Structural and functional connectivity of the subthalamic nucleus during vocal emotion decoding.
Our understanding of the role played by the subthalamic nucleus (STN) in human emotion has recently advanced with STN deep brain stimulation, a neurosurgical treatment for Parkinson's disease and obsessive-compulsive disorder. However, the potential presence of several confounds related to pathological models raises the question of how much they affect the relevance of observations regarding the physiological function of the STN itself. This underscores the crucial importance of obtaining evidence from healthy participants. In this study, we tested the structural and functional connectivity between the STN and other brain regions related to vocal emotion in a healthy population by combining diffusion tensor imaging and psychophysiological interaction analysis from a high-resolution functional magnetic resonance imaging study. As expected, we showed that the STN is functionally connected to the structures involved in emotional prosody decoding, notably the orbitofrontal cortex, inferior frontal gyrus, auditory cortex, pallidum and amygdala. These functional results were corroborated by probabilistic fiber tracking, which revealed that the left STN is structurally connected to the amygdala and the orbitofrontal cortex. These results confirm, in healthy participants, the role played by the STN in human emotion and its structural and functional connectivity with the brain network involved in vocal emotions.


[The position of medical specialists in the Netherlands (1890-1920].
At the end of the nineteenth century medical specialists came to the fore. In the larger cities they started to establish so-called dispensaries--clinics, not attached to hospitals--for medical aid of the poor. In this specialists differed from general practitioners, the GPs. With these dispensaries the specialists emphasized their own specific knowledge and skills in the treatment of patients with complaints in the field of their specialization. So, the specialists created an infrastructure which met the patients' specific requirements. Patients and municipal corporations were enthusiastic about it. The specialists needed the support, since the Dutch Medical Association [the Nederlandsche Maatschappij tot bevordering der Geneeskunst (NMG)] gave them no support at all. The most important group within the NMG, the GPs, felt that specialization threatened their sources of income and challenged their competence. Circa 1900 the GP was THE doctor for all categories of patients. Specialists, clearly recognisable by patients, disturbed this traditional structure. The NMG reacted on this new phenomenon of specialization either passively, or repressively. In theory the Association resigned itself to specialization as an inescapable result of the increased knowledge and more advanced technology. In practice, however, it was very reluctant in accepting it. There was no fundamental discussion about specialization within the Association. Recognition of a specialism depended mainly on the extent to which it threatened the practice of the GP. Within the NMG the most significant result of the differentiation of the medical profession was an internal struggle. This struggle escalated when in 1902 the Association introduced a 'National Health Service' system. On the one side, this policy created possibilities of taking action against those sections of other insurers for medical aid of the poor, on the other hand of taking repressive action against specialists. It follows that local branches could, among other things, exclude certain specialisms from the collective national health contracts, and introduce a doctor's referral for the national health patients. However, specialists depended on the national health patients to establish their claim on professional skill. This was not only based on greater knowledge than the GP's, but a specialist had also more experience. Until 1920 specialists needed a large number of national health patients to build up their experience. Until 1920 specialists needed a large number of national health patients to build up their experience. That made the introduction of the doctor's referral a threat to specialists. The introduction of a collective cashing in of the national health fees was another part of the policy of the NMG. It not only consumed time and energy, but also caused a lot of conflicts between the local GPs and the specialists. Thus the attention was diverted from the national health struggle, and replaced bij an internal 'struggle' between GPs and specialists.


Mutation accumulation and fitness effects in hybridogenetic populations: a comparison to sexual and asexual systems.
Female only unisexual vertebrates that reproduce by hybridogenesis show an unusual genetic composition. They are of hybrid origin but show no recombination between the genomes of their parental species. Instead, the paternal genome is discarded from the germline prior to meiosis, and gametes (eggs only) contain solely unrecombined maternal genomes. Hence hybridogens only transmit maternally inherited mutations. Hybridity is restored each generation by backcrossing with males of the sexual parental species whose genome was eliminated. In contrast, recombining sexual species propagate an intermixed pool of mutations derived from the maternal and paternal parts of the genome. If mutation rates are lower in female gametes than males, it raises the possibility for lower mutation accumulation in a hybridogenetic population, and consequently, higher population fitness than its sexual counterpart. We show through Monte-Carlo simulations that at higher male to female mutation ratios, and sufficiently large population sizes, hybridogenetic populations can carry a lower mutation load than sexual species. This effect is more pronounced with synergistic forms of epistasis. Mutations accumulate faster on the sexual part of the genome, and with the purifying effects of epistasis, it makes it more difficult for mutations to be transmitted on the clonal part of the genome. In smaller populations, the same mechanism reduces the speed of Muller's Ratchet and the number of fixed mutations compared to similar asexual species. Since mutation accumulation can be less pronounced in hybridogenetic populations, the question arises why hybridogenetic organisms are so scarce compared to sexual species. In considering this, it is likely that comparison of population fitnesses is not sufficient. Despite competition with the sexual parental species, hybrid populations are dependent on the maintenance of--and contact with--their sexual counterpart. Other problems may involve too little genetic diversity to respond to changing environments and problems in becoming hybridogenetic (e.g. disruption of meiosis and subsequent infertility or sterility). Yet, lower mutation accumulation in hybridogenetic populations opens the possibility that hybridogenetic species can develop into new sexual species once recombination is re-established and reproductive isolation from sexual ancestors has occurred.


Analytical Capability of Defocused µ-SORS in the Chemical Interrogation of Thin Turbid Painted Layers.
A recently developed micrometer-scale spatially offset Raman spectroscopy (μ-SORS) method provides a new analytical capability for investigating non-destructively the chemical composition of sub-surface, micrometer-scale thickness, diffusely scattering layers at depths beyond the reach of conventional confocal Raman microscopy. Here, we demonstrate experimentally, for the first time, the capability of μ-SORS to determine whether two detected chemical components originate from two separate layers or whether the two components are mixed together in a single layer. Such information is important in a number of areas, including conservation of cultural heritage objects, and is not available, for highly turbid media, from conventional Raman microscopy, where axial (confocal) scanning is not possible due to an inability to facilitate direct imaging within the highly scattering sample. This application constitutes an additional capability for μ-SORS in addition to its basic capacity to determine the overall chemical make-up of layers in a turbid system.


Automatic Registration of Footsteps in Contact Regions for Reactive Agility Training in Sports.
In collective sports, reactive agility training methodologies allow to evaluate and improve the player performance, being able to consider a mixture of technical, tactical, physical, and psychological abilities, similarly to real game-play situations. In this article, we present a new methodology for reactive agility training (neural training), the technological setup for the methodology, and a new footstep tracking algorithm, as the key element for automating the speed data gathering process, necessary for obtaining the relevant variables of the neural training approach. This new methodology is oriented to accurately measure two of the most relevant variables for reactive agility training: total response time (sprint time) and response correctness, related to a stimuli sequence presented to a player. The stimuli were designed to properly represent realistic competitive conditions for player training, contextualized to soccer. In order to automate the gathering process, a new computer vision based automatic footstep detection algorithm has been integrated to the system. The algorithm combines Kalman Filters, segmentation techniques, and perspective geometry, for obtaining highly precise detections of the moment a relevant footstep occurs in real-time, reaching a precision higher than 97%. Plus, the algorithm does not require any special marker, invasive sensor, or clothing constraint on the player.


Serum Uric Acid Levels as an Indicator for Metabolically Unhealthy Obesity in Children and Adolescents.
Metabolically healthy obesity (MHO) refers to those individuals who do not show cardiometabolic abnormalities. Our aim was to identify potential clinical and metabolic indicators that may help to distinguish between metabolically healthy and unhealthy individuals amongst overweight and obese children and adolescents. The study involved 246 overweight/obese and 212 normal-weight individuals enrolled in the LIFE Child study, aged between 6 and 18 years. Overweight/obese individuals without cardiovascular risk factors (fasting serum lipids, blood pressure, and glucose) were classified as MHO. Individuals meeting 1 or more criteria of cardiovascular risk factors were classified as metabolically unhealthy obesity (MUO). Among the 246 overweight/obese individuals, 173 (70%) were MHO and 73 (30%) were MUO. The MHO individuals were younger, more likely to be male, and had lower BMI SDS. In the logistic regression models, uric acid (UA) SDS (OR 1.61, 95% CI 1.1-2.6, p = 0.004), waist circumference SDS (OR 2.50, 95% CI 1.2-6.4, p = 0.017), and C-peptide (OR 4.05, 95% CI 3.5-91, p = 0.003) were significant indicators of MUO. Our results suggest that nearly one-third of overweight/obese children are already identified as MUO. Serum levels of UA can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO. We note that the relevance of identifying potential indicators remains the first most important step in future clinical research.


