A placebo-controlled randomized study with testosterone in Klinefelter syndrome: beneficial effects on body composition.
Males with Klinefelter syndrome (KS) are typically hypogonadal with a high incidence of metabolic disease, increased body fat and mortality. Testosterone treatment of hypogonadal patients decrease fat mass, increase lean body mass and improve insulin sensitivity, but whether this extends to patients with KS is presently unknown. In a randomized, double-blind, placebo-controlled, BMI-matched cross-over study, 13 males with KS (age: 34.8 years; BMI: 26.7 kg/m2) received testosterone (Andriol®) 160 mg per day (testosterone) or placebo treatment for 6 months. Thirteen age- and BMI-matched healthy controls were recruited. DEXA scan, abdominal computed tomography (CT) scan and a hyperinsulinemic-euglycemic clamp, muscle strength and maximal oxygen uptake measurement were performed. Total lean body mass and body fat mass were comparable between testosterone-naïve KS and controls using DEXA, whereas visceral fat mass, total abdominal and intra-abdominal fat by CT was increased (P < 0.05). Testosterone decreased total body fat (P = 0.01) and abdominal fat by CT (P = 0.04). Glucose disposal was similar between testosterone-naïve KS and controls (P = 0.3) and unchanged during testosterone (P = 0.8). Free fatty acid suppression during the clamp was impaired in KS and maximal oxygen uptake was markedly lower in KS, but both were unaffected by treatment. Testosterone increased hemoglobin and IGF-I. Testosterone treatment in adult males with KS for 6 months leads to favorable changes in body composition with reductions in fat mass, including abdominal fat mass, but does not change measures of glucose homeostasis.


Femtosecond thin disk laser oscillator with pulse energy beyond the 10-microjoule level.
We report on a passively mode-locked Yb:YAG thin disk laser oscillator that generates 11.3-microJ pulses without the use of any additional external amplification. A repetition rate of 4 MHz is obtained using a 23.4-m-long multiple-pass cavity that extends the resonator length to a total of 37 m. The nearly transform-limited pulses at 45 W of average output power have a duration of 791 fs with a 1.56-nm-broad spectrum centered at 1030 nm. The laser is operated in a helium atmosphere to eliminate the air nonlinearity inside the resonator that previously limited the pulse energy.


High tibial osteotomy with modern PEEK implants is safe and leads to lower hardware removal rates when compared to conventional metal fixation: a multi-center comparison study.
Various implant materials have been used in medial, opening-wedge high tibial osteotomy (HTO) including traditional metal and modern polyetheretherketone (PEEK) implants. The purpose of this study was to compare metal and PEEK implants and determine safety, varus deformity correction, as well as short- to mid-term hardware removal and arthroplasty rates. HTO performed with metal and PEEK implants were reviewed between 2000 and 2015 at two institutions with a minimum of 2 years follow-up. Postoperative complications, radiographic measures, and osteotomy union were compared between groups using Kruskal-Wallis and Fisher's exact testing. Survival free of hardware removal and arthroplasty was compared between groups using Kaplan-Meier testing. Risk factors for HTO conversion to arthroplasty were examined using Cox proportional hazards regression. Ninety-five HTOs were performed in 90 patients (59 M, 31 F) using 50 metal and 45 PEEK implants. Mean follow-up was 4.2 years (range 2.0-16.5). Two metal and two PEEK HTO patients experienced nonunions, resulting in revision HTO at a mean of 1.0 years postoperatively (range 0.4-1.4 years). Both implant groups demonstrated similar, significant improvements in coronal deformity, with mean angulation improving from 6.0° and 5.4° varus preoperatively to 1.1° and 1.0° valgus postoperatively for the metal (p < 0.01) and PEEK groups (p < 0.01), respectively. 2- and 5-year hardware removal-free survival was 94% and 94% for PEEK, which was significantly superior to 80% and 73% observed for metal (p = 0.02). 2- and 5-year arthroplasty-free survival was similar for the metal (98% and 94%) and PEEK groups (100% and 78%) (n.s.). HTO performed for focal cartilage defects was observed to demonstrate decreased arthroplasty risk (HR 0.36, p = 0.03) when compared to HTO performed for osteoarthritis. Both metal and PEEK implants were found to be effective in obtaining and maintaining coronal varus deformity correction, with 88% overall arthroplasty-free survival at 5 years. Metal fixation demonstrated a higher rate of hardware removal while HTO performed for medial compartment osteoarthritis predicted conversation to arthroplasty. III.


Seeking social connectedness: interdependent self-construal and impression formation using photographic cues of social connectedness.
Impression formation research has traditionally focused on either the characteristics of the target or of the participant, failing to examine their interplay. In the present study, we explored the role of interdependent self-construal on ratings of others who are portrayed as alone or connected. We hypothesized that participants with an interdependent view of the self would prefer others who are portrayed as socially connected, while the opposite would be true for participants low on interdependence. Results showed that college students high on interdependence rated a university professor photographed with another person relatively more positively than a professor photographed alone. This pattern was reversed for participants low on interdependence.


A case report: X-linked dystrophin gene mutation causing severe isolated dilated cardiomyopathy.
X-linked dilated cardiomyopathy (XLDCM) is a rare but rapidly progressive cardiomyopathy caused by dystrophin gene mutation. Mutations are more often associated with Duchenne and Becker Muscular Dystrophy, which are characterized by skeletal muscle weakness or limb girdle dystrophy. However, patients with isolated XLDCM have normal skeletal muscle but complete dystrophin loss in cardiac muscle resulting in isolated myocardial involvement without overt signs of skeletal myopathy. A previously well 16-year-old boy developed sudden onset dense left-sided weakness and facial droop. Computed tomography (CT) angiography and CT brain showed an occluded right internal carotid artery extending to the right middle cerebral artery. He underwent successful endovascular clot retrieval but developed frank pulmonary oedema and cardiogenic shock requiring inotropic support and intubation. Transthoracic echocardiography demonstrated severe left ventricular (LV) cardiomyopathy and an apical thrombus. Subsequent cardiac magnetic resonance (CMR) imaging confirmed the LV parameters and diffuse late gadolinium enhancement. Despite absence of skeletal manifestations, subsequent genetic testing revealed an X-linked dystrophin gene mutation [c.31+G>T (IVS1G>T)]. He was commenced on empirical heart failure therapy and underwent successful cardiac transplantation. X-linked dilated cardiomyopathy is a rare, rapidly progressing cardiomyopathy. Patients show normal skeletal muscle dystrophin but absent expression in cardiac muscle, resulting fibrosis, and atrophy. About 20% of affected young males have significantly reduced survival and thus the diagnosis must be considered in cases of idiopathic cardiomyopathy with CMR and genetic testing key to the diagnosis. Whilst evidence exists for empirical heart failure medications, cardiac transplantation remains the definitive treatment.


Large-scale implementation of electronic Integrated Management of Childhood Illness (eIMCI) at the primary care level in Burkina Faso: a qualitative study on health worker perception of its medical content, usability and impact on antibiotic prescription and resistance.
Electronic clinical decision algorithms (eCDAs) that guide clinicians during patient management are being deployed in resource-limited settings to improve the quality of care and rational use of medicines (especially antimicrobials). Little is known on how local clinicians perceive the use and impact of these tools in their daily practice. This study investigates clinician insights on an eIMCI tool. Specifically, we report their views on its medical content, assess their knowledge on microbes, antimicrobials and the development of resistance. This qualitative study was conducted in the frame of a large-scale implementation in Burkina Faso of an eIMCI tool developed by the Swiss NGO Terre des hommes. Twelve in-depth interviews and 2 focus-group discussions were conducted including 21 health workers from 10 primary care facilities. Emerging themes were identified using qualitative data analysis software. eIMCI users expressed a high level of satisfaction, slowness of the tablet was perceived as the major inconvenience limiting uptake. Several frequent illnesses were identified as missing in the algorithm along with guidance for fever without focus. When asked about existing types of microbes, 9 and 4 out of 21 participants could mention bacteria and virus respectively; only 5 correctly answered that antibiotics had no action on viral disease and 6 mentioned the risk of antibiotic resistance. Level of knowledge was higher in nurses than in less trained health workers. The tool was perceived as improving patient management and the rational use of antibiotics. Positive changes in health facility organisation were reported, such as task shifting and improved triage. eIMCI was also perceived as a learning tool, and users expressed a strong desire to expand the geographic and temporal scope of the intervention. The use of eICMI was widely accepted and perceived as a powerful tool guiding daily practice. Findings suggest that it has positive effects on the health care system beyond the quality of consultation. To support large uptake and sustainability, better training of health workers in infectiology is essential and the medical content of eIMCI should be optimized to include frequent diseases and, for each of them, the appropriate management plan.


[Guidelines and costs].
There is a growing interest in developing clinical guidelines which support the efficiency of medical care by weighting the potential benefits against the costs of interventions. In the recently developed Dutch guideline on reduction of serum cholesterol concentration a formal cost-effectiveness analysis is included. Based on epidemiological arguments a cost-effectiveness ratio of 40,000 Dutch guilders per life year gained was found. In comparison with other preventive health care programmes this amount was considered acceptable. In the past physicians have often taken costs into account in an implicit way when making clinical decisions. The results of the cost-effectiveness analysis vary particularly with the costs of the used statins. In the past physicians have often taken costs into account in an implicit way when making clinical decisions. However, in view of the increase in health care expenditures, it has become the responsibility of physicians to take costs into account more explicitly. Clinical guidelines with a cost-effectiveness analysis can be useful in helping physicians to provide efficient medical care.


