (range) age at diagnosis was 28 (9-48) years and 49 patients (94%) had stage III/IV. The median OS for all patients was 13.0 months and 38 patients (75%) had nephrectomy. Patients who underwent nephrectomy had superior OS compared to patients who were treated with systemic therapy only (median OS 16.4 vs 7.0 months, P < 0.001). In all, 45 patients received chemotherapy and 13 (29%) had an objective response; 28 patients received targeted therapies, with 8-week median therapy duration and no objective responses. Only seven patients (13%) survived for >24 months. RMC carries a poor prognosis. Chemotherapy provides palliation and remains the mainstay of therapy, but <20% of patients survive for >24 months, underscoring the need to develop more effective therapy for this rare tumour. In this study, nephrectomy was associated with improved OS.


Periapical fluid RANKL and IL-8 are differentially regulated in pulpitis and apical periodontitis.
The dental pulp space can become infected due to a breach in the surrounding hard tissues. This leads to inflammation of the pulp (pulpitis), soft tissue breakdown, and finally to bone loss around the root apex (apical periodontitis). The succession of the molecular events leading to apical periodontitis is currently not known. The main inflammatory mediator associated with neutrophil chemotaxis is interleukin-8 (IL-8), and with bone resorption the dyad of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). The levels of RANKL, OPG and IL-8 were studied in periapical tissue fluid of human teeth (n = 48) diagnosed with symptomatic irreversible pulpitis (SIP) and asymptomatic apical periodontitis (AAP). SIP represents the starting point, and AAP an established steady state of the disease. Periapical tissue fluid samples were collected using paper points and then evaluated using enzyme-linked immunosorbent assays (ELISAs). Target protein levels per case were calibrated against the corresponding total protein content, as determined fluorometrically. RANKL was expressed at significantly higher levels in SIP compared to AAP (P < 0.05), whereas OPG was under the detection limit in most samples. In contrast, IL-8 levels were significantly lower in SIP compared to AAP (P < 0.05). Spearman's correlation analysis between RANKL and IL-8 revealed a significantly (P < 0.05) negative correlation between the two measures (rho = -.44). The results of this study suggest that, in the development of apical periodontitis, periapical bone resorption signaling, as determined by RANKL, occurs prior to inflammatory cell recruitment signaling, as determined by IL-8.


Functional interaction between DP-1 and p53.
The cellular transcription factor DRTF1/E2F and the tumor suppressor protein p53 play important roles in controlling early cell cycle events. DRTF1/E2F is believed to coordinate and integrate the transcription of cell cycle-regulating genes, for example, those involved in DNA synthesis, with the activity of regulatory proteins, such as the retinoblastoma tumor suppressor gene product (pRb), which modulate its transcriptional activity. In contrast, p53 is thought to monitor the integrity of chromosomal DNA and when appropriate interfere with cell cycle progression, for example, in response to DNA damage. Generic DRTF1/E2F DNA binding activity and transcriptional activation arise when members of two distinct families of proteins, such as DP-1 and E2F-1, interact as DP/E2F heterodimers. In many cell types, DP-1 is a widespread component of DRTF1/E2F DNA binding activity which when expressed at high levels oncogenically transforms embryonic fibroblasts. Here, we document an association between DP-1 and p53 and demonstrate its presence in mammalian cell extracts. In vitro p53 interacts with an immunochemically distinct form of DP-1 and in vivo can regulate transcription driven by the DP-1/E2F-1 heterodimer. At the biochemical level, p53 competes with E2F-1 for DP-1, with a consequent reduction in DNA binding activity. Mutational analysis defines within DP-1 a C-terminal region required for the interaction with p53 and within p53 an N-terminal region distinct from that required to bind to MDM2. Our results establish DRTF1/E2F as a common cellular target in growth control mediated through the activities of pRb and p53 and suggest an alternative mechanism through which p53 may regulate cellular proliferation.


Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together.
Although both contain behaviourally significant concentrations of caffeine, tea is commonly perceived to be a less stimulating drink than coffee. At least part of the explanation for this may be that theanine, which is present in tea but not coffee, has relaxing effects. There is also some evidence that theanine affects cognitive performance, and it has been found to reduce blood pressure in hypertensive rats. To study the subjective, behavioural and blood pressure effects of theanine and caffeine administered alone and together, in doses relevant to the daily tea consumption of regular tea drinkers. In a randomised, double-blind, placebo-controlled study, healthy adult participants (n = 48) received either 250-mg caffeine, 200-mg theanine, both or neither of these. They completed ratings of mood, including anxiety, and alertness, and had their blood pressure measured before and starting 40 min after drug administration. Anxiety was also assessed using a visual probe task. Caffeine increased self-rated alertness and jitteriness and blood pressure. Theanine antagonised the effect of caffeine on blood pressure but did not significantly affect jitteriness, alertness or other aspects of mood. Theanine also slowed overall reaction time on the visual probe task. Theanine is a physiologically and behaviourally active compound and, while it is unclear how its effects might explain perceived differences between tea and coffee, evidence suggests that it may be useful for reducing raised blood pressure.


A systematic review of simulation-based training tools for technical and non-technical skills in ophthalmology.
To evaluate all simulation models for ophthalmology technical and non-technical skills training and the strength of evidence to support their validity and effectiveness. A systematic search was performed using PubMed and Embase for studies published from inception to 01/07/2019. Studies were analysed according to the training modality: virtual reality; wet-lab; dry-lab models; e-learning. The educational impact of studies was evaluated using Messick's validity framework and McGaghie's model of translational outcomes for evaluating effectiveness. One hundred and thirty-one studies were included in this review, with 93 different simulators described. Fifty-three studies were based on virtual reality tools; 47 on wet-lab models; 26 on dry-lab models; 5 on e-learning. Only two studies provided evidence for all five sources of validity assessment. Models with the strongest validity evidence were the Eyesi Surgical, Eyesi Direct Ophthalmoscope and Eye Surgical Skills Assessment Test. Effectiveness ratings for simulator models were mostly limited to level 2 (contained effects) with the exception of the Sophocle vitreoretinal surgery simulator, which was shown at level 3 (downstream effects), and the Eyesi at level 5 (target effects) for cataract surgery. A wide range of models have been described but only the Eyesi has undergone comprehensive investigation. The main weakness is in the poor quality of study design, with a predominance of descriptive reports showing limited validity evidence and few studies investigating the effects of simulation training on patient outcomes. More robust research is needed to enable effective implementation of simulation tools into current training curriculums.


Molecular Detection of Persistent Francisella tularensis Subspecies holarctica in Natural Waters.
Tularemia, caused by the bacterium Francisella tularensis, where F. tularensis subspecies holarctica has long been the cause of endemic disease in parts of northern Sweden. Despite this, our understanding of the natural life-cycle of the organism is still limited. During three years, we collected surface water samples (n = 341) and sediment samples (n = 245) in two areas in Sweden with endemic tularemia. Real-time PCR screening demonstrated the presence of F. tularenis lpnA sequences in 108 (32%) and 48 (20%) of the samples, respectively. The 16S rRNA sequences from those samples all grouped to the species F. tularensis. Analysis of the FtM19InDel region of lpnA-positive samples from selected sampling points confirmed the presence of F. tularensis subspecies holarctica-specific sequences. These sequences were detected in water sampled during both outbreak and nonoutbreak years. Our results indicate that diverse F. tularensis-like organisms, including F. tularensis subsp. holarctica, persist in natural waters and sediments in the investigated areas with endemic tularemia.


The Role of Hospital Inpatients in Supporting Medication Safety: A Qualitative Study.
Inpatient medication errors are a significant concern. An approach not yet widely studied is to facilitate greater involvement of inpatients with their medication. At the same time, electronic prescribing is becoming increasingly prevalent in the hospital setting. In this study we aimed to explore hospital inpatients' involvement with medication safety-related behaviours, facilitators and barriers to this involvement, and the impact of electronic prescribing. We conducted ethnographic observations and interviews in two UK hospital organisations, one with established electronic prescribing and one that changed from paper to electronic prescribing during our study. Researchers and lay volunteers observed nurses' medication administration rounds, pharmacists' ward rounds, doctor-led ward rounds and drug history taking. We also conducted interviews with healthcare professionals, patients and carers. Interviews were audio-recorded and transcribed. Observation notes and transcripts were coded thematically. Paper or electronic medication records were shown to patients in only 4 (2%) of 247 cases. However, where they were available during patient-healthcare professional interactions, healthcare professionals often viewed them in order to inform patients about their medicines and answer any questions. Interprofessional discussions about medicines seemed more likely to happen in front of the patient where paper or electronic drug charts were available near the bedside. Patients and carers had more access to paper-based drug charts than electronic equivalents. However, interviews and observations suggest there are potentially more significant factors that affect patient involvement with their inpatient medication. These include patient and healthcare professional beliefs concerning patient involvement, the way in which healthcare professionals operate as a team, and the underlying culture. Patients appear to have more access to paper-based records than electronic equivalents. However, to develop interventions to increase patient involvement with medication safety behaviours, a wider range of factors needs to be considered.