Correlates of Sexual Violence Among Men Who Have Sex With Men in Tijuana, Mexico.
Sexual violence among men who have sex with men (MSM) is prevalent in developing countries and is associated with increased HIV/STI risk. Despite high HIV prevalence (20 %) among MSM in Tijuana, Mexico, little attention has been paid to the occurrence of sexual violence in this high-risk group. The present study used a syndemic conditions framework to examine correlates of sexual violence victimization in a sample of 201 MSM surveyed in Tijuana, Mexico during 2012 and 2013. Participants were recruited through respondent-driven sampling and underwent a 2-h baseline interview and testing for HIV and syphilis. Sexual violence was defined as any incident during the past year in which the participant had been raped, sexually molested, or sexually harassed. The majority of participants self-identified as gay or bisexual, had never married, were employed, and had a high school education or greater. The average age was 29.7 years. Thirty-nine percent reported sexual violence in the past year. A hierarchical multiple linear regression model predicting more experiences of sexual violence was tested. In a final model, a higher number of experiences of sexual violence was associated with a history of childhood sexual abuse, more adult experiences of homophobia, more depression and hostility symptoms, and not living with a spouse or steady partner. The findings from this study support a model of co-occurring psychosocial factors that increase the likelihood of sexual violence experiences among MSM. Multi-level approaches to the prevention of childhood and adult experiences of sexual violence and homophobia are needed to avert the development of adverse mental and physical health outcomes associated with sexual violence victimization.


Aquaporin-4 in manganese-treated cultured astrocytes.
Manganese in excess is neurotoxic and causes CNS injury resembling that of Parkinson's disease. In brain, astrocytes predominantly take up and accumulate manganese and are thus vulnerable to its toxicity. Manganese was shown to induce cell swelling in cultured astrocytes, and oxidative/nitrosative stress (ONS) mediates such swelling. As aquaporin-4 (AQP4) is important in the mechanism of astrocyte swelling, we examined the effect of manganese on AQP4 protein levels in cultured astrocytes. Treatment of cultures with manganese increased AQP4 protein in the plasma membrane (PM), whereas total cellular AQP4 protein and mRNA levels were unchanged, suggesting that increased AQP4 levels is due to its increased stability and/or increased trafficking to the PM and not to its neosynthesis. AQP4 gene silencing by small interfering ribonucleic acid resulted in a marked reduction in astrocyte swelling by manganese. Antioxidants, as well as an inhibitor of nitric oxide synthase, diminished the increase in AQP4 protein expression, suggesting a role of ONS in the mechanism of AQP4 increase. As ONS is known to activate mitogen-activated protein kinases (MAPKs) and MAPK activation has been implicated in astrocyte swelling, we examined the effect of manganese on the activation of MAPKs and found an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, C-Jun amino-terminal kinase (JNK)1/2/3, and p38-MAPK. Inhibitors of ERK1/2 and p38-MAPK (but not of JNK) blocked (40-60%) the manganese-induced increase in AQP4 protein content and astrocyte swelling, suggesting the involvement of these kinases in the increased AQP4 content. Inhibition of oxidative stress or MAPKs may represent potential strategies for counteracting AQP4-related neurological complications associated with manganese toxicity.


Medical prevention of breast cancer.
Breast cancer is the most common cancer of women in Western Europe and North America. Effective strategies of medical prevention could reduce the burden of breast cancer mortality. The best evidence for a risk reduction exists for hormonal agents such as tamoxifen and raloxifene (22-72%) or aromatase inhibitors (50-65%). However, the severity of side effects and the lack of evidence for an improved survival compromise the risk/benefit balance. In this review the results of chemoprevention studies, including new treatment approaches, are summarized with critical discussion of their use in clinical practice.


Tilted-pulse time-resolved off-axis digital holography.
In this Letter we present an improvement of time-resolved off-axis digital holography by the use of tilted femtosecond laser pulses. The pulse front tilting of the reference beam with respect to the phase front allows larger crossing angles to be used for recording of digital holograms without significant reduction of pulse interference area (typically limited by low temporal coherence of ultrashort pulses). Such approach increases the area of interference fringes, thus enabling the higher resolution of the reconstructed image as well as better separation of dc term. Temporal resolution is not deteriorated by this method, as only the reference pulse is tilted. The proposed technique was applied for direct intensity clamping observations of light filaments in water using the laser pulses of 30 fs duration.


Single-molecule kinetics reveals signatures of half-sites reactivity in dihydroorotate dehydrogenase A catalysis.
Subunit activity and cooperativity of a homodimeric flavoenzyme, dihydroorotate dehydrogenase A (DHODA) from Lactococcus lactis, were characterized by employing single-molecule spectroscopy to follow the turnover kinetics of individual DHODA molecules, eliminating ensemble averaging. Because the enzyme-bound FMN is fluorescent in its oxidized state but not when reduced, a single DHODA molecule exhibits stepwise fluorescence changes during turnover, providing a signal to determine reaction kinetics and study cooperativity. Our results showed significant heterogeneity in the catalytic behaviors of individual dimer molecules, with only 40% interconverting between the three possible redox states: the fully fluorescent (both subunits oxidized), the half-fluorescent (one subunit oxidized and the other reduced), and the nonfluorescent (both subunits reduced). Forty percent of the single dimer traces showed turnovers between only the fully fluorescent and half-fluorescent states. The remaining 20% of the molecules interconverted only between the half-fluorescent state and the nonfluorescent state. Kinetic analysis revealed very similar reaction rates in both the reductive and oxidative half-reactions for different DHODA dimers. Our single-molecule data provide strong evidence for half-sites reactivity, in which only one subunit reacts at a time. The present study presents an effective way to explore the subunit catalytic activity and cooperativity of oligomeric enzymes by virtue of single-molecule fluorescence.


Plant natriuretic peptide active site determination and effects on cGMP and cell volume regulation.
Natriuretic peptides (NP) were first identified in animals where they play a role in the regulation of salt and water balance. This regulation is partly mediated by intracellular changes in cyclic GMP (cGMP). NP immunoanalogues occur in many plants and have been isolated, with two NP encoding genes characterised in Arabidopsis thaliana L. (AtPNP-A and AtPNP-B). Part of AtPNP-A contains the region with homology to human atrial (A)NP. We report here on the effects of recombinant AtPNP-A and smaller synthetic peptides within the ANP-homologous region with a view to identifying the biologically active domain of the molecule. Furthermore, we investigated interactions between AtPNP-A and the hormone, abscisic acid (ABA). ABA does not significantly affect Arabidopsis mesophyll protoplast volume regulation, whereas AtPNP-A and synthetic peptides promote water uptake into the protoplasts causing swelling. This effect is promoted by the membrane permeable cGMP analogue, 8-Br-cGMP, and inhibited by guanylate cyclase inhibitors indicating that increases in cGMP are an essential component of the plant natriuretic peptides (PNP) signalling cascade. ABA does not induce cGMP transients and does not affect AtPNP-A dependent cGMP increases, hence the two regulators differ in their second messenger signatures. Interestingly, AtPNP-A significantly delays and reduces the extent of ABA stimulated stomatal closure that is also based on cell volume regulation. We conclude that a complex interplay between observed PNP effects (stomatal opening and protoplast swelling) and ABA is likely to be cell type specific.


Accumulation-associated protein enhances Staphylococcus epidermidis biofilm formation under dynamic conditions and is required for infection in a rat catheter model.
Biofilm formation is the primary virulence factor of Staphylococcus epidermidis. S. epidermidis biofilms preferentially form on abiotic surfaces and may contain multiple matrix components, including proteins such as accumulation-associated protein (Aap). Following proteolytic cleavage of the A domain, which has been shown to enhance binding to host cells, B domain homotypic interactions support cell accumulation and biofilm formation. To further define the contribution of Aap to biofilm formation and infection, we constructed an aap allelic replacement mutant and an icaADBC aap double mutant. When subjected to fluid shear, strains deficient in Aap production produced significantly less biofilm than Aap-positive strains. To examine the in vivo relevance of our findings, we modified our previously described rat jugular catheter model and validated the importance of immunosuppression and the presence of a foreign body to the establishment of infection. The use of our allelic replacement mutants in the model revealed a significant decrease in bacterial recovery from the catheter and the blood in the absence of Aap, regardless of the production of polysaccharide intercellular adhesin (PIA), a well-characterized, robust matrix molecule. Complementation of the aap mutant with full-length Aap (containing the A domain), but not the B domain alone, increased initial attachment to microtiter plates, as did in trans expression of the A domain in adhesion-deficient Staphylococcus carnosus. These results demonstrate Aap contributes to S. epidermidis infection, which may in part be due to A domain-mediated attachment to abiotic surfaces.