Single-step writing of Bragg grating waveguides in fused silica with an externally modulated femtosecond fiber laser.
For the first time to our knowledge, high-strength (>30 dB) first-order Bragg grating waveguides were fabricated in bulk fused silica glass in a single-scanning step by modulating a high-repetition-rate femtosecond fiber laser with an external acousto-optic modulator. The modulation induced a waveguide segmentation by delivering controlled bursts of laser pulses to define an array of partially overlapped refractive index voxels. With appropriate choice of modulation frequency and sample scanning speed, low loss waveguides could be formed at high writing speeds to yield sharp Bragg spectral resonances tunable over the 1300 to 1550 nm telecom band. Effects of acousto-optic modulation duty cycle on propagation loss and grating strength are characterized. This modulation method offers facile control and integration of multiwavelength Bragg grating devices to enhance overall functionality of optical circuits in three-dimensional geometries.


American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients?
The recently published American Association of Orthopedic Surgeons (AAOS) guidelines for the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee surgery conflict with long-established and widely used American College of Chest Physicians (ACCP) guidelines. Both guidelines accepted that the most important goal of thromboprophylaxis in patients undergoing hip or knee replacement is to prevent pulmonary embolism (PE). The ACCP guidelines included asymptomatic (and symptomatic) deep vein thrombosis (DVT) detected by venography as a measure of the efficacy of thromboprophylaxis, whereas the AAOS rejected DVT as a valid outcome because the panelists considered the link between DVT and PE to be unproven. The AAOS position is inconsistent with evidence from imaging studies linking DVT with PE and from clinical studies demonstrating a parallel reduction of DVT and PE when antithrombotic agents are compared with placebo or untreated controls. The AAOS panel ignored the randomized data demonstrating that thromboprophylaxis reduces both DVT and PE, and many of their recommendations are based on expert opinion and lack a scientific basis. We recommend the ACCP guidelines because the methodology is explicit and rigorous and the treatment recommendations reflect all of the evidence from the randomized trials. Adoption of the ACCP guideline will ensure that patients undergoing hip and knee arthroplasty receive the best available therapies for prevention of VTE and reduce disability and death due to this common and potentially preventable condition.


Cancer incidence in relatives of British Fanconi Anaemia patients.
Fanconi anemia (FA) is an autosomal recessive DNA repair disorder with affected individuals having a high risk of developing acute myeloid leukaemia and certain solid tumours. Thirteen complementation groups have been identified and the genes for all of these are known (FANCA, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M and N/PALB2). Previous studies of cancer incidence in relatives of Fanconi anemia cases have produced conflicting results. A study of British FA families was therefore carried out to investigate this question, since increases in cancer risk in FA heterozygotes would have implications for counselling FA family members, and possibly also for the implementation of preventative screening measures in FA heterozygotes. Thirty-six families took part and data was collected on 575 individuals (276 males, 299 females), representing 18,136 person years. In this cohort, 25 males and 30 females were reported with cancer under the age of 85 years, and 36 cancers (65%) could be confirmed from death certificates, cancer registries or clinical records. A total of 55 cancers were reported in the FA families compared to an estimated incidence of 56.95 in a comparable general population cohort, and the relative risk of cancer was 0.97 (95% C.I. = 0.71-1.23, p = 0.62) for FA family members. Analysis of relative risk for individual cancer types in each carrier probability group did not reveal any significant differences with the possible exception of prostate cancer (RR = 3.089 (95% C.I. = 1.09 - 8.78; Chi2 = 4.767, p = 0.029). This study has not shown a significant difference in overall cancer risk in FA families.


[Barrett's esophagus: endoscopic treatment of high-grade dysplasia and early cancer].
In a Barrett's oesophagus without dysplasia, endoscopic control every 3-5 years is sufficient. If low-grade dysplasia is encountered in the surveillance biopsies, then endoscopy should be repeated within 3-6 months and yearly thereafter if the low-grade dysplasia persists. Antacid medication must be prescribed in cases with extensive inflammation. The endoscopic treatment of patients with high-grade dysplasia and/or early cancer of the mucosa in a Barrett's oesophagus (tissue ablation and/or mucosa resection) seems a promising alternative to surgery in view of the combination of effectiveness, limited invasiveness compared to surgical resection, and the preservation of a functional oesophagus. Data from long-term follow-up are still limited. Strict endoscopic surveillance will probably detect metachronic abnormalities in an early and still curable stage, creating a new opportunity for endoscopic treatment.


Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial.
Empirical fluoroquinolone therapy is widely used in treating complicated urinary tract infections (cUTIs), even in areas of high fluoroquinolone resistance. While it is believed that high antibiotic concentrations in urine might be sufficient to overcome and effectively treat infections caused by resistant bacteria, clinical trial data validating this assumption are limited. This post hoc analysis evaluated the efficacy of ceftolozane/tazobactam versus levofloxacin in the subgroup of patients with cUTIs caused by levofloxacin-resistant pathogens in a randomized, controlled trial (NCT01345929/NCT01345955). Hospitalized adults with cUTI/pyelonephritis were randomized to 7 days of 1.5 g of ceftolozane/tazobactam every 8 h or 750 mg of levofloxacin once daily, before availability of culture and susceptibility data. A composite of microbiological eradication and clinical cure 5 to 9 days post-therapy was assessed in the microbiological modified ITT (mMITT; n = 800) and microbiologically evaluable (ME; n = 694) populations. In the mMITT population, there were 212 patients (26.5%) with at least one baseline uropathogen that was resistant to levofloxacin. The majority of uropathogens in this subgroup were Enterobacteriaceae (n = 186) that were susceptible to ceftolozane/tazobactam [MIC ≤2 mg/L, 88.7% (165/186)]. Among patients with levofloxacin-resistant pathogens, ceftolozane/tazobactam demonstrated significantly higher composite cure rates than levofloxacin in both the mMITT [60.0% (60/100) versus 39.3% (44/112); 95% CI for the treatment difference, 7.2%-33.2%] and ME [64.0% (57/89) versus 43.4% (43/99); 95% CI for the treatment difference, 6.3%-33.7%] populations, respectively. High urinary levels of levofloxacin did not reliably cure cUTIs. Seven day treatment with ceftolozane/tazobactam was more effective than high-dose levofloxacin treatment in patients with cUTI caused by levofloxacin-resistant bacteria, and it may be an alternative treatment in settings of increased fluoroquinolone resistance.


The catalytic mechanism of angiotensin converting enzyme.
A detailed investigation of the catalytic mechanism of angiotensin converting enzyme was undertaken in order to establish a molecular basis for its mode of action. These studies include the characterization of the kinetic properties of the enzyme. In particular, a mechanism for the anion activation, a characteristic feature of angiotensin converting enzyme, has been established. The active site of the enzyme contains a catalytically essential zinc atom which appears to be directly involved in the hydrolytic step of catalysis. Further components of the active site are the carboxyl group of an aspartyl or glutamyl residue, tyrosyl, arginyl and lysyl residues. The latter one is involved in mediating the anion activation. These results have enabled us to compare the active site of angiotensin converting enzyme with those of two other zinc peptidases and, thereby, deduce a mechanism for its mode of action. These investigations have confirmed a hypothetical model of the active site of angiotensin converting enzyme which has served to construct potent inhibitors of the enzyme now being used as antihypertensive agents.


Reverse shoulder arthroplasty leads to significant biomechanical changes in the remaining rotator cuff.
After reverse shoulder arthroplasty (RSA) external and internal rotation will often remain restricted. A postoperative alteration of the biomechanics in the remaining cuff is discussed as a contributing factor to these functional deficits. In this study, muscle moment arms as well as origin-to-insertion distance (OID) were calculated using three-dimensional models of the shoulder derived from CT scans of seven cadaveric specimens. Moment arms for humeral rotation are significantly smaller for the cranial segments of SSC and all segments of TMIN in abduction angles of 30 degrees and above (p ≤ 0.05). Abduction moment arms were significantly decreased for all segments (p ≤ 0.002). OID was significantly smaller for all muscles at the 15 degree position (p ≤ 0.005), apart from the cranial SSC segment. Reduced rotational moment arms in conjunction with the decrease of OID may be a possible explanation for the clinically observed impaired external and internal rotation.


Integrative survival response evoked by heme oxygenase-1 and heme metabolites.
Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation to produce carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. The inducible HO isoform, HO-1, is involved in the protection of multiple tissues and organs. The mechanism of protective actions of HO-1 has not been completely elucidated, but recent evidence suggests that one or more of heme metabolites can mediate the protective effects of HO-1. Particularly, CO mimics the antioxidant, anti-inflammatory, anti-apoptotic and antiproliferative actions of HO-1. Many of these effects of CO depend on the production of cyclic guanosine monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) pathways. The transcription factors, including nuclear factor E2-related factor-2 (Nrf2), and their upstream kinases, including MAPK pathway, play an important regulatory role in HO-1 expression by dietary antioxidants and drugs. This review attempts to concisely summarize the molecular and biochemical characteristics of HO-1, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by dietary antioxidants and drugs. In addition, the cytoprotective roles of HO-1 shall be discussed from the perspective of each of the metabolic by-products.