A geographical analysis of breast cancer clustering in southern Ontario: generating hypotheses on environmental influences.
This article presents the results of spatial analysis of breast cancer clustering in southern Ontario. Data from the Cancer Care Ontario were analyzed using the Scan Statistic at the level of county, with further analysis conducted within counties that were identified as primary clusters at the dissemination area level. The results identified five counties as primary clusters of women diagnosed with breast cancer between 1986 and 2002: Essex (relative risk [RR] =1.096-1.061; p<0.001), Lambton (RR=1.05-1.167), Chatham-Kent (RR=1.133-1.191), Niagara (RR=1.228-1.290) and Toronto (RR=1.152-1.146). The within county analysis revealed several DAs with significantly higher (RR>3, p<0.05) rates of breast cancer, and supports our hypothesis that breast cancer risk in southern Ontario may be associated with industrial and environmental (such as pesticides) pollutants. Further research is needed to verify the environmental links within the identified clusters.


Internal Nanoparticle Structure of Temperature-Responsive Self-Assembled PNIPAM-b-PEG-b-PNIPAM Triblock Copolymers in Aqueous Solutions: NMR, SANS, and Light Scattering Studies.
In this study, we report detailed information on the internal structure of PNIPAM-b-PEG-b-PNIPAM nanoparticles formed from self-assembly in aqueous solutions upon increase in temperature. NMR spectroscopy, light scattering, and small-angle neutron scattering (SANS) were used to monitor different stages of nanoparticle formation as a function of temperature, providing insight into the fundamental processes involved. The presence of PEG in a copolymer structure significantly affects the formation of nanoparticles, making their transition to occur over a broader temperature range. The crucial parameter that controls the transition is the ratio of PEG/PNIPAM. For pure PNIPAM, the transition is sharp; the higher the PEG/PNIPAM ratio results in a broader transition. This behavior is explained by different mechanisms of PNIPAM block incorporation during nanoparticle formation at different PEG/PNIPAM ratios. Contrast variation experiments using SANS show that the structure of nanoparticles above cloud point temperatures for PNIPAM-b-PEG-b-PNIPAM copolymers is drastically different from the structure of PNIPAM mesoglobules. In contrast with pure PNIPAM mesoglobules, where solidlike particles and chain network with a mesh size of 1-3 nm are present, nanoparticles formed from PNIPAM-b-PEG-b-PNIPAM copolymers have nonuniform structure with "frozen" areas interconnected by single chains in Gaussian conformation. SANS data with deuterated "invisible" PEG blocks imply that PEG is uniformly distributed inside of a nanoparticle. It is kinetically flexible PEG blocks which affect the nanoparticle formation by prevention of PNIPAM microphase separation.


Novel male-biased expression in paralogs of the aphid slimfast nutrient amino acid transporter expansion.
A major goal of molecular evolutionary biology is to understand the fate and consequences of duplicated genes. In this context, aphids are intriguing because the newly sequenced pea aphid genome harbors an extraordinary number of lineage-specific gene duplications relative to other insect genomes. Though many of their duplicated genes may be involved in their complex life cycle, duplications in nutrient amino acid transporters appear to be associated rather with their essential amino acid poor diet and the intracellular symbiosis aphids rely on to compensate for dietary deficits. Past work has shown that some duplicated amino acid transporters are highly expressed in the specialized cells housing the symbionts, including a paralog of an aphid-specific expansion homologous to the Drosophila gene slimfast. Previous data provide evidence that these bacteriocyte-expressed transporters mediate amino acid exchange between aphids and their symbionts. We report that some nutrient amino acid transporters show male-biased expression. Male-biased expression characterizes three paralogs in the aphid-specific slimfast expansion, and the male-biased expression is conserved across two aphid species for at least two paralogs. One of the male-biased paralogs has additionally experienced an accelerated rate of non-synonymous substitutions. This is the first study to document male-biased slimfast expression. Our data suggest that the male-biased aphid slimfast paralogs diverged from their ancestral function to fill a functional role in males. Furthermore, our results provide evidence that members of the slimfast expansion are maintained in the aphid genome not only for the previously hypothesized role in mediating amino acid exchange between the symbiotic partners, but also for sex-specific roles.


3,3'-Diindolylmethane inhibits prostate cancer development in the transgenic adenocarcinoma mouse prostate model.
3,3'-Diindolylmethane (DIM) is a major in vivo derivative of indole-3-carbinol, which is present in cruciferous vegetables and has been reported to possess anti-carcinogenic properties. In the present study, we examined whether DIM inhibits the development of prostate cancer using the transgenic adenocarcinoma mouse prostate (TRAMP) model. DIM feeding inhibited prostate carcinogenesis in TRAMP mice, reduced the number of cells expressing the SV40 large tumor antigen and proliferating cell nuclear antigen, and increased the number of terminal dUTP nick-end labeling-positive cells in the dorsolateral lobes of the prostate. Additionally, DIM feeding reduced the expression of cyclin A, cyclin-dependent kinase (CDK)2, CDK4, and Bcl-xL, and increased p27 and Bax expression. To assess the mechanisms by which DIM induces apoptosis, LNCaP and DU145 human prostate cancer cells were cultured with various concentrations of DIM. DIM induced a substantial reduction in the numbers of viable cells and induced apoptosis in LNCaP and DU145 cells. DIM increased the cleavage of caspase-9, -7, -3, and poly (ADP-ribose) polymerase (PARP). DIM increased mitochondrial membrane permeability and the translocation of cytochrome c and Smac/Diablo from the mitochondria. Additionally, DIM induced increases in the levels of cleaved caspase-8, truncated Bid, Fas, and Fas ligand, and the caspase-8 inhibitor Z-IETD-FMK was shown to mitigate DIM-induced apoptosis and the cleavage of caspase-3, PARP, and Bid. These results indicate that DIM inhibits prostate carcinogenesis via induction of apoptosis and inhibition of cell cycle progression. DIM induces apoptosis in prostate cancer cells via the mitochondria- and death receptor-mediated pathways.


Naturally-occurring, osmo-remedial variants of Escherichia coli.
Two clones of Escherichia coli O27:K1:H31 and O2:H7, isolated from patients with urinary tract infection or bacteraemia, failed to grow in a synthetic minimal medium (MM) of low osmolality. They were considered to be osmo-remedial because they grew well when sufficient amounts of NaCl, mannitol or sucrose were added to raise the osmolality of the medium to > 300 mOsm/kg. The defect could also be corrected by nicotinamide or its precursors quinolinic and aspartic acids. Each clone had a unique DNA restriction enzyme profile, fimbriae and antibiotic susceptibility patterns. The osmo-remedial variants were unstable and underwent phenotypic modulation to form mixtures with osmo-tolerant forms when grown in MM. They tended to form satellites of small colonies around large colonies of osmo-tolerant cells on MM agar plates. The penicillin method of Davis was used to separate the two forms. Nicotinamide induced the expression of ompF when the osmo-remedial strains were grown under conditions of low osmolality. It is possible that the variants are defective in the synthesis of membrane-derived oligosaccharides or outer-membrane proteins, but this has yet to be determined.


Understanding newborn infant readmission: findings of the Ontario Mother and Infant Survey.
The Ontario Mother and Infant Survey examined health and social service utilization of postpartum women and newborn infants from five hospital sites. A cross-sectional multilanguage survey design with longitudinal follow-up was used: 1,250 eligible, consenting women completed a self-report questionnaire in hospital and 875 women participated in a structured telephone interview at four weeks post-discharge. Rates of newborn infant readmission ranged from 2.4% to 6.7%. The best predictors of readmission were: main source of household income was other than employment; maternal self-rating of health was poor; mother anticipated inadequate help and support at home following discharge; mother received help from friends/neighbours following discharge; and mother had concern about infant care and behaviour. Readmission was not associated with length of postpartum hospital stay. The study findings suggest that there is a complex relationship between infant health care needs, family resources and provider practices that produces clinically important, site-specific readmission patterns.