Near-patient measurements of methemoglobin, oxygen saturation, and total hemoglobin: evaluation of a new instrument for adult and neonatal intensive care.
a) To evaluate the performance of a compact, new instrument that uses disposable cuvettes to measure total hemoglobin concentration, oxygen content, and the relative concentrations of oxy- and methemoglobin in 50-microL blood samples; b) to determine whether the instrument can be used for near-patient assessment of methemoglobinemia; and c) to ascertain whether problems commonly encountered in neonatal blood samples affect the instrument's performance. Prospective study, in which the test instrument was compared with a standard method. Samples of whole blood with and without bilirubin, fetal hemoglobin, and hemolysis were analyzed on the new (test) instrument and on a widely used cooximeter (OSM3 hemoximeter, Radiometer; reference instrument). In vitro analyses of blood samples in clinical and university laboratories. There was a close linear correlation between the methomoglobin measurements of the test instrument and those measurements of the reference instrument (slope = 0.989; r2 = .989). The average difference in mean assay values between the reference instrument and the test instrument was -0.59%, i.e., < 1% methemoglobin. Repeated measurements indicated the precision was 0.5% methemoglobin. Complete hemolysis of the sample reduced the methemoglobin reading by only 0.40%. Adding bilirubin (10 to 11 mg/dL [171 to 188.1 mumol/L]), increased the methemoglobin reading by 0.23%, increased the oxyhemoglobin reading by 0.45%, and increased total hemoglobin by 0.21 g/dL. Fetal hemoglobin also had minimal effects on the readings. The test instrument is fast and easy to operate. No sample preparation or pipetting is required. To operate the instrument, the user simply connects a syringe containing the blood sample to one of the disposable cuvettes, injects 50 microL of blood into the cuvette, and inserts the cuvette into the instrument. The test instrument automatically detects the presence of the cuvette, analyzes the sample, and displays the results in < 10 secs. The findings in this study indicate that the test instrument has sufficient accuracy for near-patient testing in intensive care units. The errors introduced by hemolysis, fetal hemoglobin, and bilirubin were too small to be of clinical importance. Thus, the test instrument is essentially unaffected by complications commonly encountered in neonatal blood. The capacity of the test instrument to measure methemoglobin makes it particularly useful if inhaled nitric oxide therapy becomes a standard clinical practice.


The responsiveness of the Action Research Arm test and the Fugl-Meyer Assessment scale in chronic stroke patients.
The responsiveness of the Action Research Arm (ARA) test and the upper extremity motor section of the Fugl-Meyer Assessment (FMA) scale were compared in a cohort of 22 chronic stroke patients undergoing intensive forced use treatment aimed at improvement of upper extremity function. The cohort consisted of 13 men and 9 women, median age 58.5 years, median time since stroke 3.6 years. Responsiveness was defined as the sensitivity of an instrument to real change. Two baseline measurements were performed with a 2-week interval before the intervention, and a follow-up measurement after 2 weeks of intensive forced use treatment. The limits of agreement, according to the Bland-Altman method, were computed as a measure of the test-retest reliability. Two different measures of responsiveness were compared: (i) the number of patients who improved more than the upper limit of agreement during the intervention; (ii) the responsiveness ratio. The limits of agreement, designating the interval comprising 95% of the differences between two measurements in a stable individual, were -5.7 to 6.2 and -5.0 to 6.6 for the ARA test and the FMA scale, respectively. The possible sum scores range from 0 to 57 (ARA) and from 0 to 66 (FMA). The number of patients who improved more than the upper limit were 12 (54.5%) and 2 (9.1%); and the responsiveness ratios were 2.03 and 0.41 for the ARA test and the FMA scale, respectively. These results strongly suggest that the ARA test is more responsive to improvement in upper extremity function than the FMA scale in chronic stroke patients undergoing forced use treatment.


A Polyadenylation-Dependent 3' End Maturation Pathway Is Required for the Synthesis of the Human Telomerase RNA.
Telomere maintenance by the telomerase reverse transcriptase requires a noncoding RNA subunit that acts as a template for the synthesis of telomeric repeats. In humans, the telomerase RNA (hTR) is a non-polyadenylated transcript produced from an independent transcriptional unit. As yet, the mechanism and factors responsible for hTR 3' end processing have remained largely unknown. Here, we show that hTR is matured via a polyadenylation-dependent pathway that relies on the nuclear poly(A)-binding protein PABPN1 and the poly(A)-specific RNase PARN. Depletion of PABPN1 and PARN results in telomerase RNA deficiency and the accumulation of polyadenylated precursors. Accordingly, a deficiency in PABPN1 leads to impaired telomerase activity and telomere shortening. In contrast, we find that hTRAMP-dependent polyadenylation and exosome-mediated degradation function antagonistically to hTR maturation, thereby limiting telomerase RNA accumulation. Our findings unveil a critical requirement for RNA polyadenylation in telomerase RNA biogenesis, providing alternative approaches for telomerase inhibition in cancer.


Heterologous expression and mutagenesis of recombinant Vespa affinis hyaluronidase protein (rVesA2).
Crude venom of the banded tiger waspVespa affinis contains a variety of enzymes including hyaluronidases, commonly known as spreading factors. The cDNA cloning, sequence analysis and structural modelling of V. affinis venom hyaluronidase (VesA2) were herein described. Moreover, heterologous expression and mutagenesis of rVesA2 were performed. V. affinis venom hyaluronidase full sequence is composed of 331 amino acids, with four predicted N-glycosylation sites. It was classified into the glycoside hydrolase family 56. The homology modelling exhibited a central core (α/β)7 composed of Asp107 and Glu109, acting as the catalytic residues. The recombinant protein was successfully expressed in E. coli with hyaluronidase activity. A recombinant mutant type with the double point mutation, Asp107Asn and Glu109Gln, completely lost this activity. The hyaluronidase from crude venom exhibited activity from pH 2 to 7. The recombinant wild type showed its maximal activity at pH 2 but decreased rapidly to nearly zero at pH 3 and was completely lost at pH 4. The recombinant wild-type protein showed its maximal activity at pH 2, more acidic pH than that found in the crude venom. The glycosylation was predicted to be responsible for the pH optimum and thermal stability of the enzymes activity.


Patterns of sexual violence against adults and children during the COVID-19 pandemic in Kenya: a prospective cross-sectional study.
This study examined patterns of sexual violence against adults and children in Kenya during the COVID-19 pandemic to inform sexual violence prevention, protection, and response efforts. A prospective cross-sectional research design was used with data collected from March to August 2020. Kenya. 317 adults, 224 children. Perpetrator and survivor demographic data, characteristics of the assault. Bivariate analyses found that children were more likely than adults to be attacked during daytime (59% vs 44%, p<0.001) by a single perpetrator rather than multiple perpetrators (31% vs 13%, p<0.001) in a private as opposed to a public location (66% vs 45%, p<0.001) and by someone known to the child (76% vs 58%, p<0.001). Children were violated most often by neighbours (29%) and family members (20%), whereas adults were equally likely to be attacked by strangers (41%) and persons known to them (59%). These variables were entered as predictors into a logistic regression model that significantly predicted the age group of the survivor, χ2(5, n=541)=53.3, p<0.001. Patterns of sexual violence against adult and child survivors during the COVID-19 pandemic are different, suggesting age-related measures are needed in national emergency plans to adequately address sexual violence during the pandemic and for future humanitarian crises.


Pain Management After Outpatient Anterior Cruciate Ligament Reconstruction: A Systematic Review of Randomized Controlled Trials.
Effective pain management after anterior cruciate ligament (ACL) reconstruction improves patient satisfaction and function. To collect and evaluate the available evidence from randomized controlled trials (RCTs) on pain control after ACL reconstruction. Systematic review. A systematic literature review was performed using PubMed, Medline, Google Scholar, UpToDate, Cochrane Reviews, CINAHL, and Scopus following PRISMA guidelines (July 2014). Only RCTs comparing a method of postoperative pain control to another method or placebo were included. A total of 77 RCTs met inclusion criteria: 14 on regional nerve blocks, 21 on intra-articular injections, 4 on intramuscular/intravenous injections, 12 on multimodal regimens, 6 on oral medications, 10 on cryotherapy/compression, 6 on mobilization, and 5 on intraoperative techniques. Single-injection femoral nerve blocks provided superior analgesia to placebo for up to 24 hours postoperatively; however, this also resulted in a quadriceps motor deficit. Indwelling femoral catheters utilized for 2 days postoperatively provided superior analgesia to a single-injection femoral nerve block. Local anesthetic injections at the surgical wound site or intra-articularly provided equivalent analgesia to regional nerve blocks. Continuous-infusion catheters of a local anesthetic provided adequate pain relief but have been shown to cause chondrolysis. Cryotherapy improved analgesia compared to no cryotherapy in 4 trials, while in 4 trials, ice water and water at room temperature provided equivalent analgesic effects. Early weightbearing decreased pain compared to delayed weightbearing. Oral gabapentin given preoperatively and oral zolpidem given for the first week postoperatively each decreased opioid consumption as compared to placebo. Ibuprofen reduced pain compared to acetaminophen. Oral ketorolac reduced pain compared to hydrocodone-acetaminophen. Regional nerve blocks and intra-articular injections are both effective forms of analgesia. Cryotherapy-compression appears to be beneficial, provided that intra-articular temperatures are sufficiently decreased. Early mobilization reduces pain symptoms. Gabapentin, zolpidem, ketorolac, and ibuprofen decrease opioid consumption. Despite the vast amount of high-quality evidence on this topic, further research is needed to determine the optimal multimodal approach that can maximize recovery while minimizing pain and opioid consumption. These results provide the best available evidence from RCTs on pain control regimens after ACL reconstruction.