Influence of Essential Ginger Oil on Human Psychophysiology after Inhalation and Dermal Application.
The influence of essential ginger oil (Zingiberis aetheroleum from Zingiber officinale Roscoe) on blood pressure, heart rate and subjective well-being was investigated after inhalation and dermal application on healthy human subjects in two experiments. Additionally a GC-MS analysis of the tested oil is given. The essential oil exhibited a high amount of citral (19.4%). α-Zingiberene (17.4%), camphene (7.8%), trans, trans-a-farnesene (6.8%) and β-bisabolene (5.8%) were also prominent constituents. Compared with the control condition an activating effect was observed for ginger oil in the inhalation experiment.


Risk factors for childhood major and minor head and other injuries in a nationally representative sample.
To assess the relationship between demographic, socioeconomic, family type and behavioural factors and childhood major and minor head and other injuries. A cross-sectional study, on a large nationally representative sample of 5913 children aged 4-15 years (Health Survey for England, 1997). Frequency of major and minor head and other injuries. There were no significant associations between any of the socioeconomic factors and family type and major and minor injuries, except for major head injuries in children who lived in families receiving more than one social or financial benefit. Boys were 1.5 times more likely to suffer major head and other injuries than girls. Older children were significantly more likely to experience major and minor other injuries, but less likely to have major and minor head injuries, compared to younger children. High scores for conduct disorder and emotional symptoms were significant risk factors for other major injuries, while high scores for hyperactivity and conduct disorder were significantly related to major and minor head injuries. The risk factors assessed were often stronger for major than for minor injuries, and stronger for head than other injuries. Boys and children who exhibit certain behavioural problems such as high levels of hyperactivity were significantly more likely to report major and minor injuries affecting the head region.


Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides.
We found that Ku70, a known DNA repair factor, has a novel function to bind and inhibit Bax (Bcl-2-associated X protein), a key mediator of apoptosis. Pentapeptides derived from the Bax-binding domain of Ku70 were cell-permeable and protected cells from Bax-mediated apoptosis. These pentapeptides were called BIPs (Bax-inhibiting peptides). BIPs may become a useful therapeutic tool to reduce cellular damage. We also generated BIP mutant pentapeptides that do not inhibit Bax, but retain their cell-penetrating activity. Since both BIPs and BIP mutants are cell-permeable, these peptides were designated CPP5s (cell-penetrating pentapeptides). Among the CPP5s discovered, VPTLK (BIP) and KLPVM (BIP mutant) were confirmed to possess protein transduction activity by examination of the delivery of GFP (green fluorescent protein) into cells by these peptides. The mechanism of cell penetration by CPP5s is not known. CPP5s enter the cell at 0 and 4 degrees C. In preliminary studies, various inhibitors of endocytosis and pinocytosis did not show any significant suppression of CPP5 cell entry. CPP5s have very low toxicity in vitro and in vivo and so may be useful tools in order to develop non-toxic drug-delivery technologies.


PARIHS revisited: from heuristic to integrated framework for the successful implementation of knowledge into practice.
The Promoting Action on Research Implementation in Health Services, or PARIHS framework, was first published in 1998. Since this time, work has been ongoing to further develop, refine and test it. Widely used as an organising or conceptual framework to help both explain and predict why the implementation of evidence into practice is or is not successful, PARIHS was one of the first frameworks to make explicit the multi-dimensional and complex nature of implementation as well as highlighting the central importance of context. Several critiques of the framework have also pointed out its limitations and suggested areas for improvement. Building on the published critiques and a number of empirical studies, this paper introduces a revised version of the framework, called the integrated or i-PARIHS framework. The theoretical antecedents of the framework are described as well as outlining the revised and new elements, notably, the revision of how evidence is described; how the individual and teams are incorporated; and how context is further delineated. We describe how the framework can be operationalised and draw on case study data to demonstrate the preliminary testing of the face and content validity of the revised framework. This paper is presented for deliberation and discussion within the implementation science community. Responding to a series of critiques and helpful feedback on the utility of the original PARIHS framework, we seek feedback on the proposed improvements to the framework. We believe that the i-PARIHS framework creates a more integrated approach to understand the theoretical complexity from which implementation science draws its propositions and working hypotheses; that the new framework is more coherent and comprehensive and at the same time maintains it intuitive appeal; and that the models of facilitation described enable its more effective operationalisation.


Characterization by cyproheptadine of the dopamine-induced contraction in canine isolated arteries.
Spirally cut strips of isolated canine femoral and carotid arteries were used to characterize the vasoconstrictor effect of dopamine. A serotonin antagonist, cyproheptadine, 10- minus 7, 3 X 10- minus 7 and 10-minus 6 M, inhibited dopamine (pA2 = 7.46 plus or minus 0.11), tryptamine (pA2 = 7.38 plus or minus 0.09) and serotonin-induced contractions (pA2 = 7.59 plus or minus 0.09). Cyproheptadine shifted the threshold concentration of dopamine 2 log units to the right without altering norepinephrine response. In protection experiments, preincubation with serotonin (10-minus 5 M) for 10 minutes protected serotonin and tryptamine receptors from cyproheptadine (3 X 10-minus 7 M) and phenoxybenzamine (10-minus 6 M) blockade. Serotonin cross-protected dopamine receptors also. Reciprocally dopamine (10-minus 4 M) protected its own receptors as well as those for serotonin and tryptamine. Norepinephrine did not afford any protection of dopamine, serotonin or tryptamine receptors but did protect its own receptors from phenoxybenzamine blockade. The attempt to characterize the receptor subserving dopamine-induced contraction failed to confirm a relationship between dopamine and alpha adrenoceptors. Since dopamine, tryptamine and serotonin, unlike norepinephrine, were sensitive to cyproheptadine blockade, dopamine-induced contraction appeared to be mediated by a receptor closely related to serotonin receptors. Therefore, alpha adrenoceptors may not be exclusively involved in the vasoconstriction evoked by dopamine on canine vasculature.


Dissociative depression among women in the community.
This study screened the prevalence and correlates of dissociative disorders among depressive women in the general population. The Dissociative Disorders Interview Schedule and the posttraumatic stress disorder (PTSD) and borderline personality disorder sections of the Structured Clinical Interview for DSM-IV were administered to 628 women in 500 homes. The prevalence of current major depressive episode was 10.0%. Of the women, 26 (40.6%) had the lifetime diagnosis of a DSM-IV, dissociative disorder, yielding a prevalence of 4.1% for dissociative depression. This group was younger (mean age = 30.7 years) than the nondissociative depression women (mean age = 39.6 years). There was no difference between the 2 groups on comorbid somatization disorder, PTSD, or borderline personality disorder. Besides suicide attempts, the dissociative group was characterized by secondary features of dissociative identity disorder; Schneiderian symptoms; borderline personality disorder criteria; and extrasensory perceptions, including possession experiences. They reported suicidality, thoughts of guilt and worthlessness, diminished concentration and indecisiveness, and appetite and weight changes more frequently than the nondissociative group. Early cessation of school education and childhood sexual abuse were frequently reported by the dissociative depression group. With its distinct features, the concept of dissociative depression may facilitate understanding of treatment resistance in, development of better psychotherapy strategies for, and new thinking on the neurobiology and pharmacotherapy of depressive disorders.


Self-Supervised 3D Action Representation Learning With Skeleton Cloud Colorization.
3D Skeleton-based human action recognition has attracted increasing attention in recent years. Most of the existing work focuses on supervised learning which requires a large number of labeled action sequences that are often expensive and time-consuming to annotate. In this paper, we address self-supervised 3D action representation learning for skeleton-based action recognition. We investigate self-supervised representation learning and design a novel skeleton cloud colorization technique that is capable of learning spatial and temporal skeleton representations from unlabeled skeleton sequence data. We represent a skeleton action sequence as a 3D skeleton cloud and colorize each point in the cloud according to its temporal and spatial orders in the original (unannotated) skeleton sequence. Leveraging the colorized skeleton point cloud, we design an auto-encoder framework that can learn spatial-temporal features from the artificial color labels of skeleton joints effectively. Specifically, we design a two-steam pretraining network that leverages fine-grained and coarse-grained colorization to learn multi-scale spatial-temporal features. In addition, we design a Masked Skeleton Cloud Repainting task that can pretrain the designed auto-encoder framework to learn informative representations. We evaluate our skeleton cloud colorization approach with linear classifiers trained under different configurations, including unsupervised, semi-supervised, fully-supervised, and transfer learning settings. Extensive experiments on NTU RGB+D, NTU RGB+D 120, PKU-MMD, NW-UCLA, and UWA3D datasets show that the proposed method outperforms existing unsupervised and semi-supervised 3D action recognition methods by large margins and achieves competitive performance in supervised 3D action recognition as well.


Pre-operative ureteric catherisation for major endoscopic gynaecological surgery.
Several strategies have been implemented to better identify the course of the ureters intra-operatively due of the morbidity associated with ureteric injuries especially during gynaecological surgery. We described our experience with pre-operative ureteric catherisation in women who underwent major endoscopic gynaecological surgery. A case-controlled study of 862 women who underwent major endoscopic gynaecological surgery sourced from two health institutions were conducted. Two groups were compared: those who had pre-operative prophylactic ureteric catherisation (study group) and those who had routine cystoscopy performed immediately post surgery (control group). There were no intra-operative ureteric injuries or associated complications noted in the study group. When compared to the control group, length of hospital stay (2 days vs 5 days; p < 0.05) and overall mean time for cystoscopy (11 min vs 35 min; p < 0.05) was significantly shorter in the study group. There was no long-term morbidity recorded in the study group. Our experiences with prophylactic pre-operative bilateral ureteric catheterisation for major endoscopic gynaecological surgeries were favourable and are associated with low complication rates. Routine or adjunct use before major gynaecological and pelvic surgery combined with meticulous surgical technique can help reduce iatrogenic and unintentional ureteric injuries.