Potential role and mechanism for high mobility group box1 in childhood chronic immune thrombocytopenia.
High mobility group box1(HMGB1) can be used as PAMP or alarmins to stimulate the innate immune system; however, previous research on immune thrombocytopenic purpura (ITP) mainly focused on its adaptive immunity. The study aimed to determine whether HMGB1 is associated with chronic ITP (cITP) during childhood and investigate its role in innate immunity in childhood cITP. We recruited 80 patients to measure the expression of HMGB1, IL-17, and IL-10; 55 patients were recruited to measure the expression of TLR2 and TLR4 in monocyte and CD1c+dendritic cells, and 30 volunteers were included as controls. We focused on the expression of the NLRP3 inflammasome during childhood cITP. Furthermore, the impact of HMGB1 on the NLRP3 inflammasome was explored. The expressions of HMGB1 and IL-17 increased in children with cITP, while that of IL-10 decreased; HMGB1 was correlated with the expression of IL-17 and IL-10. The expression of TLR2 in CD14++CD16+, CD14+CD16++ monocytes increased significantly in comparison with the controls; the contrary was observed regarding TLR4. The expression of NLRP3, IL-1β, and IL-18 was significantly higher in CD14 and CD1c, respectively. As the concentration of HMGB1 increased, the expression of NLRP3, IL-1β, and IL-18 increased in different degrees. HMGB1 could be used as an early warning alarm for childhood cITP and is involved in developing cITP. HMGB1 could affect the incidence and development of chronic childhood ITP via the NLRP3, TLR2/TLR4 pathways.


Conversion to Reverse Total Shoulder Arthroplasty with and without Humeral Stem Retention: The Role of a Convertible-Platform Stem.
Revision shoulder arthroplasty is a technically challenging procedure. It is associated with increased blood loss and operative time, and it frequently necessitates revision implants, augments, and bone-grafting. Shoulder arthroplasty systems with a convertible-platform humeral stem have been developed to reduce the complexity of revision procedures by eliminating the need for humeral component explantation when converting from anatomic shoulder arthroplasty (hemiarthroplasty or total shoulder arthroplasty) to reverse total shoulder arthroplasty (rTSA). A multicenter, retrospective analysis involving 102 consecutive shoulders (102 patients) that underwent revision of an anatomic shoulder arthroplasty to an rTSA was conducted. During the revision, 73 of the shoulders needed exchange of the humeral stem (the exchange group) and 29 had retention of a convertible-platform humeral component (the retention group). Patient demographics, operative time, blood management, range of motion, complications, and patient-reported outcomes were compared between the 2 groups. Patients with retention had significantly shorter operative time (mean and standard deviation, 130 ± 48 versus 195 ± 58 minutes; p < 0.001) and lower estimated blood loss (292 ± 118 versus 492 ± 334 mL; p = 0.034). The rate of intraoperative complications was lower in the retention group (0% versus 15%; p = 0.027). Patients with retention had slightly better postoperative range of motion (active external rotation, 26° ± 23° versus 11° ± 23° [p = 0.006]; active forward elevation, 112° ± 37° versus 96° ± 33° [p = 0.055]). Shoulder arthroplasty systems that utilize a convertible-platform humeral stem offer an advantage for rTSA conversion in that a well-fixed, well-positioned humeral stem can be retained. There were significantly fewer complications as well as significantly decreased blood loss and operative time when a convertible-platform stem was utilized (p < 0.050). Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Genetic and functional characterization of the gene cluster specifying expression of Pseudomonas aeruginosa pili.
The genetic organization of the gene cluster containing pilA, the structural gene for type IV pilin of Pseudomonas aeruginosa, as well as the accessory genes pilB, pilC, and pilD, has been studied. DNA sequences capable of initiating transcription when fused to a promoterless lacZ gene have been identified in the pilA-pilB and pilB-pilC intergenic regions. Unlike pilA, which requires rpoN (encoding the sigma 54 subunit of RNA polymerase) and products of two regulatory genes, pilS and pilR, expression of pilB, pilC, or pilD did not depend on any of these transcriptional regulators. Moreover, transcription of pilA from the tac promoter in an rpoN mutant background resulted in piliated bacteria, suggesting that the RpoN-based regulatory network is specific for pilA and does not control expression of any other genes necessary for formation of pili. Insertion of the omega fragment containing strong transcriptional terminators into pilB, pilC, and pilD failed to have a polar effect on expression of downstream genes, as determined by the ability of each cloned gene to complement, in trans, the corresponding insertionally inactivated chromosomal copy. Insertions into pilC, however, resulted in decreased synthesis of PilD as determined by quantitation of PilD enzymatic activity in processing prepilin in vitro and by immunoassay. This finding suggests that PilD may require PilC for its optimal stability or correct membrane localization.


Preparation of highly exfoliated polyester-clay nanocomposites: process-property correlations.
A large number of polyester nanocomposite batches featuring different kinds of nanoclay surface modifiers and up to 6 wt % nanoclay were manufactured using a solvent-based technique. Montmorillonite platelets modified with ammonium ions of different chemical architectures were examined to study the effect of ammonium ions on the extent of surface reactions with long-chain fatty acids. The ammonium montmorillonite was first dispersed and suspended in acetone. This suspension was further esterificated with dotriacontanoic (lacceroic) acid to form high density brushes on the clay surface. This led to achieving higher basal plane spacing of the montmorillonite platelets due to the reduction of electrostatic interactions holding them. The outcome of the surface esterification was analyzed by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The esterificated ammonium-modified clays were then mixed by five different mixing strategies based on the use of a three-roll mill mixer (TRM) and/or ultrasonication (US) to obtain the desired polyester-nanoclay dispersion, intercalation, and exfoliation. The dispersion states of the modified nanoclay in polymer were characterized from XRD, scanning electron microscopy (SEM), and low and high magnification transmission electron microscopy (TEM). Mechanical, thermal, and barrier properties of the resulting composites were experimentally characterized. The Mori-Tanaka method along with an orientation distribution function was used to verify the experimental effective stiffness of the polyester nanocomposite systems. The aspect ratio of nanoclays and their level of intercalation and/or exfoliation after mixing were also confirmed by the comparison of the experimental diffusivity results with those of Fick's diffusion model. Systems having 4 and 6 wt % esterificated ammonium nanoclay and prepared according to a combined TRM/US mixing procedure showed optimal performance with balanced properties and processing ease, thereby showing potential for use in the automotive, transportation, and packaging industries.


Effect of biologic disease-modifying anti-rheumatic drugs targeting remission in axial spondyloarthritis: systematic review and meta-analysis.
To assess the efficacy of biologic DMARDs (bDMARDs) in achieving Assessment of Spondyloarthritis International Society partial remission (ASAS-PR) and/or Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS-ID), as remission-like surrogates, in axial SpA (axSpA). Data from randomized controlled trials (RCTs), including long-term extensions, were included. A systematic literature review was performed using the MEDLINE database (first search May 2018, updated February 2020) and PICO criteria according to Patients-adults with radiographic or non-radiographic axSpA; Intervention-any bDMARD; Comparator-placebo and/or any different drug; Outcomes-ASAS-PR and/or ASDAS-ID as primary or secondary endpoints. Meta-analysis was performed after assessment of the homogeneity of study designs, populations and outcomes. After screening 155 references, a total of 22 RCTs and 28 long-term extensions were retrieved. ASAS-PR was the dominant remission-like definition used. Concerning TNF inhibitors, 14/17 RCTs provided evidence of efficacy in reaching remission at different time points: 12, 16, 24 and 28 weeks (ASAS-PR in 16-62% of patients and ASDAS-ID in 24-40% of patients). With a limited number of studies available, IL-17A inhibitors exhibited remission rates of 15-21% for ASAS-PR and 11-16% for ASDAS-ID at week 16. A meta-analysis regarding ASAS-PR was performed considering RCTs with a similar duration (12, 16 or 24 weeks). The relative risk for achieving remission was 3.864 (95% CI 2.937, 5.085). bDMARDs have a clear impact in axSpA remission evaluated by ASAS-PR. Nevertheless, these data show an unmet need for improved reporting of remission-like outcomes.