Physical activity opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension.
Endothelin-1 has potent constrictor and proliferative activity in vascular smooth muscle, and essential hypertension and aging are associated with increased endothelin-1-mediated vasoconstrictor tone. The aim of this study was to investigate the effect of physical activity, hypertension and age on endothelin-1 levels in plasma and skeletal muscle and endothelin receptors in skeletal muscle in human subjects. In study 1, normotensive (46 ± 1 years, n = 11) and hypertensive (47 ± 1 years, n = 10) subjects were studied before and after 8 weeks of aerobic exercise training. In study 2, young (23 ± 1 years, n = 8), older lifelong sedentary (66 ± 2 years, n = 8) and older lifelong endurance-trained (62 ± 2 years, n = 8) subjects were studied in a cross-sectional design. Skeletal muscle and plasma endothelin-1 levels were increased with age and plasma endothelin-1 levels were higher in hypertensive than normotensive individuals. Eight weeks of exercise training normalized plasma endothelin-1 levels in the hypertensive subjects and increased the protein expression of the ET(A) receptor in skeletal muscle of normotensive subjects. Similarly, individuals that had performed lifelong physical activity had similar plasma and muscle endothelin-1 levels as the young controls and had higher ET(A) receptor levels. Our findings suggest that aerobic exercise training opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension. This effect may explain some of the beneficial effects of training on the cardiovascular system in older and hypertensive subjects.


Co-producing research with youth: The NeurOx young people's advisory group model.
The 1989 UN Convention on the Rights of the Child states that children have the right to be heard in all matters affecting them. The Convention inspired a surge in research that investigates young people's perspectives on health and wellness-related concerns and that involves children as 'co-researchers'. Young people's advisory groups (YPAGs) are a widely used method to enable young people's involvement in all research stages, but there is a lack of academic literature to guide researchers on how to set up, run and evaluate the impact of such groups. In this paper, we provide a step-by-step model, grounded in our own experience of setting up and coordinating the Oxford Neuroscience, Ethics and Society Young People's Advisory Group (NeurOx YPAG). This group supports studies at the intersection of ethics, mental health and novel technologies. Our model covers the following stages: deciding on the fit for co-production, recruiting participants, developing collective principles of work, running a meeting and evaluating impact. We emphasize that throughout this process, researchers should take a critical stance by reflecting on whether a co-production model fits their research scope and aims; ensuring (or aspiring to) representativeness within the group; valuing different kinds of expertise; and undertaking on-going evaluations on the impact of the group on both the young people and the research. Adopting a critical and reflective attitude can increase researchers' capacity to engage youth in democratic and inclusive ways, and to produce research outputs that are aligned with the target audience's needs and priorities.


Substance Use, Criminal Recidivism, and Mortality in Criminal Justice Clients: A Comparison between Men and Women.
Background. This study aimed to map differences between male and female offenders with substance abuse, with respect to descriptive characteristics and risk factors for mortality and criminal recidivism. Methods. Criminal justice clients with substance abuse problems (n = 7085) were interviewed with the Addiction Severity Index. Mortality and data on return to criminal justice were retrieved from national registers. Results. Female offenders reported heavier substance use patterns, more psychiatric symptoms, and more often a partner with substance abuse, but had lower mortality (2% versus 4%) and criminal recidivism (62% versus 71%) during follow-up. Having a substance-abusing partner was associated with criminal recidivism among females. Conclusions. Female offenders with substance abuse differ from their male counterparts. Males and females had different risk factors for criminal recidivism.


Melanisation of Aspergillus terreus-Is Butyrolactone I Involved in the Regulation of Both DOPA and DHN Types of Pigments in Submerged Culture?
Pigments and melanins of fungal spores have been investigated for decades, revealing important roles in the survival of the fungus in hostile environments. The key genes and the encoded enzymes for pigment and melanin biosynthesis have recently been found in Ascomycota, including Aspergillus spp. In Aspergillus terreus, the pigmentation has remained mysterious with only one class of melanin biogenesis being found. In this study, we examined an intriguing, partially annotated gene cluster of A. terreus strain NIH2624, utilizing previously sequenced transcriptome and improved gene expression data of strain MUCL 38669, under the influence of a suggested quorum sensing inducing metabolite, butyrolactone I. The core polyketide synthase (PKS) gene of the cluster was predicted to be significantly longer on the basis of the obtained transcriptional data, and the surrounding cluster was positively regulated by butyrolactone I at the late growth phase of submerged culture, presumably during sporulation. Phylogenetic analysis of the extended PKS revealed remarkable similarity with a group of known pigments of Fusarium spp., indicating a similar function for this PKS. We present a hypothesis of this PKS cluster to biosynthesise a 1,8-dihydroxynaphthalene (DHN)-type of pigment during sporulation with the influence of butyrolactone I under submerged culture.


Analysing taxonomic structures and local ecological processes in temperate forests in North Eastern China.
One of the core issues of forest community ecology is the exploration of how ecological processes affect community structure. The relative importance of different processes is still under debate. This study addresses four questions: (1) how is the taxonomic structure of a forest community affected by spatial scale? (2) does the taxonomic structure reveal effects of local processes such as environmental filtering, dispersal limitation or interspecific competition at a local scale? (3) does the effect of local processes on the taxonomic structure vary with the spatial scale? (4) does the analysis based on taxonomic structures provide similar insights when compared with the use of phylogenetic information? Based on the data collected in two large forest observational field studies, the taxonomic structures of the plant communities were analyzed at different sampling scales using taxonomic ratios (number of genera/number of species, number of families/number of species), and the relationship between the number of higher taxa and the number of species. Two random null models were used and the "standardized effect size" (SES) of taxonomic ratios was calculated, to assess possible differences between the observed and simulated taxonomic structures, which may be caused by specific ecological processes. We further applied a phylogeny-based method to compare results with those of the taxonomic approach. As expected, the taxonomic ratios decline with increasing grain size. The quantitative relationship between genera/families and species, described by a linearized power function, showed a good fit. With the exception of the family-species relationship in the Jiaohe study area, the exponents of the genus/family-species relationships did not show any scale dependent effects. The taxonomic ratios of the observed communities had significantly lower values than those of the simulated random community under the test of two null models at almost all scales. Null Model 2 which considered the spatial dispersion of species generated a taxonomic structure which proved to be more consistent with that in the observed community. As sampling sizes increased from 20 m × 20 m to 50 m × 50 m, the magnitudes of SESs of taxonomic ratios increased. Based on the phylogenetic analysis, we found that the Jiaohe plot was phylogenetically clustered at almost all scales. We detected significant phylogenetically overdispersion at the 20 m × 20 m and 30 m × 30 m scales in the Liangshui plot. The results suggest that the effect of abiotic filtering is greater than the effects of interspecific competition in shaping the local community at almost all scales. Local processes influence the taxonomic structures, but their combined effects vary with the spatial scale. The taxonomic approach provides similar insights as the phylogenetic approach, especially when we applied a more conservative null model. Analysing taxonomic structure may be a useful tool for communities where well-resolved phylogenetic data are not available.


Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD.
The C9ORF72 hexanucleotide repeat expansion is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal age-related neurodegenerative diseases. The C9ORF72 expansion encodes five dipeptide repeat proteins (DPRs) that are produced through a non-canonical translation mechanism. Among the DPRs, proline-arginine (PR), glycine-arginine (GR), and glycine-alanine (GA) are the most neurotoxic and increase the frequency of DNA double strand breaks (DSBs). While the accumulation of these genotoxic lesions is increasingly recognized as a feature of disease, the mechanism(s) of DPR-mediated DNA damage are ill-defined and the effect of DPRs on the efficiency of each DNA DSB repair pathways has not been previously evaluated. Using DNA DSB repair assays, we evaluated the efficiency of specific repair pathways, and found that PR, GR and GA decrease the efficiency of non-homologous end joining (NHEJ), single strand annealing (SSA), and microhomology-mediated end joining (MMEJ), but not homologous recombination (HR). We found that PR inhibits DNA DSB repair, in part, by binding to the nucleolar protein nucleophosmin (NPM1). Depletion of NPM1 inhibited NHEJ and SSA, suggesting that NPM1 loss-of-function in PR expressing cells leads to impediments of both non-homologous and homology-directed DNA DSB repair pathways. By deleting NPM1 sub-cellular localization signals, we found that PR binds NPM1 regardless of the cellular compartment to which NPM1 was directed. Deletion of the NPM1 acidic loop motif, known to engage other arginine-rich proteins, abrogated PR and NPM1 binding. Using confocal and super-resolution immunofluorescence microscopy, we found that levels of RAD52, a component of the SSA repair machinery, were significantly increased iPSC neurons relative to isogenic controls in which the C9ORF72 expansion had been deleted using CRISPR/Cas9 genome editing. Western analysis of post-mortem brain tissues confirmed that RAD52 immunoreactivity is significantly increased in C9ALS/FTD samples as compared to controls. Collectively, we characterized the inhibitory effects of DPRs on key DNA DSB repair pathways, identified NPM1 as a facilitator of DNA repair that is inhibited by PR, and revealed deficits in homology-directed DNA DSB repair pathways as a novel feature of C9ORF72-related disease.