Glucose homeostasis in magnesium-deficient rats.
Glucose homeostasis was studied in rats fed diets containing 750,200, or 100 mg/kg Mg for 6 to 8 weeks, from the age of 4 weeks. Weight gain of the rats receiving 200 and 100 mg/kg diets was decreased. This resulted from both a lower food intake and reduced effectiveness of the ingested food. Fed or fasting plasma glucose levels were similar in the three groups. During an intravenous glucose tolerance test, the rate of glucose disappearance was higher in Mg 100 rats than in controls. By contrast, during an oral glucose tolerance test, the rise in plasma glucose was greater and more sustained in Mg 100 rats. During both tests, the insulin response was markedly lower in Mg-deficient rats than in controls. This could be partially due to the reduced insulin content of the pancreas of these animals. The impairment of tolerance to oral glucose was corrected by 5 weeks on a high-Mg diet. After intravenous injection of insulin, the fall in plasma glucose levels was also slightly more pronounced in Mg 100 rats. During no test did we observe a significant difference between glucose or insulin responses in Mg 200 or Mg 750 rats. These results, thus, show that chronic Mg deficiency alters several parameters of glucose homeostasis in the rat.


Emergency department on-call status for pediatric orthopaedics: a survey of the POSNA membership.
The emergency room on-call status of pediatric orthopaedic surgeons is an important factor affecting their practices and lifestyles and was last evaluated in 2006. The entire membership of the Pediatric Orthopaedic Society of North America (POSNA) was surveyed in 2010 for information regarding their emergency room on-call status with 382 surveys returned of over 1000 e-mailed to members of POSNA. Detailed information about on-call coverage, support, and frequency was obtained in answers to 14 different questions. Compared with the prior survey in 2006, the 2010 survey indicated that a higher percentage of pediatric orthopaedic surgeons receive compensation for taking emergency room call; a higher percentage cover pediatric patients only when on-call; and accessibility to operating rooms in a timely manner for trauma cases, although limited, has improved for pediatric patients. Utilization of support staff to meet on-call trauma coverage demands, such as residents, physician's assistants, and nurse practitioners, is becoming more common. Concentration of pediatric orthopaedic trauma has increased the coverage demands on pediatric orthopaedists. This has resulted in a change in reimbursement strategies, and allocation of OR time and hospital staffing resources.


Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease.
ISIS-2302, an antisense oligonucleotide directed against intercellular adhesion molecule 1, was effective in steroid refractory Crohn's disease in a pilot trial. The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn's disease (CACD). A dose-interval, multicenter, placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD (Crohn's Disease Activity Index [CDAI], 200-400). The primary endpoint was steroid-free remission (CDAI <150) at week 14. Only 2 of 60 (3.3%) ISIS-2302-treated and no placebo patients reached the primary endpoint. Steroid-free remission at week 26 (secondary endpoint) was reached in 8 of 60 (13.3%) active treatment and 1 of 15 (6.7%) placebo patients. A greater proportion of ISIS-2302-treated than placebo patients achieved a steroid dose <10 mg/day at weeks 14 and 26 (48.3% vs. 33.3% and 55.0% vs. 40.0%, respectively, and a glucocorticoid dose of 0 mg [prednisone equivalent] at week 26 [23.3% vs. 6.7%, respectively]). Treatment with ISIS-2302 was safe. The most common side effects were injection site reactions in the active treatment group (23% in ISIS-2302-treated patients vs. none in placebo patients). No statistically significant differences in the frequency of side effects were detected between dose groups. The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint. Positive trends were observed in some of the secondary endpoints.


Transmission dynamics of co-endemic Plasmodium vivax and P. falciparum in Ethiopia and prevalence of antimalarial resistant genotypes.
Ethiopia is one of the few African countries where Plasmodium vivax is co-endemic with P. falciparum. Malaria transmission is seasonal and transmission intensity varies mainly by landscape and climate. Although the recent emergence of drug resistant parasites presents a major issue to malaria control in Ethiopia, little is known about the transmission pathways of parasite species and prevalence of resistant markers. This study used microsatellites to determine population diversity and gene flow patterns of P. falciparum (N = 226) and P. vivax (N = 205), as well as prevalence of drug resistant markers to infer the impact of gene flow and existing malaria treatment regimes. Plasmodium falciparum indicated a higher rate of polyclonal infections than P. vivax. Both species revealed moderate genetic diversity and similar population structure. Populations in the northern highlands were closely related to the eastern Rift Valley, but slightly distinct from the southern basin area. Gene flow via human migrations between the northern and eastern populations were frequent and mostly bidirectional. Landscape genetic analyses indicated that environmental heterogeneity and geographical distance did not constrain parasite gene flow. This may partly explain similar patterns of resistant marker prevalence. In P. falciparum, a high prevalence of mutant alleles was detected in codons related to chloroquine (pfcrt and pfmdr1) and sulfadoxine-pyrimethamine (pfdhps and pfdhfr) resistance. Over 60% of the samples showed pfmdr1 duplications. Nevertheless, no mutation was detected in pfK13 that relates to artemisinin resistance. In P. vivax, while sequences of pvcrt-o were highly conserved and less than 5% of the samples showed pvmdr duplications, over 50% of the samples had pvmdr1 976F mutation. It remains to be tested if this mutation relates to chloroquine resistance. Monitoring the extent of malaria spread and markers of drug resistance is imperative to inform policy for evidence-based antimalarial choice and interventions. To effectively reduce malaria burden in Ethiopia, control efforts should focus on seasonal migrant populations.


Investigation of optical limiting in iron oxide nanoparticles.
We present the study of optical limiting in iron oxide nanoparticles of diameters 31, 44, and 61 nm dispersed in toluene under exposure to nanosecond laser pulses at 532 nm. In the low fluence region smaller size nanoparticles show better optical limiting compared to larger size nanoparticles while in the high fluence region all the three samples show same limiting performance. Experimental results were compared with the well reported limiter fullerene C(60) dissolved in toluene. Iron oxide nanoparticles show better optical limiting compared to C(60) in the intermediate fluence region and comparable performance in the high fluence region. The pico-second Z-scan studies indicate that the contribution of electronic nonlinear refractive index and the two-photon absorption to the optical limiting is negligible. Our observations further indicate that the dominant mechanism for the optical limiting in iron oxide nanoparticles is nonlinear scattering.


Speak to me! An overview of patient communication systems.
One way to match professional expertise to the insatiable demand for patient information is to use new communication technologies. Patient communication systems and the opportunities they offer are explored. When using these emerging technologies, risks also should be addressed: not only must the information be accurate, but the systems must be secure.


Remarriage patterns among recent widows and widowers.
Remarriage is one of the most important determinants of physical and economic well-being among the widowed. The goal of this study is to estimate how hazard rates for remarriage vary among widows and widowers on the basis of both observable and unobservable characteristics. The remarriage estimates rely on nationally representative samples of widows and widowers from the Panel Study of Income Dynamics. Continuous-time hazard rate regressions indicate strong age and duration dependence effects for middle-aged widows and widowers and for older widowers. Among middle-aged widows, blacks and those with dependent children in the home have lower rates of remarriage. For middle-aged widowers, living in urbanized areas limits the prospects of remarriage. For older widowers, education and, to some extent, economic status appear to have positive effects on the remarriage rates. Overall, age and time since widowhood have the strongest and most consistent effects on remarriage rates for different widowed groups.


Predicting carer health effects for use in economic evaluation.
Illnesses and interventions can affect the health status of family carers in addition to patients. However economic evaluation studies rarely incorporate data on health status of carers. We investigated whether changes in carer health status could be 'predicted' from the health data of those they provide care to (patients), as a means of incorporating carer outcomes in economic evaluation. We used a case study of the family impact of meningitis, with 497 carer-patient dyads surveyed at two points. We used regression models to analyse changes in carers' health status, to derive predictive algorithms based on variables relating to the patient. We evaluated the predictive accuracy of different models using standard model fit criteria. It was feasible to estimate models to predict changes in carers' health status. However, the predictions generated in an external testing sample were poorly correlated with the observed changes in individual carers' health status. When aggregated, predictions provided some indication of the observed health changes for groups of carers. At present, a 'one-size-fits-all' predictive model of carer outcomes does not appear possible and further research aimed to identify predictors of carer's health status from (readily available) patient data is recommended. In the meanwhile, it may be better to encourage the targeted collection of carer data in primary research to enable carer outcomes to be better reflected in economic evaluation.