Determinants of success in national programs to eliminate lymphatic filariasis: a perspective identifying essential elements and research needs.
The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000. To understand why some national programs have been more successful than others, a panel of individuals with expertise in LF elimination efforts met to assess available data from programs in 8 countries. The goal was to identify: 1) the factors determining success for national LF elimination programs (defined as the rapid, sustained reduction in microfilaremia/antigenemia after repeated mass drug administration [MDA]); 2) the priorities for operational research to enhance LF elimination efforts. Of more than 40 factors identified, the most prominent were 1) initial level of LF endemicity; 2) effectiveness of vector mosquitoes; 3) MDA drug regimen; 4) population compliance. Research important for facilitating program success was identified as either biologic (i.e., [1] quantifying differences in vectorial capacity; [2] identifying seasonal variations affecting LF transmission) or programmatic (i.e., [1] identifying quantitative thresholds, especially the population compliance levels necessary for success, and the antigenemia or microfilaremia prevalence at which MDA programs can stop with minimal risk of resumption of transmission; [2] defining optimal drug distribution strategies and timing; [3] identifying those individuals who are "persistently non-compliant" during MDAs, the reasons for this non-compliance and approaches to overcoming it). While addressing these challenges is important, many key determinants of program success are already clearly understood; operationalizing these as soon as possible will greatly increase the potential for national program success.


Following evolutionary paths to protein-protein interactions with high affinity and selectivity.
How do intricate multi-residue features such as protein-protein interfaces evolve? To address this question, we evolved a new colicin-immunity binding interaction. We started with Im9, which inhibits its cognate DNase ColE9 at 10(-14) M affinity, and evolved it toward ColE7, which it inhibits promiscuously (Kd > 10(-8) M). Iterative rounds of random mutagenesis and selection toward higher affinity for ColE7, and selectivity (against ColE9 inhibition), led to an approximately 10(5)-fold increase in affinity and a 10(8)-fold increase in selectivity. Analysis of intermediates along the evolved variants revealed that changes in the binding configuration of the Im protein uncovered a latent set of interactions, thus providing the key to the rapid divergence of new Im7 variants. Overall, protein-protein interfaces seem to share the evolvability features of enzymes, that is, the exploitation of promiscuous interactions and alternative binding configurations via 'generalist' intermediates, and the key role of compensatory stabilizing mutations in facilitating the divergence of new functions.


Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population.
We characterized the basis for the follicular lymphoproliferation in transgenic mice bearing a Bcl-2-immunoglobulin (Bcl-2-Ig) minigene representing the t(14;18) of human follicular lymphoma. Discriminatory S1 nuclease protection assays revealed that the Bcl-2-Ig transgene was overexpressed relative to endogenous mouse Bcl-2 in spleen and thymus. Western (immunoblot) analysis demonstrated the overproduction of the human 25-kilodalton Bcl-2 protein, which arose from the transgene, in spleen, thymus, and the expanded B-cell subset. Despite the generalized lymphoid pattern of deregulation, two-color flow cytometry and density gradient centrifugation indicated that the expanded lymphocytes were predominantly small, resting B cells coexpressing B220, immunoglobulin M (IgM), IgD, Ia, and kappa. Cell cycle analysis confirmed that about 97% of these expanded B cells reside in G0/G1. An extensive characterization of transgenic lines revealed a fourfold excess of IgM-IgD-expressing B cells in spleen and dramatically increased numbers in bone marrow. While resting, these cells proliferated in response to lipopolysaccharide and anti-IgM and demonstrated normal B-cell colony formation in soft agar. Moreover, these B cells, which demonstrated an extended survival in vitro even in the absence of stroma, were also resting in G0, yet were capable of proliferative responses. These findings provide consistent evidence that the accumulation of B cells after Bcl-2 overproduction is secondary to prolonged cell survival and not increased cell cycling. This suggests a unique role for Bcl-2 as a proto-oncogene that enhances cell survival independent of promoting cell division.


Prevalence, clinical predictors, and outcome of hypocalcaemia in severely-malnourished under-five children admitted to an urban hospital in Bangladesh: a case-control study.
Hypocalcaemia is common in severely-malnourished children and is often associated with fatal outcome. There is very limited information on the clinical predicting factors of hypocalcaemia in hospitalized severely-malnourished under-five children. Our objective was to evaluate the prevalence, clinical predicting factors, and outcome of hypocalcaemia in such children. In this case-control study, all severely-malnourished under-five children (n=333) admitted to the Longer Stay Ward (LSW), High Dependency Unit (HDU), and Intensive Care Unit (ICU) of the Dhaka Hospital of icddr,b between April 2011 and April 2012, who also had their total serum calcium estimated, were enrolled. Those who presented with hypocalcaemia (serum calcium <2.12 mmol/L) constituted the cases (n=87), and those admitted without hypocalcaemia (n=246) constituted the control group in our analysis. The prevalence of hypocalcaemia among severely-malnourished under-five children was 26% (87/333). The fatality rate among cases was significantly higher than that in the controls (17% vs 5%; p < 0.001). Using logistic regression analysis, after adjusting for potential confounders, such as vomiting, abdominal distension, and diastolic hypotension, we identified acute watery diarrhoea (AWD) (OR 2.19, 95% CI 1.08-4.43, p = 0.030), convulsion on admission (OR 21.86, 95% CI 2.57-185.86, p = 0.005), and lethargy (OR 2.70, 95% CI 1.633-5.46, p = 0.006) as independent predictors of hypocalcaemia in severely-malnourished children. It is concluded, severely-malnourished children presenting with hypocalcaemia have an increased risk of death than those without hypocalcaemia. AWD, convulsion, and lethargy assessed on admission to hospital are the clinical predictors of hypocalcaemia in such children. Presence of these features in hospitalized children with severe acute malnutrition (SAM) should alert clinicians about the possibility of hypocalcaemia and may help undertake potential preventive measures, such as calcium supplementation, in addition to other aspects of management of such children, especially in the resource-poor settings.


Electron transfer mechanism and the locality of the system-bath interaction: a comparison of local, semilocal, and pure dephasing models.
We simulate the effects of two types of dephasing processes, a nonlocal dephasing of system eigenstates and a dephasing of semilocal eigenstates, on the rate and mechanism of electron transfer (eT) through a series of donor-bridge-acceptor systems, D-B(N)-A, where N is the number of identical bridge units. Our analytical and numerical results show that pure dephasing, defined as the perturbation of system eigenstates through the system-bath interaction, does not disrupt coherent eT because it induces no localization; electron transfer may proceed through superexchange in a system undergoing only pure dephasing. A more physically reasonable description may be obtained via a system-bath interaction that reflects the perturbation of more local electronic structure by local nuclear distortions and dipole interactions. The degree of locality of this interaction is guided by the structure of the system Hamiltonian and by the nature of the measurement performed on the system (i.e., the nature of the environment). We compare our result from this "semilocal" model with an even more local phenomenological dephasing model. We calculate electron transfer rate by obtaining nonequilibrium steady-state solutions for the elements of a reduced density matrix; a semigroup formalism is used to write down the dissipative part of the equation of motion.


A rare type of renal cell carcinoma in a girl: hybrid renal cell carcinoma.
Hybrid renal cell carcinoma (HRCN) is a rare type of renal tumor with characteristic pathologic features, including oncocytic and chromophobe cellular content, and shows more favorable prognosis than renal cell carcinoma. The early-stage tumors show favorable outcome, and postoperative regular clinical and radiological follow-up is adequate in most cases. However, close follow-up is mandatory for tumors with histopathologically coexistence of squamous, papillary, and/or eosinophilic RCC component. This report describes a 12-year-old girl with a stage I HRCN who was closely followed after nephrectomy with no further treatment.


Compact adaptive optics line scanning ophthalmoscope.
We have developed a compact retinal imager that integrates adaptive optics (AO) into a line scanning ophthalmoscope (LSO). The bench-top AO-LSO instrument significantly reduces the size, complexity, and cost of research AO scanning laser ophthalmoscopes (AOSLOs), for the purpose of moving adaptive optics imaging more rapidly into routine clinical use. The AO-LSO produces high resolution retinal images with only one moving part and a significantly reduced instrument footprint and number of optical components. The AO-LSO has a moderate field of view (5.5 deg), which allows montages of the macula or other targets to be obtained more quickly and efficiently. In a preliminary human subjects investigation, photoreceptors could be resolved and counted within approximately 0.5 mm of the fovea. Photoreceptor counts matched closely to previously reported histology. The capillaries surrounding the foveal avascular zone could be resolved, as well as cells flowing within them. Individual nerve fiber bundles could be resolved, especially near the optic nerve head, as well as other structures such as the lamina cribrosa. In addition to instrument design, fabrication, and testing, software algorithms were developed for automated image registration and cone counting.