An identity-based model for adolescent health in the Islamic Republic of Iran: a qualitative study.
We conducted this study on 52 adolescents from Tehran to investigate their perspectives on health. We used the grounded theory approach and the constant comparison analysis method. Identity emerged as a core variable along with the concepts of friendship and relationships, education, family, lack of limitation and community. Identity affects adolescents' health regarding the emerged concepts. Participants believed that psychosocial health-related factors were more important than physical and individual health factors. Therefore, social welfare, healthy family/friendship, and caring for adolescents' individuality are important for healthy adolescence.


Non-surgical improvement of cervical lordosis is possible in advanced spinal osteoarthritis: a CBP® case report.
[Purpose] To present a case of the non-surgical improvement in cervical kyphosis in a patient with history of cervical spine trauma and advanced osteoarthritis. [Subject and Methods] A 38 year old male presented with a chief complaint of chronic neck pain that was not substantially relieved by recent previous traditional physiotherapy and chiropractic manipulation. The cervical radiograph demonstrated a cervical hypolordosis of 5° as measured by the Harrison posterior tangent method from C2-C7. There was a 15° kyphosis at C4-C6 with advanced degenerative changes consistent with previous spine trauma. The patient was treated by CBP® methods incorporating cervical extension traction, extension exercises, and spinal manipulation for 30 sessions over an 18 week period. [Results] After the treatment sessions, there was a substantial (27°) increase in global C2-C7 lordosis, and 5° decrease in C4-C6 degenerative kyphosis corresponding to the reduction in neck pain and disability, and an improvement in overall health status as indicated on the SF-36 health questionnaire. [Conclusion] Although degenerative spondylosis of the cervical spine will have physical limitations to non-surgical correction, this case serves as an example that it is possible to reduce degenerative kyphosis and increase global cervical lordosis corresponding to health improvements in these patients.


KTF-1, a transcriptional activator of Xenopus embryonic keratin expression.
Nuclear extracts from embryos of Xenopus laevis were shown to contain a protein activity, KTF-1, which binds in vitro to the promoter of the embryonic, epidermis-specific keratin gene, XK81A1. Mobility shift assays, methylation interference and footprinting analysis were used to show that the KTF-1 binding site contains an imperfect, palindromic sequence, ACCCTGAGGCT. This sequence occurs once in the XK81A1 promoter, 152-162 base pairs upstream of the transcription start site. A construct of the keratin gene in which this sequence was altered so that it no longer binds KTF-1 in vitro showed severely reduced transcription levels upon injection into Xenopus embryos, but retained epidermal specificity. Addition of KTF-1 binding sites also enhanced epidermal and non-epidermal activity of a heterologous promoter, Xenopus beta-globin, in embryos. These results suggest that KTF-1 is a general activator of embryonic keratin transcription, which acts in concert with other factors to produce high levels of epidermis-specific expression.


Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood.
Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence. The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood. A sample of singleton children (n = 33,437) was drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 8 mo, 4 y, and 7 y (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test). The main analyses examined the relationship between neurocognitive measures and paternal or maternal age when adjusted for potential confounding factors. Advanced paternal age showed significant associations with poorer scores on all of the neurocognitive measures apart from the Bayley Motor score. The findings were broadly consistent in direction and effect size at all three ages. In contrast, advanced maternal age was generally associated with better scores on these same measures. The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood. In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.


Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner.
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.


Anatomical study of superficial fascia and localized fat deposits of abdomen.
The development of liposuction and abdominoplasty has renewed interest in the anatomy of the localized fat deposits (LFD) areas of the abdomen. This study aims at ascertaining the gross anatomy of superficial fascia and the localized fat deposits of abdomen. Eight adult cadavers (four males and four females) were dissected. Attachments, number of layers of fascia and colour, shape and maximum size of the fat lobules in loin, and upper and lower abdomen were noted. Thickness of deep membranous layer of superficial fascia of upper abdomen and lower abdomen were measured by metal casing electronic digital calipers, with resolution being 10 μm. The independent sample t-test, ANOVA for comparison and Pearson coefficient for correlation were used. Superficial fascia of the abdomen was multilayered in the midline and number of layers reduced laterally. The shape, size, color, and arrangement of fat lobules were different in different locations. The thickness of the fascia of the lower abdomen in males (mean 528.336 ± SE38.48) was significantly (P < 0.041) more than that in females. (Mean 390.822 ± SE36.24). Pearson correlation between thickness of the membranous layer of the upper and lower abdomen revealed moderately positive correlation (r=0.718; P<0.045). The LFD in the central region of the abdomen corresponds to the area of multilayered fascia with smaller fat lobules. The relatively thinner supporting fascia of the lower abdomen in females may be responsible for excessive bulges of the lower abdomen. The fat lobule anatomy at different sites under study was different.


Electron paramagnetic resonance investigation of purified catalyst-free single-walled carbon nanotubes.
Electron paramagnetic resonance of single-walled carbon nanotubes (SWCNTs) has been bedevilled by the presence of paramagnetic impurities. To address this, SWCNTs produced by laser ablation with a nonmagnetic PtRhRe catalyst were purified through a multiple step centrifugation process in order to remove amorphous carbon and catalyst impurities. Centrifugation of a SWCNT solution resulted in sedimentation of carbon nanotube bundles containing clusters of catalyst particles, while isolated nanotubes with reduced catalyst particle content remained in the supernatant. Further ultracentrifugation resulted in highly purified SWCNT samples with a narrow diameter distribution and almost no detectable catalyst particles. Electron paramagnetic resonance (EPR) signals were detected only for samples which contained catalyst particles, with the ultracentrifuged SWCNTs showing no EPR signal at X-band (9.4 GHz) and fields < 0.4 T.


Comparative analysis of bupivacaine and ropivacaine for infiltration analgesia for bilateral breast surgery.
Local anesthesia infiltration has been established as a preferred method of perioperative analgesia in many cosmetic operations. In an attempt to maximize the risk-benefit ratio of local anesthesia, a study was conducted to compare efficacy of two local anaesthetic agents. Bupivacaine was compared to ropivacaine in a bilaterally symmetrical breast surgery model. A local anaesthetic solution containing either bupivacaine or ropivacaine was infiltrated into each of the breasts of 15 patients undergoing either breast augmentation or breast reduction. Both surgeon and patient were blinded to the nature of local anaesthetic agent injected. Patients were requested to score their pain at 1, 2, 6, and 10 hours after surgery on a visual analog scale. The results were analyzed statistically using a cross-sectional time-series regression model employing the random effects option of the xtreg command from Strata Release 6 statistical software. We found that overall analgesia achieved with bupivacaine and ropivacaine infiltrations was not statistically different. The use of a higher dose of ropivacaine is likely to have removed the clinical advantage noted for the bupivacaine group. There was, however, a statistical and clinical difference in the efficacy of local anaesthetic infiltration of both agents in breast augmentation patients as compared to breast reduction patients, local anaesthetic being less effective in patients who had submuscular breast augmentation than in patients who had breast reduction. In view of these findings, it appears reasonable to recommend the use of ropivacaine in high-dose infiltration breast analgesia, as it is reported to be less cardiotoxic than bupivacaine. Serious attention needs also to be given to the adequacy of field infiltration of local anesthesia in submuscular breast augmentation.


Effects of process parameters on cutting temperature in dry machining of ball screw.
Temperature in the cutting zone during dry machining has a significant effect on the tool life and surface integrity of the workpiece. This paper describes a comprehensive research on the cutting temperature in dry machining of ball screw under whirling milling by using infrared imaging. The effects of tool parameter and geometric parameter of workpiece together with the cutting parameters on the maximum and average temperatures in the cutting zone were analyzed in full detail. The influencing degree of these parameters on the maximum and average temperatures was affected by the value ranges of the parameters. In addition, the regression model and back propagation (BP) neural network model were proposed for predicting the maximum and average temperatures in the cutting zone. The verification of the predictive models showed that compared to the regression model, BP neural network model could predict the cutting temperature with high precision. The R2 of BP neural network model for predicting the maximum and average cutting temperatures in the cutting zone was higher than 99.8%, and the mean relative error and root mean square error were less than 4% and 19%, respectively.


Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.
Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.


Missing voices: Profile and extent of acquired communication disorders in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia using linked administrative records.
Limited data exist on the extent of specific functional sequelae, including acquired communication disorder, among Aboriginal stroke survivors, making planning of multidisciplinary services difficult. To obtain estimates of the extent and profile of acquired communication disorder in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia and investigate potential disparities in receiving in-hospital speech pathology services among survivors with acquired communication disorder. Stroke cases surviving their first stroke episode during 2002-2011 were identified using Western Australia-wide person-based linked hospital and mortality data, and their five-year comorbidity profiles determined. The mid-year prevalence of stroke cases with acquired communication disorder was estimated for 2011. Regression methods were used to investigate determinants of receiving speech pathology services among acquired communication disorder cases. Of 14,757 stroke survivors aged 15-79 years admitted in 2002-2011, 33% had acquired communication disorder (22% aphasia/dysphasia) and 777 (5.3%) were Aboriginal. Aboriginal patients were more likely to be younger, live remotely, and have comorbidities. A diagnosis of aphasia was more common in Aboriginal than non-Aboriginal patients 15-44 years (p = 0.003). A minimum of 107 Aboriginal and 2324 non-Aboriginal stroke patients with acquired communication disorder lived in Western Australia in 2011. Aboriginal status was not associated with receiving in-hospital speech services among acquired communication disorder patients in unadjusted or adjusted models. The relative youth, geographical distribution, high comorbidity prevalence, and cultural needs of Aboriginal stroke patients with acquired communication disorder should inform appropriate service design for speech pathology and rehabilitation. Innovative models are required to address workforce issues, given low patient volumes.