Anatomical studies of the human clitoris.
Endogenous or exogenous testosterone exposure to the fetus during gestation may result in masculinization of the external genitalia. Surgical correction requires a clear understanding of normal female anatomy. We report observations from our anatomical dissections on which we base our approach to reduction clitoroplasty. A total of 14 normal human fetal clitoral specimens at 8 to 24 weeks of gestation were serially sectioned after formalin fixation. Every tenth section was stained with Masson's trichrome, smooth muscle alpha-actin and the neuronal markers PGP 9.5 or S-100. Computer reconstruction using imaging software permitted 3-dimensional analysis of the nerves, corporeal bodies and glans clitoris. These specimens were compared with 2 obtained postnatally at feminizing genitoplasty. The normal fetal clitoris consists of 2 corporeal bodies with a midline septum. The ultrastructure of the female corporeal bodies is similar to that of the male counterpart. The glans clitoris forms a cap on top of the distal end of the narrowed corporeal bodies. There is a midline septum starting on the ventral aspect and extending approximately halfway into the glans. Large bundles of nerves course along the corporeal bodies with the highest density on the dorsal aspect or top. No nerves were noted at the 12 o'clock position, although nerves extend completely around the tunica in a fashion similar to that of the fetal penis. Glans innervation is provided by multiple perforating branches entering at the dorsal junction of the corporeal body and glans. The lowest density of nerves in the glans is on the ventral aspect in juxtaposition to the glans septum. In surgical specimens obtained from patients with congenital adrenal hyperplasia nerves were adjacent to the excised tunica of the corporeal bodies, especially on the lateral aspect. A clear understanding of the anatomy of the human clitoris is important for surgical reconstruction. As in the human penis, nerves in the clitoris form an extensive network around the tunica of the corporeal body with a nerve-free zone at the midline 12 o'clock position. Care should be taken to preserve all nerves. Reduction of the glans clitoris should not violate the extensive innervation that predominates on the dorsal aspect of the glans. The normal clitoris has corporeal bodies that are smaller but analogous to those of the penis. One may consider their function when extensive resection is considered.


Inflammation and the incidence of type 2 diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).
Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups. Incident type 2 diabetes was assessed among men and women aged 45-84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000-2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose > or =126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen. Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1-2.2]) and CRP (1.7 [1.3-2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants. Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.


Anterior cricoidotomy for congenital and acquired subglottic stenosis in infants and children.
Anterior cricoidotomy or "cricoid split" was described in 1980 as an open incisional procedure for failed extubation in neonates. In the past year, we modified the technique to an endoscopic-percutaneous cricoidotomy in 22 patients. We broadened the eligible population to include children with a mature membranous stenosis or a congenital subglottic stenosis. Our overall success rate of 80% (73% in the premature group) demonstrates that a cricoidotomy can be used in children older than the neonatal group and suggests that a cricoidotomy does not need to be an open operative procedure, and should be considered before a tracheotomy in the child with a subglottic injury or narrowing.


Management of pyoderma gangrenosum--an update.
Pyoderma gangrenosum is a neutrophilic dermatosis with distinctive clinical manifestations. It is frequently associated with systemic diseases like inflammatory bowel disease, rheumatoid arthritis and myeloproliferative diseases. The etiopathogenesis of pyoderma gangrenosum is still not well understood. Clinically it is classified into ulcerative, pustular, bullous and vegetative types. The diagnosis mainly depends on the recognition of evolving clinical features as there are no specific investigations for the diagnosis. It is essential to exclude other infectious diseases before therapy is initiated as corticosteroids and immunosuppressant therapy are the mainstays in the treatment of this disease. Recently, drugs like tacrolimus, mycophenolate mofetil and infliximab have shown promising results in this condition. Recent concepts regarding the various types of pyoderma gangrenosum and its management are reviewed.


A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.
The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.


Immediate hypersensitivity phenomena in bullous pemphigoid: critical concepts.
The immediate hypersensitivity phenomena in bullous pemphigoid (BP) will be discussed in this review. There is prominent involvement of eosinophils in the pathogenesis of human BP. Activation of these eosinophils in BP may lead not only to tissue damage, but also to regulation of the immune response. Stimulation of Th2 cells is responsible for the production of IgG4 and IgE autoantibodies to the hemidesmosomal proteins, 180-kDa BP antigen and 230-kDa BP antigen.


Cytotoxic activities of selected medicinal plants from Iran and phytochemical evaluation of the most potent extract.
Methanolic extract of 15 Iranian medicinal plants were prepared and tested for their cytotoxic activities against three cancer cell lines (MCF7, HepG2, WEHI164) and one normal cell line (MDBK). Some plants showed cytotoxic activities. The extract of Ferula szowitsiana root, which proved to be the most active, was chosen for further phytochemical studies. The major compounds of the most potent acetone extract were isolated. They were identified as chimgin and chimganin, two known monoterpenoids, by spectroscopic means. Their cytotoxic activity was evaluated in three cell lines. The results show that these compounds are responsible, at least in part, for the cytotoxic activity of this plant.


Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats.
Here, we sought to compare the efficacy of combining exercise and metformin for the treatment of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) in hyperphagic, obese, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats (age: 20 wk, hyperglycemic and hyperinsulinemic; n = 10/group) were randomly assigned to sedentary (O-SED), SED plus metformin (O-SED + M; 300 mg·kg(-1)·day(-1)), moderate-intensity exercise training (O-EndEx; 20 m/min, 60 min/day, 5 days/wk treadmill running), or O-EndEx + M groups for 12 wk. Long-Evans Tokushima Otsuka (L-SED) rats served as nonhyperphagic controls. O-SED + M, O-EndEx, and O-EndEx + M were effective in the management of type 2 diabetes, and all three treatments lowered hepatic steatosis and serum markers of liver injury; however, O-EndEx lowered liver triglyceride content and fasting hyperglycemia more than O-SED + M. In addition, exercise elicited greater improvements compared with metformin alone on postchallenge glycemic control, liver diacylglycerol content, hepatic mitochondrial palmitate oxidation, citrate synthase, and β-HAD activities and in the attenuation of markers of hepatic fatty acid uptake and de novo fatty acid synthesis. Surprisingly, combining metformin and aerobic exercise training offered little added benefit to these outcomes, and in fact, metformin actually blunted exercise-induced increases in complete mitochondrial palmitate oxidation and β-HAD activity. In conclusion, aerobic exercise training was more effective than metformin administration in the management of type 2 diabetes and NAFLD outcomes in obese hyperphagic OLETF rats. Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations.


Bone cements: review of their physiochemical and biochemical properties in percutaneous vertebroplasty.
Percutaneous vertebroplasty is an effective treatment for aggressive vertebral hemangiomas, osteoporotic vertebral compression fractures, spinal metastases, and myelomas. As percutaneous vertebroplasty is more commonly performed to treat various forms of back pain, new or modified cements are being used. This review examines the physiochemical and biomechanical properties of various bone cements and additives.


Idiopathic Hypoparathyroidism (IHP) Presenting as "Schizophrenia:" A Case Report.
Idiopathic hypoparathyroidism (IHP) with the onset of psychosis is a rare case in the psychiatric clinic. In this case report, we summarize the three facets of IHP, which contains the clinical, biochemical, and radiological features. Besides, the differential diagnosis of this case is supposed to be a highlight that IHP could have the main complaints of psychotic symptoms and featured signs on neuroimaging manifestation.


Passing distance, speed and perceived risks to the cyclist and driver in passing events.
Up to 38% of crashes between motor vehicles and cyclists involve overtaking and close passes, contributing to a fear of cycling for both current and potential riders. Consequently, most research has focused on the cyclist's perceptions of risk in passing events; but the driver's perceptions may be more influential determinants of passing distances and thus, objective crash risk. In an online cross-sectional survey, participants viewed 24 video clips of naturalistic passing events (external view akin to being a following driver) on urban roads in Queensland, Australia and judged distance and safety for both the portrayed cyclist and the passing driver. The passing events were filmed at a low-speed site (40 km/h speed limit) and a high-speed site (70 km/h speed limit). The 240 cyclist participants were more likely to rate the pass as unsafe for the portrayed cyclist than the 71 non-cyclist participants. Narrow passing distance, parked vehicles, oncoming vehicles, and higher motor vehicle speeds were significant predictors of rating the pass as unsafe for the portrayed cyclist and the passing driver. In addition, female participants were more likely to rate the pass as unsafe for the driver. Participant age, attitudes toward cyclists and frequency of passing cyclists did not significantly affect safety judgments. Traffic and roadway characteristics largely underlie perceptions of safety for both the cyclist and the driver when passing, even after accounting for passing distance. External, objective factors are more important than attitudes toward cyclists. Attempts to improve the subjective and objective safety of passing events may be more successful if their focus is on modifying traffic and roadway characteristics, rather than attempting to change drivers' attitudes toward cyclists. Limitations on motor-vehicle passing speed should be incorporated as part of safe bicycle passing laws.


Association of Bone Mineral Density and Bone Turnover Markers with the Risk of Diabetes: Hong Kong Osteoporosis Study and Mendelian Randomization.
Preclinical studies demonstrated that bone plays a central role in energy metabolism. However, how bone metabolism is related to the risk of diabetes in humans is unknown. We investigated the association of bone health (bone mineral density [BMD] and bone turnover markers) with incident type-2 diabetes mellitus (T2DM) based on the Hong Kong Osteoporosis Study (HKOS). A total of 993 and 7160 participants from the HKOS were studied for the cross-sectional and prospective analyses, respectively. The cross-sectional study evaluated the association of BMD and bone biomarkers with fasting glucose and glycated hemoglobin (HbA1c ) levels, whereas the prospective study examined the associations between BMD at study sites and the risk of T2DM by following subjects a median of 16.8 years. Body mass index (BMI) was adjusted in all full models. Mendelian randomization (MR) was conducted for causal inference. In the cross-sectional analysis, lower levels of circulating bone turnover markers and higher BMD were significantly associated with increased fasting glucose and HbA1c levels. In the prospective analysis, higher BMD (0.1 g/cm2 ) at the femoral neck and total hip was associated with increased risk of T2DM with hazard ratios (HRs) of 1.10 (95% confidence interval [CI], 1.03 to 1.18) and 1.14 (95% CI, 1.08 to 1.21), respectively. The presence of osteoporosis was associated with a 30% reduction in risk of T2DM compared to those with normal BMD (HR = 0.70; 95% CI, 0.55 to 0.90). The MR results indicate a robust genetic causal association of estimated BMD (eBMD) with 2-h glucose level after an oral glucose challenge test (estimate = 0.043; 95% CI, 0.007 to 0.079) and T2DM (odds ratio = 1.064; 95% CI, 1.036 to 1.093). Higher BMD and lower levels of circulating bone biomarkers were cross-sectionally associated with poor glycemic control. Moreover, higher BMD was associated with a higher risk of incident T2DM and the association is probably causal. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Connecting localized DNA strand displacement reactions.
Logic circuits based on DNA strand displacement reactions have been shown to be versatile enough to compute the square root of four-bit numbers. The implementation of these circuits as a set of bulk reactions faces difficulties which include leaky reactions and intrinsically slow, diffusion-limited reaction rates. In this paper, we consider simple examples of these circuits when they are attached to platforms (DNA origamis). As expected, constraining distances between DNA strands leads to faster reaction rates. However, it also induces side-effects that are not detectable in the solution-phase version of this circuitry. Appropriate design of the system, including protection and asymmetry between input and fuel strands, leads to a reproducible behaviour, at least one order of magnitude faster than the one observed under bulk conditions.