Facial reanimation using hypoglossal-facial nerve anastomosis after schwannoma removal.
In this series, the split type hypoglossal-facial nerve anastomosis resulted in more favorable outcomes in terms of both facial function and tongue atrophy. This study compared surgical techniques for hypoglossal-facial nerve anastomosis after schwannoma removal and evaluated which technique achieves better facial outcomes and less tongue morbidity. This study included 14 patients who underwent hypoglossal-facial nerve anastomosis after schwannoma removal and were followed for more than 1 year. Three surgical techniques were performed: end-to-end, end-to-side, and split anastomoses. Facial palsy and tongue atrophy after anastomosis were evaluated using the scales suggested by House-Brackmann and Martins, respectively. Tumor volume and the time to surgery were also evaluated, and the effects on facial outcomes were analyzed. Overall, nine of 14 (64.3%) patients had favorable facial outcomes, and eight of 14 (57.1%) had favorable tongue outcomes. Regarding facial palsy, five of seven (71.4%) end-to-end, three of four (75%) split, and only one of three (33.3%) end-to-side patients had favorable facial function. Regarding tongue atrophy, all three (100%) end-to-side, three of four (75%) split, and two of seven (28.6%) end-to-end patients had favorable tongue outcomes. The effects of tumor volume and time to surgery on facial outcome were not significant.


Enantioselective cooperative proton-transfer catalysis using chiral ammonium phosphates.
Chiral phosphorate anions are shown to be highly enantioselective templates for proton-transfer catalysis. A salt generated in situ from a bridgehead amine and a BINOL-derived chiral phosphoric acid serves as an effective proton-shuttle that exhibits remarkable enantioselectivity in a bioinspired, triple co-operative catalysis involving an achiral NHC. Thioesters with a β-chiral center can be prepared in a single step from substituted cinnamaldehyde derivatives, with up to 99% yield and 99% ee. Heteroaryl groups are well tolerated in these reactions, despite the presence of basic sites.


Efficacies of alkaline protease, elastase and exotoxin A toxoid vaccines against gut-derived Pseudomonas aeruginosa sepsis in mice.
The protective efficacies of vaccines prepared from Pseudomonas aeruginosa alkaline protease, elastase and exotoxin A toxoids against gut-derived P. aeruginosa sepsis in mice were evaluated. Specific pathogen-free mice given P. aeruginosa strain D4 orally followed by cyclophosphamide (to promote translocation across the gut wall) died of bacteraemia. Mice immunised with one of the three individual toxoid vaccines were not significantly protected when compared to control mice immunised with bovine serum albumin. Combined immunisation with alkaline protease and elastase toxoids likewise showed no significant protective activity. However, combined immunisation with alkaline protease and exotoxin A toxoids significantly increased the survival rate, which reached 60% (compared with a 7.1% survival rate in the control group). These results show that alkaline protease and exotoxin A play important roles as pathogenic factors in gut-derived sepsis and that a combination of the two exoenzyme toxoids represents a logical candidate for vaccination against P. aeruginosa sepsis.


Transdermal dihydrotestosterone treatment of 'andropause'.
Male ageing coincides on average with progressive impairment of testicular function. The most striking plasma changes are an increase in sex hormone binding globulin (SHBG) and a decrease in non SHBG-bound testosterone, which is the only testosterone subfraction effectively bioavailable for target tissues. In healthy subjects the bioavailable testosterone declines by approximately 1% per year between 40 and 70 years but a more pronounced decline has been observed in non-healthy groups, especially in high cardiovascular risks groups. Relative androgen deficiency is likely to have unfavourable consequences on muscle, adipose tissue, bone, haematopoiesis, fibrinolysis, insulin sensitivity, central nervous system, mood and sexual function and might be treated by an appropriate androgen supplementation. The potential risk for prostate has been the main reason for limiting indications of such treatment. Testosterone (T) and dihydrotestosterone (DHT) are two potent androgens which have opposite effects regarding aromatase activity, an enzyme present in prostate stroma and suspected to have a pathogenic influence through local oestradiol synthesis. T is the main substrate for aromatase and oestradiol synthesis while DHT is not aromatizable and, at sufficient concentration, decreases T and oestradiol levels. A 1.8 years survey of 37 men aged 55-70 years treated with daily percutaneous DHT treatment suggested that high plasma levels of DHT (> 8.5 nmol/l) effectively induced clinical benefits while slightly but significantly reducing prostate size. Early stages of prostate hypertrophy require synergic stimulation by both DHT and oestradiol, and suppressing oestradiol instead of DHT seems easier and better adapted to the specific situation of aged hypogonadic men.(ABSTRACT TRUNCATED AT 250 WORDS)


Estimated risk of radiation-induced breast cancer from mammographic screening for young BRCA mutation carriers.
BRCA mutation carriers are recommended to start mammographic screening for breast cancer as early as age 25-30 years. We used an excess relative risk model (based on a pooled analysis of three cohorts with 7600 subjects who received radiation exposure) to estimate the lifetime risk of radiation-induced breast cancer from five annual mammographic screenings in young (<40 years) BRCA mutation carriers. We then estimated the reduction in breast cancer mortality required to outweigh the radiation risk. Breast cancer rates for mutation carriers were based on a pooled analysis of 22 pedigree studies with 8139 subjects. For BRCA1 mutation carriers, the estimated lifetime risk of radiation-induced breast cancer mortality per 10,000 women resulting from annual mammography was 26 (95% confidence interval [CI] = 14 to 49) for screening at age 25-29 years, 20 (95% CI = 11 to 39) for screening at age 30-34 years, and 13 (95% CI = 7 to 23) for screening at age 35-39 years. To outweigh these risks, screening would have to reduce breast cancer mortality by 51% (95% CI = 27% to 96%) at age 25-29 years, by 12% (95% CI = 6% to 23%) at age 30-34 years, and by 4% (95% CI = 2% to 7%) at age 35-39 years; estimates were similar for BRCA2 mutation carriers. If we assume that the mortality reduction from mammography is 15%-25% or less for young women, these results suggest that there would be no net benefit from annual mammographic screening of BRCA mutation carriers at age 25-29 years; the net benefit would be zero or small at age 30-34 years, but there should be some net benefit at age 35 or older. These results depend on a number of assumptions due to the absence of empiric data. The impact of varying these assumptions was therefore examined.


Current and historical concepts of opiate treatment in psychiatric disorders.
In recent years psychiatric research has rediscovered the theoretical and clinical importance of opiates, especially for the understanding of depressive disorders. However, opiate treatment is not a new therapeutic concept in psychiatry. The use of opium for "melancholia" and "mania" may be traced to ancient classical medicine. After Paracelsus and Sydenham, the psychiatry of the German Romantic Era widely discussed therapeutic opium use with the Engelken family going on to develop a structured opium treatment of depression in the first half of the nineteenth century. Although the underlying scientific problems of psychiatric opium therapy were never solved, it gained an outstanding position as a practical treatment for over 100 years.


Serum mercury level and multiple sclerosis.
Exposure to heavy metals has been associated to a higher incidence of multiple sclerosis. In this work, we present a possible relationship between serum mercury levels and development of multiple sclerosis in Isfahan, the third largest city in Iran. Seventy-four patients affected by multiple sclerosis were retrieved from multiple sclerosis (MS) clinic in Isfahan, Iran. By matching sex and age, 74 healthy volunteers were chosen as control group. Blood samples were collected and serum mercury content was determined. Serum mercury level in MS patients was significantly higher than controls (9.6 ± 10.17 vs. 5.7 ± 8.6, P = 0.037). Concerning all MS patients, serum mercury value was significantly higher than the mercury concentration founded in control subjects {odd ratio: 2.39 (CI, 1.96-2.94), P = 0.00}. Serum mercury level is higher in MS patients with odd ratio equal to 2.39 compared with healthy individuals. It may reveal that high mercury levels in serum might help MS development in susceptible individuals. More studies with larger sample size are needed to confirm this hypothesis.


[Social inequalities in premature cardiovascular mortality in a medium-size Brazilian city].
Cardiovascular diseases are the main cause of death in many countries. In Brazil, premature cardiovascular death is more frequent than in wealthy countries. The aim of this study was to analyze the relationship between premature cardiovascular death and socioeconomic conditions in urban areas. The study design was ecological, with the urban areas of a medium-size municipality in Minas Gerais State, Brazil, as the units of analysis. The relationship between standardized mortality ratio and social development index (SDI) was studied with a binomial negative generalized linear model. The urban regions with the best socioeconomic conditions had significantly lower cardiovascular mortality. The reduction of socioeconomic inequalities in medium-size cities could help decrease health inequities.