Technique and outcomes of robot-assisted median arcuate ligament release for celiac artery compression syndrome.
Celiac artery compression by the median arcuate ligament (MAL) is a potential cause of postprandial abdominal pain and weight loss that overlaps with other common syndromes. Robotic technology may alter the current paradigm for surgical intervention. Open MAL release is often performed with concurrent bypass for celiac stenosis due to the morbidity of reintervention, whereas the laparoscopic approach is associated with high rates of conversion to open due to bleeding. We hypothesized that a robot-assisted technique might minimize conversion events to open, decrease perioperative morbidity, and defer consideration of vascular bypass at the initial operative setting. We retrospectively analyzed patients treated for MAL syndrome by a multidisciplinary team at a tertiary medical center between September 2012 and December 2013. Diagnosis was based on symptom profile and peak systolic velocity (PSV) >200 cm/s during celiac artery duplex ultrasound imaging. All patients underwent robot-assisted MAL release with simultaneous circumferential neurolysis of the celiac plexus. Postoperative celiac duplex and symptom profiles were reassessed longitudinally to monitor outcomes. Nine patients (67% women) were evaluated for postprandial pain (100%) and weight loss (100%). All patients had celiac stenosis by mesenteric duplex ultrasound imaging (median PSV, 342; range, 238-637 cm/s), and cross-sectional imaging indicated a fishhook deformity in five (56%). Robot-assisted MAL release was completed successfully in all nine patients (100%) using a standardized surgical technique. Estimated blood loss was <50 mL, with a median hospital stay of 2 days (range, 2-3 days). No postoperative complications of grade ≥3, readmissions or reoperations were observed. All patients (100%) improved symptomatically at the 25-week median follow-up. Three patients experienced complete resolution on postoperative celiac duplex ultrasound imaging, and six patients showed an improved but persistent stenosis (PSV >200 cm/s) compared with preoperative velocities (P < .05 by Wilcoxon signed rank). No patients required additional treatment. Robot-assisted MAL release can be performed safely and effectively with avoidance of conversion events and minimal morbidity. Potential factors contributing to success are patient selection by a multidisciplinary team and replication of the open surgical technique by means of robot-assisted dexterity and visualization. The need for delayed reintervention for persistently symptomatic celiac stenosis is uncertain.


Cannabis and its derivatives: review of medical use.
Use of cannabis is often an under-reported activity in our society. Despite legal restriction, cannabis is often used to relieve chronic and neuropathic pain, and it carries psychotropic and physical adverse effects with a propensity for addiction. This article aims to update the current knowledge and evidence of using cannabis and its derivatives with a view to the sociolegal context and perspectives for future research. Cannabis use can be traced back to ancient cultures and still continues in our present society despite legal curtailment. The active ingredient, Δ9-tetrahydrocannabinol, accounts for both the physical and psychotropic effects of cannabis. Though clinical trials demonstrate benefits in alleviating chronic and neuropathic pain, there is also significant potential physical and psychotropic side-effects of cannabis. Recent laboratory data highlight synergistic interactions between cannabinoid and opioid receptors, with potential reduction of drug-seeking behavior and opiate sparing effects. Legal rulings also have changed in certain American states, which may lead to wider use of cannabis among eligible persons. Family physicians need to be cognizant of such changing landscapes with a practical knowledge on the pros and cons of medical marijuana, the legal implications of its use, and possible developments in the future.


Management of dyslipidemia in children and adolescents with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an independent risk factor for atherosclerosis, placing children and adolescents with SLE at great risk for developing cardiovascular sequelae, including myocardial infarction, in adulthood. Dyslipidemia and other traditional cardiac risk factors occur frequently in pediatric SLE and are often under-recognized and under-treated. Two dyslipidemia patterns are evident in pediatric SLE. Active disease is characterized by elevated triglycerides (TG) and low high density lipoprotein (HDL). With SLE treatment HDL and TG often normalize, while total cholesterol and low density lipoprotein (LDL) rise. The complex pathophysiology of dyslipidemia in SLE involves cytokines, autoantibodies, disease activity, medications, diet, and physical activity level, as well as other factors. Routine screening for dyslipidemia with fasting lipid profiles is indicated for children and adolescents with SLE. If lipoprotein levels are abnormal, first line therapy involves diet and exercise interventions for a minimum of six months. For persistent dyslipidemia, several pharmacologic therapies are available. Hydroxychloroquine, a common treatment for SLE, can improve lipid profiles and should be considered for all patients with SLE. Statins and bile acid sequestrants are typically added first for dyslipidemia, while niacin and fibrates are reserved for refractory disease and optimally prescribed in a multidisciplinary lipid clinic. Future research is needed to further illuminate the mechanisms of dyslipidemia in pediatric SLE with well designed clinical trials to determine the safest and most effective interventions to correct lipid profiles and prevent atherosclerosis.


Effects of mutation on selection limits in finite populations with multiple alleles.
The ultimate response to directional selection (i.e., the selection limit) under recurrent mutation is analyzed by a diffusion approximation for a population in which there are k possible alleles at a locus. The limit mainly depends on two scaled parameters S (= 4Ns sigma a) and theta (= 4Nu) and k, the number of alleles, where N is the effective population size, u is the mutation rate, s is the selection coefficient, and sigma 2a is the variance of allelic effects. When the selection pressure is weak (S less than or equal to 0.5), the limit is given approximately by 2S sigma a[1 - (1 + c2)/k]/(theta + 1) for additive effects of alleles, where c is the coefficient of variation of the mutation rates among alleles. For strong selection, other approximations are devised to analyze the limit in different parameter regions. The effect of mutation on selection limits largely relies on the potential of mutation to introduce new and better alleles into the population. This effect is, however, bounded under the present model. Unequal mutation rates among alleles tend to reduce the selection limit, and can have a substantial effect only for small numbers of alleles and weak selection. The selection limit decreases as the mutation rate increases.


"Body-In-The-Loop": Optimizing Device Parameters Using Measures of Instantaneous Energetic Cost.
This paper demonstrates methods for the online optimization of assistive robotic devices such as powered prostheses, orthoses and exoskeletons. Our algorithms estimate the value of a physiological objective in real-time (with a body "in-the-loop") and use this information to identify optimal device parameters. To handle sensor data that are noisy and dynamically delayed, we rely on a combination of dynamic estimation and response surface identification. We evaluated three algorithms (Steady-State Cost Mapping, Instantaneous Cost Mapping, and Instantaneous Cost Gradient Search) with eight healthy human subjects. Steady-State Cost Mapping is an established technique that fits a cubic polynomial to averages of steady-state measures at different parameter settings. The optimal parameter value is determined from the polynomial fit. Using a continuous sweep over a range of parameters and taking into account measurement dynamics, Instantaneous Cost Mapping identifies a cubic polynomial more quickly. Instantaneous Cost Gradient Search uses a similar technique to iteratively approach the optimal parameter value using estimates of the local gradient. To evaluate these methods in a simple and repeatable way, we prescribed step frequency via a metronome and optimized this frequency to minimize metabolic energetic cost. This use of step frequency allows a comparison of our results to established techniques and enables others to replicate our methods. Our results show that all three methods achieve similar accuracy in estimating optimal step frequency. For all methods, the average error between the predicted minima and the subjects' preferred step frequencies was less than 1% with a standard deviation between 4% and 5%. Using Instantaneous Cost Mapping, we were able to reduce subject walking-time from over an hour to less than 10 minutes. While, for a single parameter, the Instantaneous Cost Gradient Search is not much faster than Steady-State Cost Mapping, the Instantaneous Cost Gradient Search extends favorably to multi-dimensional parameter spaces.


Enhanced targeting of triple-negative breast carcinoma and malignant melanoma by photochemical internalization of CSPG4-targeting immunotoxins.
Triple-negative breast cancer (TNBC) and malignant melanoma are highly aggressive cancers that widely express the cell surface chondroitin sulfate proteoglycan 4 (CSPG4/NG2). CSPG4 plays an important role in tumor cell growth and survival and promotes chemo- and radiotherapy resistance, suggesting that CSPG4 is an attractive target in cancer therapy. In the present work, we applied the drug delivery technology photochemical internalization (PCI) in combination with the novel CSPG4-targeting immunotoxin 225.28-saporin as an efficient and specific strategy to kill aggressive TNBC and amelanotic melanoma cells. Light-activation of the clinically relevant photosensitizer TPCS2a (fimaporfin) and 225.28-saporin was found to act in a synergistic manner, and was superior to both PCI of saporin and PCI-no-drug (TPCS2a + light only) in three TNBC cell lines (MDA-MB-231, MDA-MB-435 and SUM149) and two BRAFV600E mutated malignant melanoma cell lines (Melmet 1 and Melmet 5). The cytotoxic effect was highly dependent on the light dose and expression of CSPG4 since no enhanced cytotoxicity of PCI of 225.28-saporin compared to PCI of saporin was observed in the CSPG4-negative MCF-7 cells. The PCI of a smaller, and clinically relevant CSPG4-targeting toxin (scFvMEL-rGel) validated the CSPG4-targeting concept in vitro and induced a strong inhibition of tumor growth in the amelanotic melanoma xenograft A-375 model. In conclusion, the combination of the drug delivery technology PCI and CSPG4-targeting immunotoxins is an efficient, specific and light-controlled strategy for the elimination of aggressive cells of TNBC and malignant melanoma origin. This study lays the foundation for further preclinical evaluation of PCI in combination with CSPG4-targeting.


Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors.
The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human α3β4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca(2+) imaging, (86)Rb(+) efflux, and voltage-clamp measurements. Coapplication of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. These effects increased with agonist concentration. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Notably, menthol acted in a voltage-independent manner and reduced the mean open time of single channels without affecting their conductance, arguing against a simple channel-blocking effect. Further, menthol slowed or prevented the recovery of nAChRs from desensitization, indicating that it probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [(3)H]epibatidine. Taken together, these data indicate that menthol promotes desensitization of α3β4 nAChRs by an allosteric action.


Characterization and thermal dehydration kinetics of highly crystalline mcallisterite, synthesized at low temperatures.
The hydrothermal synthesis of a mcallisterite (Mg2(B6O7(OH)6)2 · 9(H2O)) mineral at low temperatures was characterized. For this purpose, several reaction temperatures (0-70°C) and reaction times (30-240 min) were studied. Synthesized minerals were subjected to X-ray diffraction (XRD), fourier transform infrared (FT-IR), and Raman spectroscopies and scanning electron microscopy (SEM). Additionally, experimental analyses of boron trioxide (B2O3) content and reaction yields were performed. Furthermore, thermal gravimetry and differential thermal analysis (TG/DTA) were used for the determination of thermal dehydration kinetics. According to the XRD results, mcallisterite, which has a powder diffraction file (pdf) number of "01-070-1902," was formed under certain reaction parameters. Pure crystalline mcallisterite had diagnostic FT-IR and Raman vibration peaks and according to the SEM analysis, for the minerals which were synthesized at 60°C and 30 min of reaction time, particle size was between 398.30 and 700.06 nm. Its B2O3 content and reaction yield were 50.80 ± 1.12% and 85.80 ± 0.61%, respectively. Finally, average activation energies (conversion values (α) that were selected between 0.1 and 0.6) were calculated as 100.40 kJ/mol and 98.31 kJ/mol according to Ozawa and Kissinger-Akahira-Sunose (KAS) methods, respectively.


MRI Study of the Posterior Visual Pathways in Primary Open Angle Glaucoma.
The purpose of the study was to evaluate neurodegeneration along brain visual pathways in primary open angle glaucoma (POAG) using improved analysis methods of volumetric and diffusion tensor magnetic resonance imaging (MRI) data. Eleven POAG patients (60.0±9.2 y) with primarily mild to moderate POAG and 11 age-matched controls (55.9±7.5 y) were studied using structural and diffusion tensor MRI. Surface-based segmentation was applied to structural MRI to obtain visual cortical area and volume. Fiber tracking was applied to diffusion tensor data to obtain diffusion parameters along the optic tract and optic radiation. MRI parameters in glaucoma patients were compared with the corresponding left and right visual fields and retinal nerve fiber layer thicknesses, instead of with the left and right eye. Area and volume of the primary visual cortex were significantly reduced in POAG patients compared with controls (P<0.05) but did not correlate with visual field loss. Fractional anisotropy was reduced at multiple locations along the optic tracts and optic radiations in POAG patients compared with controls. Axial and radial diffusivity along the fiber tracts showed trends but were not significantly different between POAG patients and controls when averaged over the whole structures. Only fractional anisotropy (P<0.05) of the optic radiations was significantly correlated with visual field loss. No MRI parameters were correlated with retinal nerve fiber layer thickness. Improved analysis techniques of MRI data improves delineation of degeneration in the brain visual pathways and further supports the notion that neurodegeneration is involved with glaucoma pathogenesis.


Monitoring and Analysis of Respiratory Patterns Using Microwave Doppler Radar.
Noncontact detection characteristic of Doppler radar provides an unobtrusive means of respiration detection and monitoring. This avoids additional preparations, such as physical sensor attachment or special clothing, which can be useful for certain healthcare applications. Furthermore, robustness of Doppler radar against environmental factors, such as light, ambient temperature, interference from other signals occupying the same bandwidth, fading effects, reduce environmental constraints and strengthens the possibility of employing Doppler radar in long-term respiration detection, and monitoring applications such as sleep studies. This paper presents an evaluation in the of use of microwave Doppler radar for capturing different dynamics of breathing patterns in addition to the respiration rate. Although finding the respiration rate is essential, identifying abnormal breathing patterns in real-time could be used to gain further insights into respiratory disorders and refine diagnostic procedures. Several known breathing disorders were professionally role played and captured in a real-time laboratory environment using a noncontact Doppler radar to evaluate the feasibility of this noncontact form of measurement in capturing breathing patterns under different conditions associated with certain breathing disorders. In addition to that, inhalation and exhalation flow patterns under different breathing scenarios were investigated to further support the feasibility of Doppler radar to accurately estimate the tidal volume. The results obtained for both experiments were compared with the gold standard measurement schemes, such as respiration belt and spirometry readings, yielding significant correlations with the Doppler radar-based information. In summary, Doppler radar is highlighted as an alternative approach not only for determining respiration rates, but also for identifying breathing patterns and tidal volumes as a preferred nonwearable alternative to the conventional contact sensing methods.


The pathogenic equine streptococci.
Streptococci pathogenic for the horse include S. equi (S. equi subsp. equi), S. zooepidemicus (S. equi subsp. zooepidemicus), S. dysgalactiae subsp. equisimilis and S. pneumoniae capsule Type III. S. equi is a clonal descendent or biovar of an ancestral S. zooepidemicus strain with which it shares greater than 98% DNA homology and therefore expresses many of the same proteins and virulence factors. Rapid progress has been made in identification of virulence factors and proteins uniquely expressed by S. equi. Most of these are expressed either on the bacterial surface or are secreted. Notable examples include the antiphagocytic SeM and the secreted pyrogenic superantigens SePE-I and H. The genomic DNA sequence of S. equi will greatly accelerate identification and characterization of additional virulence factors and vaccine targets. Although it is the most frequently isolated opportunist pyogen of the horse, S. zooepidemicus has been the subject of few contemporary research studies. Variation in the protectively immunogenic SzP proteins has, however, been well characterized. Given its opportunist behavior, studies are urgently needed on regulation of virulence factors such as capsule and proteases. Likewise, information is also very limited on virulence factors and associated gene regulation of S. dysgalactiae subspecies equisimilis. It has recently been shown that equine isolates of Streptococcus pneumoniae are clonal, a feature shared with S. equi. All equine isolates express capsule Type III, are genetically similar, and have deletions in the genes for autolysin and pneumolysin. In summary, the evolving picture of the interaction of the equine pathogenic streptococci and their host is that of multiple virulence factors active at different stages of pathogenesis. The inherent complexity of this interaction suggests that discovery of effective combinations of immunogens from potential targets identified in genomic sequence will be laborious.


Repeated Nicotine Strengthens Gamma Oscillations in the Prefrontal Cortex and Improves Visual Attention.
Nicotine has strong addictive as well as procognitive properties. While a large body of research on nicotine continues to inform us about mechanisms related to its reinforcing effects, less is known about clinically relevant mechanisms that subserve its cognitive-enhancing properties. Understanding the latter is critical for developing optimal strategies for treating cognitive deficits. The primary brain region implicated in cognitive functions improved by nicotine is the prefrontal cortex (PFC). Here we assessed the impact of nicotine on unit activity and local field potential oscillations in the PFC of behaving rats. An acute dose of nicotine produced a predominantly inhibitory influence on population activity, a small increase in gamma oscillations, and a decrease in theta and beta oscillations. After a daily dosing regimen, a shift to excitatory-inhibitory balance in single-unit activity and stronger gamma oscillations began to emerge. This pattern of plasticity was specific to the gamma band as lower frequency oscillations were suppressed consistently across daily nicotine treatments. Gamma oscillations are associated with enhanced attentional capacity. Consistent with this mechanism, the repeat dosing regimen in a separate cohort of subjects led to improved performance in an attention task. These data suggest that procognitive effects of nicotine may involve development of enhanced gamma oscillatory activity and a shift to excitatory-inhibitory balance in PFC neural activity. In the context of the clinical use of nicotine and related agonists for treating cognitive deficits, these data suggest that daily dosing may be critical to allow for development of robust gamma oscillations.