Effectiveness of hand hygiene in an epidemic context. Systematic review.
To assess the effectiveness of Hand Hygiene (HH) in preventing infections and the transmission of pathogens, in an epidemic context, in community and hospital settings. It is a systematic review of the literature based on a document request, conducted on PubMed, using the following search equation: "(" Hand Hygiene "[All Fields] OR" Hand Disinfection "[All Fields]) AND ("Epidemics" [All Fields] OR "Pandemics" [All Fields]) ". All publications related to the effectiveness of the preventive intervention for HH in an epidemic setting were Included. A total of 16 publications were included, of which the majority proved the effectiveness of HH and its promotion in reducing infections during an epidemic. In a clinical trial, promoting HH in an intervention group significantly reduced the prevalence of infections (24.4% vs. 11.1%). Two systematic reviews have shown the effectiveness of HH in preventing the transmission of germs with ORs between 0.52 and 0.62. Four case-control studies and three cross-sectional studies concluded with the protective effect of HH with ORs varying between 0.06 and 0.71. A cohort study showed that low adherence to HH recommendations was associated with a higher infection rate (77.5% vs 95%; p = 0.02). A single systematic review did not conclude that HH was effective in the epidemic setting. The effectiveness of HH in the fight against epidemics has been demonstrated. It is dependent on the engagement and the active participation of the different intervenient. Hence the need to increase accessibility to different methods of HH and to promote the importance of this prevention strategy could be assured through education and awareness.


A Rare and Subtle Etiology of Chronic Oropharyngeal Pain: Isolated Internal Carotid Artery Kinking without Stenosis.
Carotid artery kinking is a frequent finding in duplex ultrasonography. However, isolated morphological changes without significant carotid stenosis are rarely symptomatic. Neck pain is a rare symptom in patients with carotid artery kinks. The vascular etiology in patients with persistent neck pain is usually overlooked. A 58-year-old female patient with chronic neck pain presented to our clinic. Following multidisciplinary team review, the symptoms were found due to the kinking of the internal carotid artery. In this report, we present the clinical presentation of the patient with the kinking of the internal carotid artery without stenosis, surgical management of the pathology, and a brief literature review.


Twice-daily and once-daily nedocromil sodium 2% ophthalmic solution for the treatment of seasonal allergic conjunctivitis.
In this 8-week open-label, prospective study, 30 patients with grass pollen allergy and ocular itching instilled nedocromil sodium 2% ophthalmic solution twice daily for a 5-day baseline period, followed by once-daily dosing thereafter. Physicians assessed clinical signs after the twice-daily period and after weeks 1 and 3 of the once-daily period; patients rated ocular symptoms daily. Use of specified rescue medication was permitted. Symptom scores for ocular itching, stinging, redness, swelling, burning, tearing, and light sensitivity did not differ significantly between the dosage periods. Scores for erythema, edema, conjunctival injection, and the entire conjunctiva decreased slightly during once-daily administration; discharge scores were unchanged. Of the 20 patients who used rescue medication, only 5 increased their usage by more than two doses per week during the once-daily period. Eighty-three percent of patients were willing to continue the once-daily regimen during the next allergy season. Physicians rated overall control of seasonal allergic conjunctivitis with once-daily administration as "good" or "moderate" in 100% of the patients; 93% of patients applied those ratings themselves. Nedocromil sodium 2% ophthalmic solution instilled once daily maintains control of symptoms in patients who are established on a twice-daily regimen.


Spectrally resolved single-shot wavefront sensing of broadband high-harmonic sources.
Wavefront sensors are an important tool to characterize coherent beams of extreme ultraviolet radiation. However, conventional Hartmann-type sensors do not allow for independent wavefront characterization of different spectral components that may be present in a beam, which limits their applicability for intrinsically broadband high-harmonic generation (HHG) sources. Here we introduce a wavefront sensor that measures the wavefronts of all the harmonics in a HHG beam in a single camera exposure. By replacing the mask apertures with transmission gratings at different orientations, we simultaneously detect harmonic wavefronts and spectra, and obtain sensitivity to spatiotemporal structure such as pulse front tilt as well. We demonstrate the capabilities of the sensor through a parallel measurement of the wavefronts of 9 harmonics in a wavelength range between 25 and 49 nm, with up to λ/32 precision.


Triangulating nutrigenomics, metabolomics and microbiomics toward personalized nutrition and healthy living.
The unique physiological and genetic characteristics of individuals influence their reactions to different dietary constituents and nutrients. This notion is the foundation of personalized nutrition. The field of nutrigenetics has witnessed significant progress in understanding the impact of genetic variants on macronutrient and micronutrient levels and the individual's responsiveness to dietary intake. These variants hold significant value in facilitating the development of personalized nutritional interventions, thereby enabling the effective translation from conventional dietary guidelines to genome-guided nutrition. Nevertheless, certain obstacles could impede the extensive implementation of individualized nutrition, which is still in its infancy, such as the polygenic nature of nutrition-related pathologies. Consequently, many disorders are susceptible to the collective influence of multiple genes and environmental interplay, wherein each gene exerts a moderate to modest effect. Furthermore, it is widely accepted that diseases emerge because of the intricate interplay between genetic predisposition and external environmental influences. In the context of this specific paradigm, the utilization of advanced "omic" technologies, including epigenomics, transcriptomics, proteomics, metabolomics, and microbiome analysis, in conjunction with comprehensive phenotyping, has the potential to unveil hitherto undisclosed hereditary elements and interactions between genes and the environment. This review aims to provide up-to-date information regarding the fundamentals of personalized nutrition, specifically emphasizing the complex triangulation interplay among microbiota, dietary metabolites, and genes. Furthermore, it highlights the intestinal microbiota's unique makeup, its influence on nutrigenomics, and the tailoring of dietary suggestions. Finally, this article provides an overview of genotyping versus microbiomics, focusing on investigating the potential applications of this knowledge in the context of tailored dietary plans that aim to improve human well-being and overall health.


The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum.
Plasmodium falciparum is the causative agent of the most burdensome form of human malaria, affecting 200-300 million individuals per year worldwide. The recently sequenced genome of P. falciparum revealed over 5,400 genes, of which 60% encode proteins of unknown function. Insights into the biochemical function and regulation of these genes will provide the foundation for future drug and vaccine development efforts toward eradication of this disease. By analyzing the complete asexual intraerythrocytic developmental cycle (IDC) transcriptome of the HB3 strain of P. falciparum, we demonstrate that at least 60% of the genome is transcriptionally active during this stage. Our data demonstrate that this parasite has evolved an extremely specialized mode of transcriptional regulation that produces a continuous cascade of gene expression, beginning with genes corresponding to general cellular processes, such as protein synthesis, and ending with Plasmodium-specific functionalities, such as genes involved in erythrocyte invasion. The data reveal that genes contiguous along the chromosomes are rarely coregulated, while transcription from the plastid genome is highly coregulated and likely polycistronic. Comparative genomic hybridization between HB3 and the reference genome strain (3D7) was used to distinguish between genes not expressed during the IDC and genes not detected because of possible sequence variations. Genomic differences between these strains were found almost exclusively in the highly antigenic subtelomeric regions of chromosomes. The simple cascade of gene regulation that directs the asexual development of P. falciparum is unprecedented in eukaryotic biology. The transcriptome of the IDC resembles a "just-in-time" manufacturing process whereby induction of any given gene occurs once per cycle and only at a time when it is required. These data provide to our knowledge the first comprehensive view of the timing of transcription throughout the intraerythrocytic development of P. falciparum and provide a resource for the identification of new chemotherapeutic and vaccine candidates.


[Hormonal regulation of membrane calcium channels in the heart].
It has been shown on the trabecules of frog auricle by potential recording, that prostaglandin E1 (PGE1) increases the number of working calcium channels of the membrane. PGE1, PGE2, acetylcholine, indometacin--inhibitor of PG synthesis and aminazine 2--calmodulin inhibitor do not decrease novodrin--induced intensification of calcium current. The results suggest that a change of cAMP level inside the cell modulates the number of working calcium channels. PG and calmodulin are not necessary for novodrin--stimulation of adenylatcyclase (AC). The effect of acetylcholine is not connected with AC inhibition.


Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer.
We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.