Midwives and nutrition education during pregnancy: a literature review.
This review explored the extent to which the role of midwives in nutrition education during pregnancy has been reported in the literature and areas requiring further research were identified. A review of the literature was undertaken. Articles included in the review were published in English, in scholarly journals, and provided information about the knowledge, education, and attitudes of midwives towards nutrition during pregnancy. Few studies were identified. The included studies were exploratory and descriptive. Studies had reported that midwives lacked a basic knowledge of nutrition requirements during pregnancy. This might be attributed to inadequate nutrition education provided in both undergraduate and postgraduate midwifery programmes. The nutrition education components of midwifery courses were not identified within the studies reviewed. Limited international or Australian research is available that reports on the role of midwives in nutrition education during pregnancy and the nutrition content of midwifery curricula. This represents an important omission in midwives capacity to support the health of pregnant women and their babies. More research is required to explore the educational needs of midwives to enhance nutritional care for pregnant women.


Nefazodone in the treatment of generalized social phobia: a randomized, placebo-controlled trial.
Numerous studies have demonstrated the efficacy of serotonergic antidepres-sants, particularly the selective serotonin reuptake inhibitors (SSRIs), in the treatment of social phobia. We evaluated the efficacy, safety, and tolerability of nefazodone, a 5-HT(2) antagonist, in patients with generalized social phobia (GSP). One hundred five patients with GSP (confirmed using the Structured Clinical Interview for DSM-IV) from 4 Canadian outpatient anxiety clinics were assigned randomly to nefazodone (300-600 mg/day, flexible dose) or placebo for 14 weeks of double-blind treatment. Data were collected from October 12, 1999, through December 8, 2001. Primary efficacy outcomes were the Clinical Global Impressions-Improvement scale (CGI-I) score and the Liebowitz Social Anxiety Scale score. In the intent-to-treat sample, 16 (31.4%) of 51 subjects taking nefazodone and 12 (23.5%) of 51 subjects taking placebo were rated as much or very much improved on the CGI-I at endpoint (chi(2) = 0.79, p = .38). With the exception of the Social Phobia Scale, no significant differences were found in measures of social phobia when comparing the nefazodone and placebo groups. These findings suggest that nefazodone is not an effective agent in the treatment of GSP. These data parallel some recent findings with the use of the SSRI fluoxetine in GSP. The lack of efficacy of 2 serotonergic antidepressants in GSP suggests that serotonin reuptake inhibition may not be the only mechanism of action required for efficacy to occur in the treatment of GSP.


Surface profile measurement in white-light scanning interferometry using a three-chip color CCD.
White-light scanning interferometry (WLSI) is a useful technique to measure surface profile when a test object contains discontinuous structures or microstructures. A black and white CCD camera is usually utilized to capture interferograms, and a series of corresponding algorithms is used to achieve the profile measurement. However, the color information in the interferograms is lost. A novel profile measurement method that uses phase information in different color channels (red-green-blue) of an interferogram obtained using a three-chip color CCD in WLSI is proposed. The phase values are extracted by a windowed Fourier transform algorithm. Simulation and experimental results are presented to demonstrate the validity of the proposed method.


Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis.
After multiple sclerosis (MS) relapse while a patient is receiving an injectable disease-modifying drug, many physicians advocate therapy switch, but the relative effectiveness of different switch decisions is often uncertain. To compare the effect of the oral immunomodulator fingolimod with that of all injectable immunomodulators (interferons or glatiramer acetate) on relapse rate, disability, and treatment persistence in patients with active MS. Matched retrospective analysis of data collected prospectively from MSBase, an international, observational cohort study. The MSBase cohort represents a population of patients with MS monitored at large MS centers. The analyzed data were collected between July 1996 and April 2014. Participants included patients with relapsing-remitting MS who were switching therapy to fingolimod or injectable immunomodulators up to 12 months after on-treatment clinical disease activity (relapse or progression of disability), matched on demographic and clinical variables. Median follow-up duration was 13.1 months (range, 3-80). Indication and attrition bias were controlled with propensity score matching and pairwise censoring, respectively. Head-to-head analyses of relapse and disability outcomes used paired, weighted, negative binomial models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity analyses were conducted. Patients had received fingolimod, interferon beta, or glatiramer acetate for a minimum of 3 months following a switch of immunomodulatory therapy. Annualized relapse rate and proportion of relapse-free patients, as well as the proportion of patients without sustained disability progression. Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. The fingolimod group had a lower mean annualized relapse rate (0.31 vs 0.42; 95% CI, 0.02-0.19; P=.009), lower hazard of first on-treatment relapse (hazard ratio [HR], 0.74; 95% CI, 0.56-0.98; P=.04), lower hazard of disability progression (HR, 0.53; 95% CI, 0.31-0.91; P=.02), higher rate of disability regression (HR, 2.0; 95% CI, 1.2-3.3; P=.005), and lower hazard of treatment discontinuation (HR, 0.55; P=.04) compared with the injectable group. Switching from injectable immunomodulators to fingolimod is associated with fewer relapses, more favorable disability outcomes, and greater treatment persistence compared with switching to another injectable preparation following on-treatment activity of MS.


Post Vaccine Rubella During a Measles Outbreak: Clinical Case.
Rubella is a vaccine preventable infection, and congenital rubella the most feared complication of this disease. Although young adult women are at greatest risk of post-vaccine rubella, this is also the group who potentially benefits the most from vaccine protection. Since post-vaccine disease has a mild and self-limited course, the benefit clearly exceeds the risk. During a measles outbreak in the north of Portugal, a 38-year-old woman presented with cervical posterior lymphadenopathies, fever and a maculo-papular rash one week after the administration of the measles, mumps and rubella vaccine. Measles was discarded and rubella viremia was demonstrated. Symptoms of rubella are non-specific and laboratory confirmation is essential. This is particularly relevant during a measles outbreak.


NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells.
Clinically successful hematopoietic cell transplantation is dependent on hematopoietic stem and progenitor cells. Here we identify the matricellular protein Nephroblastoma Overexpressed (Nov, CCN3) as being essential for their functional integrity. Nov expression is restricted to the primitive (CD34) compartments of umbilical vein cord blood, and its knockdown in these cells by lentivirus-mediated RNA interference abrogates their function in vitro and in vivo. Conversely, forced expression of Nov and addition of recombinant Nov protein both enhance primitive stem and/or progenitor activity. Taken together, our results identify Nov (CCN3) as a regulator of human hematopoietic stem or progenitor cells.


Oxinobactin and sulfoxinobactin, abiotic siderophore analogues to enterobactin involving 8-hydroxyquinoline subunits: thermodynamic and structural studies.
The synthesis of two new iron chelators built on the tris-l-serine trilactone scaffold of enterobactin and bearing a 8-hydroxyquinoline (oxinobactin) or 8-hydroxyquinoline-5-sulfonate (sulfoxinobactin) unit has been described. The X-ray structure of the ferric oxinobactin has been determined, exhibiting a slightly distorted octahedral environment for Fe(III) and a Δ configuration. The Fe(III) chelating properties have been examined by potentiometric and spectrophotometric titrations in methanol-water 80/20% w/w solvent for oxinobactin and in water for sulfoxinobactin. They reveal the extraordinarily complexing ability (pFe(III) values) of oxinobactin over the p[H] range 2-9, the pFe value at p[H] 7.4 being 32.8. This was supported by spectrophotometric competition showing that oxinobactin removes Fe(III) from ferric enterobactin at p[H] 7.4. In contrast, the Fe(III) affinity of sulfoxinobactin was largely lower as compared to oxinobactin but similar to that of the ligand O-TRENSOX having a TREN backbone. These results are discussed in relation to the predisposition by the trilactone scaffold of the chelating units. Some comparisons are also made with other quinoline-based ligands and hydroxypyridinonate ligand (hopobactin).