Myopia and glaucoma: diagnostic and therapeutic challenges.
There is strong epidemiologic evidence linking myopia with glaucomatous disease, but a myopic optic nerve can pose significant challenges with regard to making the correct diagnosis of glaucoma. This review provides an overview of these diagnostic and therapeutic challenges with a particular focus on how the growing prevalence of myopia among specific populations may impact such therapy. For a given individual, the link between myopia and glaucoma remains murky in many circumstances, largely because of the fact that it is difficult to separate out myopia-related structural and functional abnormalities from 'true' glaucomatous changes. Using optical coherence tomography (OCT) imaging, myopia has been found to be associated with temporal displacement and thinning of the superior and inferior nerve fiber layer bundles. In particular, sequential generations of 'Asian' ethnicities have been noted to demonstrate increasing rates of high myopia at earlier ages, sometimes with associated visual field defects at normal intraocular pressures. As is the case with any progressive condition, it is often not possible to distinguish glaucomatous from nonglaucomatous disease based on a single examination, and thus follow-up with OCT or perimetry from an established baseline is useful. Although myopia is a known risk factor for glaucoma, it may also result in structural and functional defects that cannot be distinguished from those caused by glaucoma based solely on cross-sectional information. Longitudinal observation may be necessary to distinguish among the multiple effects of myopia on the optic nerve and the natural history of glaucoma, which may vary substantially amongst those who are affected.


The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.
The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation.


Patterns of exposure to sexually explicit material among sex offenders, child molesters, and controls.
The Meese Commission Report claimed exposure to sexually explicit material leads to sex offenses and recommended examining developmental patterns and pornography experiences of offenders. This second phase of our study examines developmental patterns and sexually explicit material experiences of sex offenders, a subgroup of child molesters, and controls. Results indicate sex offenders (but not the child molester subgroup) began masturbating at a significantly younger age than controls. Sexually explicit material was used during the first masturbatory experience of 33.3% of sex offenders and 14% of controls. Child molesters were significantly older than controls when exposed to sexually explicit material. Frequency of adult use of sexually explicit material does not differ significantly among groups.


Framingham cardiovascular disease risk scores and incident frailty: the English longitudinal study of ageing.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.


Management of dyslipidaemia - evidence and practical recommendations.
Dyslipidaemia is a common condition managed in general practice. This article reviews the evidence and gives practical advice for the management of dyslipidaemia in general practice. It is essential to identify people at risk of cardiovascular disease (CVD) and to instigate appropriate treatment strategies. An assessment of absolute risk is the most appropriate method of identifying those at a higher risk of CVD where CVD is not overt. People with an absolute risk of >15% of a cardiovascular event in the next 5 years should be actively treated. Drug therapy should also be considered in those estimated to be at 10-15% risk of a cardiovascular event in the next 5 years if they have additional risk factors. It is important to select an appropriate lipid lowering therapy (or combination of drugs) in order to reach lipid targets, which need to consider not just LDL-c but also HDL-c and triglycerides. Lifestyle management should underpin all lipid management strategies.


Coordination in networks for improved mental health service.
Well-organised clinical cooperation between health and social services has been difficult to achieve in Sweden as in other countries. This paper presents an empirical study of a mental health coordination network in one area in Stockholm. The aim was to describe the development and nature of coordination within a mental health and social care consortium and to assess the impact on care processes and client outcomes. Data was gathered through interviews with 'joint coordinators' (n=6) from three rehabilitation units. The interviews focused on coordination activities aimed at supporting the clients' needs and investigated how the joint coordinators acted according to the consortium's holistic approach. Data on The Camberwell Assessment of Need (CAN-S) showing clients' satisfaction was used to assess on set of outcomes (n=1262). The findings revealed different coordination activities and factors both helping and hindering the network coordination activities. One helpful factor was the history of local and personal informal cooperation and shared responsibilities evident. Unclear roles and routines hindered cooperation. This contribution is an empirical example and a model for organisations establishing structures for network coordination. One lesson for current policy about integrated health care is to adapt and implement joint coordinators where full structural integration is not possible. Another lesson, based on the idea of patient quality by coordinated care, is specifically to adapt the work of the local addiction treatment and preventive team (ATPT)-an independent special team in the psychiatric outpatient care that provides consultation and support to the units and serves psychotic clients with addictive problems.


Left superior pulmonary venous thrombosis complicated with splenic infarction after video-assisted thoracoscopic left upper lobectomy.
A 72-year-old man underwent video-assisted thoracoscopic left upper lobectomy for small cell lung cancer. After 16 days, he experienced epigastric abdominal pain and vomiting, and was taken by ambulance to our hospital. Contrast-enhanced computed tomography (CT) showed a propagation of thrombus in the stump of the left superior pulmonary vein (LSPV) complicated with splenic infarction. The patient received anticoagulation therapy with heparin and warfarin, and further progression of the thrombus or any systemic embolic event was not observed during hospitalization. Here, we report a patient presenting with LSPV thrombosis complicated with splenic infarction after video-assisted thoracoscopic surgery (VATS), and describe several months follow-up CT imaging results after administration of an oral anticoagulation therapy. <Learning objective: Pulmonary venous thrombosis after lung surgery is a rare, but critical, condition. Only few cases have been previously reported and all cases described LSPV thrombus. We also demonstrated LSPV thrombus after VATS lobectomy, and clearly showed follow-up results after anticoagulation therapy. Our case indicates the need for periodic CT imaging follow-up after left upper lobectomy and may call attention to thoracic surgeons, internal medicine, and cardiology physicians regarding this complication.>.


A general model to optimise CuII labelling efficiency of double-histidine motifs for pulse dipolar EPR applications.
Electron paramagnetic resonance (EPR) distance measurements are making increasingly important contributions to studies of biomolecules underpinning health and disease by providing highly accurate and precise geometric constraints. Combining double-histidine (dH) motifs with CuII spin labels shows promise for further increasing the precision of distance measurements, and for investigating subtle conformational changes. However, non-covalent coordination-based spin labelling is vulnerable to low binding affinity. Dissociation constants of dH motifs for CuII-nitrilotriacetic acid were previously investigated via relaxation induced dipolar modulation enhancement (RIDME), and demonstrated the feasibility of exploiting the dH motif for EPR applications at sub-μM protein concentrations. Herein, the feasibility of using modulation depth quantitation in CuII-CuII RIDME to simultaneously estimate a pair of non-identical independent KD values in such a tetra-histidine model protein is addressed. Furthermore, we develop a general speciation model to optimise CuII labelling efficiency, depending upon pairs of identical or disparate KD values and total CuII label concentration. We find the dissociation constant estimates are in excellent agreement with previously determined values, and empirical modulation depths support the proposed model.


Emerging nitrogenous disinfection byproducts: Transformation of the antidiabetic drug metformin during chlorine disinfection of water.
As an environmental contaminant of anthropogenic origin metformin is present in the high ng/L- up to the low μg/L-range in most surface waters. Residues of metformin may lead to the formation of disinfection by-products during chlorine disinfection, when these waters are used for drinking water production. Investigations on the underlying chemical processes occurring during treatment of metformin with sodium hypochlorite in aqueous medium led to the discovery of two hitherto unknown transformation products. Both substances were isolated and characterized by HPLC-DAD, GC-MS, HPLC-ESI-TOF, (1)H-NMR and single-crystal X-ray structure determination. The immediate major chlorination product is a cyclic dehydro-1,2,4-triazole-derivate of intense yellow color (Y; C4H6ClN5). It is a solid chlorimine of limited stability. Rapid formation was observed between 10 °C and 30 °C, as well as between pH 3 and pH 11, in both ultrapure and tap water, even at trace quantities of reactants (ng/L-range for metformin, mg/L-range for free chlorine). While Y is degraded within a few hours to days in the presence of light, elevated temperature, organic solvents and matrix constituents within tap water, a secondary degradation product was discovered, which is stable and colorless (C; C4H6ClN3). This chloroorganic nitrile has a low photolysis rate in ambient day light, while being resistant to heat and not readily degraded in the presence of organic solvents or in the tap water matrix. In addition, the formation of ammonia, dimethylamine and N,N-dimethylguanidine was verified by cation exchange chromatography.


Traffic noise and cardiovascular risk: the Caerphilly and Speedwell studies, third phase--10-year follow up.
The authors tested the hypothesis that prolonged exposure to road traffic noise causes ischemic heart disease in a 10-y follow-up cohort study of middle-aged men. In the Caerphilly and Speedwell studies, 2512 and 2348 men, respectively, who were 45-59 y of age were seen in the initial cross-sectional phase and at follow-up intervals of 10 y. Adjusted odds ratios of 1.1 (95% confidence interval = 0.6, 1.9) and 0.9 (95% confidence interval = 0.6, 1.4) were found in the total cohorts. However, the relative risk was 1.3 (95% confidence interval = 0.8, 2.2) in the pooled reconstructed cohort of men who were followed for 6 y (i.e., from phase 2 to phase 3) and for whom room orientation and window-opening habits could be considered. Furthermore, the relative risk increased to 1.6 (95% confidence interval = 0.9, 3.0) in the subsample of men who had lived at least 15 y in their present homes at the time of recruitment. Living adjacent to streets with high traffic noise levels was associated with an adjusted (for covariates) increase in relative risk of 1.01-1.02/y in residence--a result that was only borderline significant (p < .10).