Metal-injection and interface density engineering induced nickel diselenide with rapid kinetics for high-energy sodium storage.
The key to the innovation of sodium-ion batteries (SIBs) is to find efficient sodium-storage electrode. Here, metal Mo doping of NiSe2 is proposed by modified electrospinning strategy followed by in situ conversion process. The Mo-NiSe2 anchoring on hollow carbon nanofibers (HCNFs) would make full use of the multi-channel HCNFs in the inner layer and the active sites of Mo-NiSe2 in the outer layer, which plays an important role in buffering the volume stress of Na+ (de)insertion and reducing the adsorption energy barrier of Na+. Innovatively, it is proposed to jointly regulate the SIBs performance of NiSe2 by both metal atom doping and interface effects, thereby adjusting the sodium ion adsorption barrier of NiSe2. The Mo-NiSe2@HCNFs exhibits remarkable performance in SIBs, demonstrating a high specific capacity of 396 mAh/g after 100 cycles at 1 A/g. Moreover, it maintains outstanding cycling stability, retaining 77.6 % of its capacity (211 mAh/g) even after 1000 cycles at 10 A/g. This comprehensive electrochemical performances are due to the structural stability and outstanding electronic conductance of the Mo-NiSe2@HCNFs, as evidenced by the diffusion analysis and ex situ charge-discharge process characterization. Furthermore, coupled with the Na3V2(PO4)2O2F cathodes, the full cell also achieves a high energy density of 123 Wh kg-1. The theoretical calculation of the hypervalent Mo doing further proves the benefit of its Na+ adsorption and denser conduction band distribution. This study provides a reference for the construction of transition metal selenide via doping and interface engineering in sodium storage.


Making real options analysis more accessible for climate change adaptation. An application to afforestation as a flood management measure in the Scottish Borders.
Climate change uncertainty makes decisions for adaptation investments challenging, in particular when long time horizons and large irreversible upfront costs are involved. Often the costs will be immediate and clear, but the benefits may be uncertain and only occur in the distant future. Robust decision-making methods such as real options analysis (ROA) handle uncertainty better and are therefore useful to guide decision-making for climate change adaptation. ROA allows for learning about climate change by developing flexible strategies that can be adjusted over time. Practical examples of ROA to climate change adaptation are still relatively limited and tend to be complex. We propose an application that makes ROA more accessible to policy-makers by using the user-friendly and freely available UK climate data of the UKCP09 weather generator, which provides projections of future rainfall, deriving transition probabilities for the ROA in a straightforward way and demonstrating how the analysis can be implemented in spreadsheet format using backward induction. The application is to afforestation as a natural flood management measure (NFM) in a rural catchment in Scotland. The applicability of ROA to broadleaf afforestation as a NFM has not been previously investigated. Different ROA strategies are presented based on varying the damage cost from flooding, fixed cost and the discount rate. The results illustrate how learning can lower the overall investment cost of climate change adaptation but also that the cost structure of afforestation does not lend itself very well to ROA.


Narratives about distributed health literacy during the COVID-19 pandemic.
The promotion of health literacy was a key public health strategy during the COVID-19 pandemic. However, the role of social networks and relationships for support with health literacy-related tasks in the context of the COVID-19 pandemic is scarcely understood. Moving beyond traditional notions of health literacy, which focus on individual skills and knowledge, this study uses the concept of distributed health literacy to explore how individuals make meaning of and respond to health literacy and make their literacy skills available to others through their relational and socially situated and lived experiences of the COVID-19 pandemic. Drawing on 89 semi-structured interviews conducted in three European countries (Italy, Portugal, and Switzerland) between October and December 2021, we found narratives of stabilization, hybridization, and disruption that show how health literacy concerning COVID-19 is a complex social construct intertwined with emotional, cognitive, and behavioral responses distributed among individuals, communities, and institutions within socioeconomic and political contexts that affect their existence. This paper opens new empirical directions to understand the critical engagement of individuals and communities toward health information aimed at making sense of a complex and prolonged situation of uncertainty in a pandemic.


Microbe-Metabolite Associations Linked to the Rebounding Murine Gut Microbiome Postcolonization with Vancomycin-Resistant Enterococcus faecium.
Vancomycin-resistant Enterococcus faecium (VREfm) is an emerging antibiotic-resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between Bacteroidetes and Tenericutes within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone and to subsequent VREfm challenge. Using neural networking approaches to find cooccurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with Bacteroides, indicative of a transition toward a preantibiotic naive microbiome. This study shows the impacts of antibiotics on the gut ecosystem and the progression of the microbiome in response to colonization with VREfm. Our results offer insights toward identifying potential nonantibiotic alternatives to eliminate VREfm through metabolic reengineering to preferentially select for Bacteroides IMPORTANCE This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.


Highly parallel genomic assays.
Recent developments in highly parallel genome-wide assays are transforming the study of human health and disease. High-resolution whole-genome association studies of complex diseases are finally being undertaken after much hypothesizing about their merit for finding disease loci. The availability of inexpensive high-density SNP-genotyping arrays has made this feasible. Cancer biology will also be transformed by high-resolution genomic and epigenomic analysis. In the future, most cancers might be staged by high-resolution molecular profiling rather than by gross cytological analysis. Here, we describe the key developments that enable highly parallel genomic assays.


Multiple myeloma: a model for scientific and clinical progress.
Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease.


[Analysis of metabolic factors and relevance with the grade and stage in patients with renal cell carcinoma].
To investigate the association between metabolic factors, such as obesity, blood pressure, blood glucose, serum lipid profile, and the histopathological characteristics of renal cell carcinoma. The medical records of 382 consecutive renal cell carcinoma patients who underwent radical or partial nephrectomy at Peking University People's Hospital from January 2009 to January 2015 were retrospectively reviewed. Metabolic factors were collected from the records, including weight, body mass index, waist circumstance, blood pressure, fasting blood glucose, serum total triglyceride, serum total cholesterol, serum low-density lipoprotein-cholesterol and serum high-density lipoprotein-cholesterol. The patients were divided into different groups according to tumor grade, stage and diameter. Statistics analysis, such as t test, Mann-Whitney U test and Logistic analysis, were performed to investigate the association between metabolic factors and grade, stage and tumor diameter of renal cell carcinoma. A total of 80 (20.94%) of the tumors were classified as high grade disease, 63 (16.49%) were classified as advanced disease and 153 (40.05%) tumor diameter more than 4 cm. The patients in high grade group were found to have lower high-density lipoprotein-cholesterol level than in low grade group (P=0.015), body mass index, total cholesterol and high-density lipoprotein-cholesterol were found to be lower in advanced disease than in localized disease (P=0.022, P=0.005 and P=0.006, respectively), and low-density lipoprotein-cholesterol was found to be lower in larger tumors (P=0.030). Other factors were comparable between the different groups. The results of Logistic analyses showed that, body mass index (OR=0.906, 95%CI: 0.852-0.986, P=0.023) and total cholesterol (OR=0.660, 95%CI: 0.492-0.884, P=0.005) were associated with the tumor stage, high-density lipoprotein- cholesterol level was significantly associated with tumor grade (OR=0.293, 95%CI: 0.108-0.797, P=0.016) and stage (OR=0.204, 95%CI: 0.065-0.635, P=0.006), and low-density lipoprotein-cholesterol level was significantly associated with tumor diameter (OR=0.756, 95%CI: 0.586-0.975, P=0.031). The results of our study indicate that metabolic factors, especially obesity and serum lipid profile, are closely related with the histopathological characteristics of renal cell carcinoma.


Improving CT prediction of treatment response in patients with metastatic colorectal carcinoma using statistical learning theory.
Significant interest exists in establishing radiologic imaging as a valid biomarker for assessing the response of cancer to a variety of treatments. To address this problem, we have chosen to study patients with metastatic colorectal carcinoma to learn whether statistical learning theory can improve the performance of radiologists using CT in predicting patient treatment response to therapy compared with the more traditional RECIST (Response Evaluation Criteria in Solid Tumors) standard. Predictions of survival after 8 months in 38 patients with metastatic colorectal carcinoma using the Support Vector Machine (SVM) technique improved 30% when using additional information compared to WHO (World Health Organization) or RECIST measurements alone. With both Logistic Regression (LR) and SVM, there was no significant difference in performance between WHO and RECIST. The SVM and LR techniques also demonstrated that one radiologist consistently outperformed another. This preliminary research study has demonstrated that SLT algorithms, properly used in a clinical setting, have the potential to address questions and criticisms associated with both RECIST and WHO scoring methods. We also propose that tumor heterogeneity, shape, etc. obtained from CT and/or MRI scans be added to the SLT feature vector for processing.


[Prebiotics: concept, properties and beneficial effects].
Prebiotics are non-digestible food ingredients (oligosaccharides) that reach the colon and are used as substrate by microorganisms producing energy, metabolites and micronutrients used for the host; in addition they also stimulate the selective growth of certain beneficial species (mainly bifidobacteria and lactobacilli) in the intestinal microbiota. In this article, a multidisciplinary approach to understand the concept of prebiotic carbohydrates, their properties and beneficial effects in humans has been carried out. Definitions of prebiotics, reported by relevant international organizations and researchers, are described. A comprehensive description of accepted prebiotics having strong scientific evidence of their beneficial properties in humans (inulin-type fructans, FOS, GOS, lactulose and human milk oligosaccharides) is reported. Emerging prebiotics and those which are in the early stages of study have also included in this study. Taken into account that the chemical structure greatly influences carbohydrates prebiotic properties, the analytical techniques used for their analysis and characterization are discussed. In vitro and in vivo models used to evaluate the gastrointestinal digestion, absorption resistance and fermentability in the colon of prebiotics as well as major criteria to design robust intervention trials in humans are described. Finally, a comprehensive summary of the beneficial effects of prebiotics for health at systemic and intestinal levels is reported. The research effort on prebiotics has been intensive in last decades and has demonstrated that a multidisciplinary approach is necessary in order to claim their health benefits.