Retinal vessel wall signs and the 5 year incidence of age related maculopathy: the Blue Mountains Eye Study.
To assess whether retinal arteriolar wall changes (focal narrowing and arteriovenous nicking) are associated with an increased 5 year risk of age related maculopathy (ARM). The Blue Mountains Eye Study examined 3654 residents aged 49+ years living in a defined area, during 1992-4 (82.4% participation). After 5 years, 2335 surviving participants (75.1%) were re-examined during 1997-9. Retinal photographs were graded using the Wisconsin ARM grading system. Incident late (neovascular or atrophic) or early stage ARM was defined using a side by side grading method. Focal arteriolar narrowing (localised constricted arteriolar segments causing a sausage-like appearance), and arteriovenous (AV) nicking (constriction on both sides of the venule where crossed by an arteriole), were graded by comparison with standard photographs. All retinal vessels passing through a circumferential zone 0.5-1.0 disc diameters from the optic disc margin were measured from digitised images. Summarised estimates for central retinal arteriolar equivalent (CRAE) represent an average diameter of arterioles for that eye. Associations were assessed after adjusting for age, sex, smoking, mean arterial blood pressure, and other vascular risk factors. Of 2314 baseline participants at risk of late stage ARM, either late stage lesion developed in 34 participants (1.5%). Of 2203 at risk of early stage ARM, this sign developed in 197 participants (8.9%). Focal arteriolar narrowing was present at baseline in at least one eye of 162 survivors (6.9%) and severe AV nicking was present in 187 people (8.1%). Over 5 years, 4.9% of subjects with and 1.2% of those without focal narrowing developed either late stage ARM lesion, age adjusted relative risk (RR) 2.3, 95% confidence interval (CI) 1.0 to 5.1, multivariate adjusted odds ratios (OR) 2.1 (95% CI 0.9 to 4.9). Similarly, 3.7% of subjects with and 1.3% of those without severe AV nicking developed late ARM lesions, age adjusted RR 2.1 (95% CI 0.9 to 5.1), multivariate adjusted OR 2.2 (95% CI 0.9 to 5.6). Corresponding age adjusted RR and multivariate adjusted OR for development of early stage ARM were 1.4 (95% CI 0.9 to 2.0) and 1.3 (95% CI 0.8 to 2.1) for focal arteriolar narrowing, and 1.6 (95% CI 1.0 to 2.3) and 1.8 (95% CI 1.1 to 2.9) for severe AV nicking, respectively. No associations between baseline CRAE and 5 year incident late or early stage ARM were found. Although of borderline statistical significance, the consistent associations found in this study suggest that structural retinal arteriolar changes may either contribute to ARM progression or may share common pathological pathways with ARM.


Influence of light handrail use on the biomechanics of stair negotiation in old age.
The high incidence of falls in older adults during stair negotiation suggests that this task is physically challenging and potentially dangerous. The present study aimed to examine the influence of light handrail use on the biomechanics of stair negotiation in old age. Thirteen older adults ascended and descended a purpose-built staircase at their self-selected speed: (i) unaided and (ii) with light use of the handrails. Ground reaction forces (GRFs) were measured from force platforms mounted into each step and motion capture was used to collect kinematic data. Knee and ankle joint moments were calculated using the kinetic and kinematic data. The horizontal separation between the centre of mass (COM) and the centre of pressure (COP) was assessed in the sagittal and frontal planes. During stair ascent, handrail use caused a different strategy to be employed compared to unaided ascent with a redistribution of joint moments. Specifically, the ankle joint moment (of the trailing leg) was reduced with handrail use, which has previously been shown to approach its limits during unaided stair ascent, but the knee joint moment (of the leading leg) increased. Previous research has shown that a larger joint moment reserve is available at the knee during unaided stair ascent. During stair descent, the ankle joint moment increased with handrail use, this was associated, however, with a more effective control of balance as shown by a reduced COM-COP separation in the direction of progression compared to unaided descent. These results indicate that although the biomechanical mechanisms are different for stair ascent and descent, the safety of stair negotiation is improved for older adults with light use of the handrails.


Fast detection of SARS-CoV-2 RNA via the integration of plasmonic thermocycling and fluorescence detection in a portable device.
The diagnosis of severe acute respiratory syndrome 2 (SARS-CoV-2) infection by quantitative PCR with reverse transcription (RT-qPCR) typically involves bulky instrumentation in centralized laboratories and an assay time of 1-2 h. Here, we show that SARS-CoV-2 RNA can be detected in 17 min via a portable device integrating reverse transcription, fast thermocycling (via plasmonic heating through magneto-plasmonic nanoparticles) and in situ fluorescence detection following magnetic clearance of the nanoparticles. The device correctly classified all nasopharyngeal, oropharyngeal and sputum samples from 75 patients with COVID-19 and 75 healthy controls, with good concordance in fluorescence intensity with standard RT-qPCR (Pearson coefficients > 0.7 for the N1, N2 and RPP30 genes). Fast, portable and automated nucleic acid detection should facilitate testing at the point of care.


HIV Drug Resistance Profiles and Clinical Outcomes in Patients with Viremia Maintained at Very Low Levels.
We describe an observational study of clinical, virologic and drug resistance profiles in HIV-positive antiretroviral adherent subjects with stable low level viremia (LLV) 50-1,000 copies/mL for more than 12 months. Subjects were followed from time of first detectable viral load (VL). In total, 102 episodes of LLV were detected among 80 individuals. The median (mean, range) HIV copy number at genotyping was 250 (486, <50-3900) copies/mL after 14 (17.9, 0-58) months of LLV. Few patients maintained LLV for the entire 9 year period of observation, with half (52%) experiencing viremic progression following a stable period of LLV either spontaneously or after treatment interruption or failed regimen intensification. In the setting of prolonged periods of sustained LLV, mean duration 22 (range 8 - 106) months, drug resistance (DR) was almost universal. Resistance to ≥1 on-treatment drugs was defined in 97% of specimens and DR to all drugs in the treatment regimen in over half of all patients. Evolution of DR mutations during the period of LLV was observed in 20/28 (71%) subjects with specimens available for follow-up testing. This evolution was associated with viremic progression to levels >1000 copies/mL (p=0.03). Our data suggest that DR present in patients with LLV is likely to impact long term clinical outcomes, highlighting the importance of optimizing techniques to detect the presence of drug resistant HIV in the setting of LLV and the need for larger prospective studies to assess the emergence of DR in the setting of sustained LLV and the impact of this DR on treatment outcomes.


Fast Genome-Wide QTL Association Mapping on Pedigree and Population Data.
Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel.


Lethal interactions between parasites and prey increase niche diversity in a tropical community.
Ecological specialization should minimize niche overlap, yet herbivorous neotropical flies (Blepharoneura) and their lethal parasitic wasps (parasitoids) exhibit both extreme specialization and apparent niche overlap in host plants. From just two plant species at one site in Peru, we collected 3636 flowers yielding 1478 fly pupae representing 14 Blepharoneura fly species, 18 parasitoid species (14 Bellopius species), and parasitoid-host associations, all discovered through analysis of molecular data. Multiple sympatric species specialize on the same sex flowers of the same fly host-plant species-which suggests extreme niche overlap; however, niche partitioning was exposed by interactions between wasps and flies. Most Bellopius species emerged as adults from only one fly species, yet evidence from pupae (preadult emergence samples) show that most Bellopius also attacked additional fly species but never emerged as adults from those flies.


En face choroidal vascular feature imaging in acute and chronic central serous chorioretinopathy using swept source optical coherence tomography.
To evaluate the variable depth tomographic features of choroidal vasculature in acute and chronic central serous chorioretinopathy (CSC) using swept source optical coherence tomography (SS-OCT) en face imaging. We retrospectively reviewed the en face SS-OCT images of 29 patients that presented with acute (12 eyes) or chronic (17 eyes) CSC. All of the patient eyes underwent 6×6 macular scans with SS-OCT (DRI OCT-1, Topcon, Tokyo, Japan), fluorescein angiography and indocyanine green angiography. The en face image was used to investigate the choroidal vasculature of each layer. Moreover, we determined that some parts corresponded to choriocapillaris and Sattler's layer attenuation, whereas choroidal vessel dilatation was associated with Haller's layer. At Haller's layer level, choroidal vessel dilatation was observed in 11 of 12 acute CSC (91.7%) and 15 of 17 chronic CSC (88.2%). In acute CSC, choroidal vessel dilatation was divided into focal (9/11; 81.8%) and diffuse (2/11; 18.2%) patterns. The chronic CSC cases demonstrated different patterns of choroidal vessel dilatation: focal (5/15; 33.3%) and diffuse (10/15; 66.6%). Ten of the acute CSC eyes (83.3%) and 14 of the chronic CSC eyes (82.4%) were found to have obscured choriocapillaris and Sattler's layers on en face imaging. En face imaging of SS-OCT is useful when combined with angiography in CSC for evaluating choroidal vessel dilatation at Haller's layer and to identify obscured upper layers. We identified different choroidal vessel dilatation patterns between acute and chronic CSC. These findings might be useful for pathophysiological understanding of CSC.