Molecular sieving through S layers of Bacillus stearothermophilus strains.
The permeability properties and the exclusion limits of the crystalline surface layers (S layers) of two selected strains of Bacillus stearothermophilus were investigated. Measurements were performed of passive solute uptake into the intracellular space of native or glutaraldehyde-treated sacculi. Native sacculi were prepared from whole cells by extracting the cytoplasmic membrane with Triton X-100 under conditions which preserved the integrity of the S layer and the peptidoglycan-containing layer. The permeability barrier was found to consist of three adjacent layers, namely, the S layer, the peptidoglycan-containing layer, and an incomplete S layer attached to the inner face of the peptidoglycan-containing layer. In glutaraldehyde-treated sacculi the peptidoglycan was digested after stabilizing the S-layer lattice by chemical cross-linking. The solutes selected for the uptake measurements were mannose, proteins, and dextrans of increasing molecular weights. The S layers of both strains allowed free passage for molecules with a molecular weight of up to 30,000 and showed sharp exclusion limits between molecular weights of 30,000 and 45,000, suggesting a limiting pore diameter of about 4.5 nm.


Phosphonate Decomposition-Induced Polyoxomolybdate Dumbbell-Type Cluster Formation: Structural Analysis, Proton Conduction, and Catalytic Sulfoxide Reduction.
The reaction of MoO42- with a number of phosphonic acids [bis(phosphonomethyl)glycine, R,S-hydroxyphosphonoacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, phenylphosphonic acid, aminotris(methylene phosphonic acid), and 1,2-ethylenediphosphonic acid] under oxidizing (H2O2) hydrothermal conditions at low pH leads to rupture of the P-C bond, release of orthophosphate ions, and generation of the octanuclear, phosphate-bridged, polyoxometalate molybdenum cluster (NH4)5[Mo8(OH)2O24(μ8-PO4)](H2O)2 (POMPhos). This cluster has been fully characterized and its structure determined. It was studied as a proton conductor, giving moderate values of σ = 2.13 × 10-5 S·cm-1 (25 °C) and 1.17 × 10-4 S·cm-1 (80 °C) at 95% relative humidity, with Ea = 0.27 eV. The POMPhos cluster was then thermally treated at 310 °C, yielding (NH4)2.6(H3O)0.4(PO4Mo12O36) together with an amorphous impurity containing phosphate and molybdenum oxide. This product was also studied for its proton conductivity properties, giving rise to an impressively high value of σ = 2.43 × 10-3 S·cm-1 (25 °C) and 6.67 × 10-3 S·cm-1 (80 °C) at 95% relative humidity, 2 orders of magnitude higher than those corresponding to the "as-synthesized" solid. The utilization of POMPhos in catalytic reduction of different sulfoxides was also evaluated. POMPhos acts as an efficient homogeneous catalyst for the reduction of diphenyl sulfoxide to diphenyl sulfide, as a model reaction. Pinacol was used as a low-cost, environmentally friendly, and highly efficient reducing agent. The effects of different reaction parameters were investigated, namely the type of solvent and reducing agent, presence of acid promoter, reaction time and temperature, loading of catalyst and pinacol, allowing to achieve up to 84-99% yields of sulfide products under optimized conditions. Substrate scope was tested on the examples of diaryl, alkylaryl, dibenzyl, and dialkyl sulfoxides and excellent product yields were obtained.


Evidence for cytochrome P450 2A6 and 3A4 as major catalysts for N'-nitrosonornicotine alpha-hydroxylation by human liver microsomes.
The tobacco specific carcinogen N'-nitrosonornicotine (NNN), is believed to be a causative agent for esophageal cancer in smokers. NNN requires metabolic activation to exert its carcinogenic potential. Metabolism occurs through cytochrome P450 (P450) catalyzed 2'- and 5'-hydroxylation, which generates unstable metabolites that decompose to 4-hydroxy-1-(3-pyridyl)-1-butanone ('keto alcohol') and 4-hydroxy-4-(3-pyridyl)butanal, respectively. The latter cyclyzes to 5-(3-pyridyl)-2-hydroxytetrahydrofuran ('lactol'). 2'-Hydroxylation of NNN is believed to be the pathway critical for esophogeal NNN carcinogenesis in the rat. The ability of human liver microsomes and expressed human P450s to metabolize [5-(3)H]NNN to keto alcohol and lactol was determined by reverse phase HPLC with radioflow detection. At low NNN concentrations, 11 human liver microsomes metabolized NNN primarily by 5'-hydroxylation to lactol. This reaction was strongly correlated (r = 0.92) with coumarin 7-hydroxylation, suggesting that NNN 5'-hydroxylation is catalyzed mainly by P450 2A6. 2'-Hydroxylation of NNN by human liver microsomes correlated with 6beta-hydroxylation of testosterone, a P450 3A4-specific activity (r = 0.94). The relative rates of 2'- and 5'-hydroxylation by human P450s 2A6, 2E1, 2D6 and 3A4 expressed in Sf9 cells by the baculovirus-insect cell expression system, and human P450 3A4 produced by stable expression in Chinese hamster ovary cells, were determined. Human P450 2A6 metabolized 1 microM NNN exclusively by 5'-hydroxylation. The rate of lactol formation was 317 pmol/min per nmol P450. Human P450s 2E1 and 2D6 also metabolized NNN only to lactol, but at much lower rates, 0.4 and 0.8 pmol/min per nmol of P450 respectively. In contrast, the metabolism of NNN by expressed human P450 3A4 was specific for keto alcohol formation. The Km for 5'-hydroxylation by baculovirus-expressed P450 2A6 was 2.1 microM, and k(cat) was 953 pmol/min per nmol of P450. The Km for lactol formation by human liver microsomes containing high levels of P450 2A6, was 5 microM . Human liver microsomes exhibited a Km of 312 microM for keto alcohol formation. Coumarin, 8-methoxypsoralen (P450 2A6 inhibitors), and anti-2A6 monoclonal antibody were strong inhibitors of NNN-derived lactol formation in human liver microsomes. Troleandomycin, an inhibitor of P450 3A4, effectively inhibited the metabolism of NNN to keto alcohol by human liver microsomes. These results are consistent with P450 2A6 mediated 5'-hydroxylation and P450 3A4 mediated 2'-hydroxylation of NNN in human liver microsomes.


Effects of neutrophil, natural killer cell, and macrophage depletion on murine Clostridium piliforme infection.
Clostridium piliforme infection (Tyzzer's disease) induces enterohepatic disease in many domestic and laboratory animals. Murine susceptibility to Tyzzer's disease varies with host strain, age, and immune status However, little is known about the role of the immune system in control of this disease. To investigate the role of host immunity in Tyzzer's disease, mice were depleted of either neutrophils, natural killer cells, or macrophages by antibody administration or chemotherapy. After depletion, DBA/2 mice, which are naturally susceptible to C. piliforme, or naturally resistant C57BL/6 mice were inoculated intravenously with C. piliforme. Animals were euthanized 3 days postinoculation and evaluated for gross and histologic lesions and hepatic bacterial load. In juvenile DBA/2 or C57BL/6 mice, depletion of either neutrophils or natural killer cells increased severity of disease. In adult mice, depletion of natural killer cells significantly increased severity of Tyzzer's disease in the resistant (C57BL/6) but not in the susceptible (DBA/2) strain. Macrophage depletion did not alter the course of infection in either mouse strain. These studies indicate an important role for neutrophils and natural killer cells in the pathogenesis of murine Tyzzer's disease. The role of macrophages in murine C. piliforme infection will require further evaluation.


MeVa2.1.dOVA and MeVa2.2.dOVA: two novel BRAFV600E-driven mouse melanoma cell lines to study tumor immune resistance.
While immunotherapy has become standard-of-care for cutaneous melanoma patients, primary and acquired resistance prevent long-term benefits for about half of the late-stage patients. Pre-clinical models are essential to increase our understanding of the resistance mechanisms of melanomas, aiming to improve the efficacy of immunotherapy. Here, we present two novel syngeneic transplantable murine melanoma cell lines derived from the same primary tumor induced on BrafV600E Pten-/- mice: MeVa2.1 and MeVa2.2. Derivatives of these cell lines expressing the foreign antigen ovalbumin (dOVA) showed contrasting immune-mediated tumor control. MeVa2.2.dOVA melanomas were initially controlled in immune-competent hosts until variants grew out that had lost their antigens. By contrast, MeVa2.1.dOVA tumors were not controlled despite presenting the strong OVA antigen, as well as infiltration of tumor-reactive CD8+ T cells. MeVa2.1.dOVA displayed reduced sensitivity to T cell-mediated killing and growth inhibition in vitro by both IFN-γ and TNF-α. MeVa2.1.dOVA tumors were transiently controlled in vivo by either targeted therapy, adoptive T cell transfer, regulatory T cell depletion, or immune checkpoint blockade. MeVa2.1.dOVA could thus become a valuable melanoma model to evaluate novel immunotherapy combinations aiming to overcome immune resistance mechanisms.