JBP1 and JBP2 proteins are Fe2+/2-oxoglutarate-dependent dioxygenases regulating hydroxylation of thymidine residues in trypanosome DNA.
We have recently demonstrated that O-linked glucosylation of thymine in trypanosome DNA (base J) regulates polymerase II transcription initiation. In vivo analysis has indicated that base J synthesis is initiated by the hydroxylation of thymidine by proteins (JBP1 and JBP2) homologous to the Fe(2+)/2-oxoglutarate (2-OG)-dependent dioxygenase superfamily where hydroxylation is driven by the oxidative decarboxylation of 2-OG, forming succinate and CO(2). However, no direct evidence for hydroxylase activity has been reported for the JBP proteins. We now demonstrate recombinant JBP1 hydroxylates thymine specifically in the context of dsDNA in a Fe(2+)-, 2-OG-, and O(2)-dependent manner. Under anaerobic conditions, the addition of Fe(2+) to JBP1/2-OG results in the formation of a broad absorption spectrum centered at 530 nm attributed to metal chelation of 2-OG bound to JBP, a spectroscopic signature of Fe(2+)/2-OG-dependent dioxygenases. The N-terminal thymidine hydroxylase domain of JBP1 is sufficient for full activity and mutation of residues involved in coordinating Fe(2+) inhibit iron binding and thymidine hydroxylation. Hydroxylation in vitro and J synthesis in vivo is inhibited by known inhibitors of Fe(2+)/2-OG-dependent dioxygenases. The data clearly demonstrate the JBP enzymes are dioxygenases acting directly on dsDNA, confirming the two-step J synthesis model. Growth of trypanosomes in hypoxic conditions decreases JBP1 and -2 activity, resulting in reduced levels of J and changes in parasite virulence previously characterized in the JBP KO. The influence of environment upon J biosynthesis via oxygen-sensitive regulation of JBP1/2 has exciting implications for the regulation of gene expression and parasite adaptation to different host niches.


Hyperperfusion of ictal seizure focus demonstrated by MR perfusion imaging.
MR using a susceptibility-weighted sequence and dynamic contrast enhancement with gadolinium demonstrated relative hyperperfusion of the right temporoparietal cortex in a patient in focal status epilepticus. A single-photon emission CT (SPECT) scan also demonstrated hyperperfusion of the right temporoparietal cortex. Perfusion MR, SPECT, and electroencephalogram normalized when the seizures ended.


Laser-induced carbon plasma emission spectroscopic measurements on solid targets and in gas-phase optical breakdown.
We report measurements of time- and spatially averaged spontaneous-emission spectra following laser-induced breakdown on a solid graphite/ambient gas interface and on solid graphite in vacuum, and also emission spectra from gas-phase optical breakdown in allene C3H4 and helium, and in CO2 and helium mixtures. These emission spectra were dominated by CII (singly ionized carbon), CIII (doubly ionized carbon), hydrogen Balmer beta (Hbeta), and Swan C2 band features. Using the local thermodynamic equilibrium and thin plasma assumptions, we derived electron number density and electron temperature estimates. The former was in the 10(16) cm(-3) range, while the latter was found to be near 20000 K. In addition, the vibration-rotation temperature of the Swan bands of the C2 radical was determined to be between 4500 and 7000 K, using an exact theoretical model for simulating diatomic emission spectra. This temperature range is probably caused by the spatial inhomogeneity of the laser-induced plasma plume. Differences are pointed out in the role of ambient CO2 in a solid graphite target and in gas-phase breakdown plasma.


Fission of pancreatic islets during postnatal growth of the mouse.
A cell composition analysis was made of the pancreatic islets in postnatal H253 mice. This line has a lacZ insertion on the X chromosome so that in female hemizygotes 50% of cells should be positive for beta-galactosidase and 50% negative. Immediately after birth, the islets were of a heterogeneous cell composition. However, by 4 weeks some islets have become homogeneous. This suggests that islets progress towards monoclonality in a similar way to the intestinal crypts and stomach gastric glands. Pancreatic islets may therefore represent 'structural proliferative units' in the overall histological organization of the pancreas. Reduction of genetic heterogeneity might arise from cell turnover, fission of islets or both. Analysis of the cell composition of the X-inactivation mosaic mice also provides the first clear evidence for islet fission in pancreatic development. Irregularly shaped islets resembling dumb-bells, with a characteristic neck of alpha-cells, were observed with decreasing frequency with increasing age. Three-dimensional reconstruction confirmed their resemblance to conjoined islets. The cell composition analysis showed: (1) the relatedness of the two sides of a dumb-bell islet is significantly higher than between two non-dumb-bell islets and (2) the relatedness of two randomly selected islets decreases as the distance between them increases. This suggests that dumb-bell islets are in a state of fission rather than fusion, and that islet fission is a mode of islet production in the postnatal pancreas.


A pilot study of cerebral and haemodynamic physiological changes during sedation with dexmedetomidine or propofol in patients with acute brain injury.
Sedation for the mechanically-ventilated, brain-injured patient remains challenging. The purpose of this pilot study was to compare the cerebral physiologic effects of sedation with propofol versus dexmedetomidine in mechanically-ventilated, brain-injured patients. Using a randomised, crossover, unblinded clinical trial, we enrolled patients with severe brain injury (Glasgow Coma Score ≤8) from traumatic injury, subarachnoid haemorrhage or intracerebral haemorrhage undergoing multimodal monitoring (intracranial pressure, brain temperature, oximetry and microdialysis). Patients received an infusion of either propofol or dexmedetomidine for six hours and then a crossover for the subsequent six hours after sufficient washout/in. Clinical and physiological measurements were recorded hourly. In eight patients, (four traumatic injury, three subarachnoid haemorrhage and one intracerebral haemorrhage), the mean dose of propofol used was 25.5 µg/kg/minute while the mean dose of dexmedetomidine was 0.54 µg/kg/hour. All subjects were effectively sedated to a goal of Richmond Agitation Sedation Scale -2 and Bispectral Index of 50-70 throughout the study period. We did not observe any statistically significant differences between the groups in systemic or cerebral physiologic metrics. Though differences were noted in cerebral metabolic substrates (lactate/pyruvate ratio), none were statistically significant. In our pilot cohort, dexmedetomidine and propofol appear equally effective in sedating severely brain-injured patients and neither is associated with adverse physiological effects as measured by multimodal monitoring. Larger long-term studies are required to determine whether clinically favourable benefits demonstrated in the medical critical care setting also apply to this patient population.


Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA): a pragmatic, open-label, randomised controlled trial.
Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasound-based pictorial information about subclinical carotid atherosclerosis, targeting both primary care physicians and individuals, improves prevention. Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA) is a pragmatic, open-label, randomised controlled trial that was integrated within the Västerbotten Intervention Programme, an ongoing population-based cardiovascular disease prevention programme in northern Sweden. Individuals aged 40, 50, or 60 years with one or more conventional risk factors were eligible to participate. Participants underwent clinical examination, blood sampling, and ultrasound assessment of carotid intima media wall thickness and plaque formation. Participants were randomly assigned 1:1 with a computer-generated randomisation list to an intervention group (pictorial representation of carotid ultrasound plus a nurse phone call to confirm understanding) or a control group (not informed). The primary outcomes, Framingham risk score (FRS) and European systematic coronary risk evaluation (SCORE), were assessed after 1 year among participants who were followed up. This study is registered with ClinicalTrials.gov, number NCT01849575. 3532 individuals were enrolled between April 29, 2013, and June 7, 2016, of which 1783 were randomly assigned to the control group and 1749 were assigned to the intervention group. 3175 participants completed the 1-year follow-up. At the 1-year follow-up, FRS and SCORE differed significantly between groups (FRS 1·07 [95% CI 0·11 to 2·03, p=0·0017] and SCORE 0·16 [0·02 to 0·30, p=0·0010]). FRS decreased from baseline to the 1-year follow-up in the intervention group and increased in the control group (-0·58 [95% CI -0·86 to -0·30] vs 0·35 [0·08 to 0·63]). SCORE increased in both groups (0·13 [95% CI 0·09 to 0·18] vs 0·27 [0·23 to 0·30]). This study provides evidence of the contributory role of pictorial presentation of silent atherosclerosis for prevention of cardiovascular disease. It supports further development of methods to reduce the major problem of low adherence to medication and lifestyle modification. Västerbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicine, and Carl Bennet Ltd, Sweden.


Criticality and mechanical enhancement in composite fiber networks.
Many biological materials consist of sparse networks of disordered fibers, embedded in a soft elastic matrix. The interplay between rigid and soft elements in such composite networks leads to mechanical properties that can go far beyond the sum of those of the constituents. Here we present lattice-based simulations to unravel the microscopic origins of this mechanical synergy. We show that the competition between fiber stretching and bending and elastic deformations of the matrix gives rise to distinct mechanical regimes, with phase transitions between them that are characterized by critical behavior and diverging strain fluctuations and with different mechanisms leading to mechanical enhancement.