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Pulmonary arterial hypertension (PAH) is a rapidly progressing disease whereby elevated mean pulmonary artery pressure (mPAP >20mmHg) leads to right ventricular (RV) dysfunction and death. A pilot study has demonstrated the feasibility and safety of using CardioMEMS™ HF System to remotely monitor mPAP and guide medical therapy in PAH (PMID:31265832), while numerous retrospective studies evaluating initial combination with early aggressive parenteral prostanoid therapy have shown marked mPAP reduction leads to significant improvement of RV function and long-term outcomes in patients with PAH (PMID:34905704, PMID:36058492). A prospective study is warranted. ARTISAN (A fterload R eduction T o I mprove Right Ventricular S tructure A nd Fu N ction), is a prospective, multicenter, open-label clinical trial to evaluate the effect of early and rapid treprostinil therapy to reduce mPAP and reverseRV remodeling in PAH. NCT 05203510. Subjects will be PAH treatment naïve or received endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy less than 6 months, mPAP>35mmHg, WHO functional class II or III, Registry to EValuate EArly and Long-term PAH disease management (REVEAL) Lite 2 risk score ≤9. After initiating parenteral treprostinil with rapid dose titration based on mPAP assessment, subjects may transition to oral treprostinil while continuing upward dose titration to further reduce mPAP. mPAP will be closely monitored using the CardioMEMS HF System, while RV structure and function will be monitored with cardiac magnetic resonance imaging (cMRI) and echocardiography. Approximately 50 subjects will be enrolled. Primary endpoint is change in RV ejection fraction from baseline to Month 12, measured by cMRI. Key secondary endpoints include mPAP, clinical improvement, ratio of stroke volume to end systolic volume measured by cMRI, REVEAL Lite 2 risk score, ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure measured by echocardiography, and survival through Month 36. The prospectively designed ARTISAN clinical trial aims to explore the hypothesis that early and rapid treprostinil afterload-lowering therapy results in a disease modifying treatment option for PAH. [ABSTRACT FROM AUTHOR]

Central venous catheter (CVC) insertion is commonly undertaken in the ICU. The use of ultrasound (US) to facilitate CVC insertion is standard and is supported by guidelines. Because the subclavian vein cannot be insonated where it underlies the clavicle, its use as a CVC site is now less common. The axillary vein, however, can be seen on US just distal to the subclavian vein and placement of a CVC at this site gives a result which is functionally indistinguishable from a subclavian CVC. We evaluated placement of US-guided axillary CVCs in mechanically ventilated intensive care patients. Data were collected for 125 consecutive US-guided axillary CVC procedures in ventilated patients in an adult intensive care setting. All lines were inserted using real-time US guidance with an out-of-plane technique. One hundred and twenty-five procedures occurred in 119 patients. Successful line placement was achieved in 117 out of 125 (94%) procedures. Complications included four procedures that required repeating due to catheter malposition and one arterial puncture. The median number of attempts per procedure was one (IQR 1 to 2). Thirty-nine (31%) patients had a body mass index of 30 or above, 43 (34%) patients had a coagulopathy and 70 (56%) patients had significant ventilator dependence (FiO2 of 0.5 or above, or positive end expiratory pressure 10 cmH2O or above). The technique of US-guided axillary CVC access can be undertaken successfully in ventilated intensive care patients, even in challenging circumstances. Taken together with existing work on the utility and safety of this technique, we suggest that it be adopted more widely in the intensive care population. [ABSTRACT FROM AUTHOR]

Background:The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.Methods:Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg−1 days 1 and 15 plus paclitaxel 90 mg m−2 days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg−1 day 1 plus capecitabine 1000 mg m−2 bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs.Results:The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP.Conclusions:A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340). [ABSTRACT FROM AUTHOR]

Abstract: Background: We report safety data from a randomised, phase III study (CECOG/BC.1.3.005) evaluating first-line bevacizumab plus paclitaxel or capecitabine for locally recurrent or metastatic breast cancer. Patients and methods: Patients aged ⩾18years with human epidermal growth factor receptor-2-negative breast adenocarcinoma were randomised to Arm A: bevacizumab 10mg/kg days 1 and 15; paclitaxel 90mg/m2 days 1, 8, and 15, every 4weeks; or Arm B: bevacizumab 15mg/kg day 1; capecitabine 1000mg/m2 b.i.d., days 1–14, every 3weeks, until disease progression, unacceptable toxicity or consent withdrawal. Results: A post hoc interim safety analysis included 561 patients (Arm A: 284, Arm B: 277). The regimens demonstrated similar frequencies of all-grade and serious adverse events (SAEs), but different safety profiles. Treatment-related events occurred in 85.2% (Arm A) and 78.0% (Arm B) of patients. Fatigue was most common in Arm A (30.6% versus 23.5% Arm B), and hand–foot syndrome (HFS) most common in Arm B (49.5% versus 2.5% Arm A). Diarrhoea (Arm A: 0.4%, Arm B: 1.4%) and pulmonary embolism (Arm A: 0.7%, Arm B: 1.1%) were the most frequently reported SAEs. Conclusion: These findings are in-line with safety data for bevacizumab plus paclitaxel or capecitabine, reported in previous phase III trials. [Copyright &y& Elsevier]

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats (N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only. [ABSTRACT FROM AUTHOR]

BackgroundThe prevalence of psychological distress and common mental disorders has been shown to peak in midlife but analyses have ignored the association of poor material circumstances with prevalence. This study aimed to test the hypothesis that the midlife prevalence peak occurs only in lower-income households.MethodPooled data were used from the annual Health Survey for England, a nationally representative cross-sectional study, on community-dwelling individuals aged ⩾16 years from years 1997 to 2006 (n=100 457). 12-item General Health Questionnaire scores, reported mental illness diagnoses and receipt of relevant medication were assessed in relation to household income and age. Analyses were separated by gender and adjusted for age, ethnicity, smoking, social class, education and co-morbidities.ResultsPrevalence of psychological distress, diagnoses and treatments rose with age until early middle age and declined subsequently. In analyses conducted separately by income categories, this pattern was marked in low-income groups but absent in high-income groups. Income-related inequalities in the prevalence of psychological distress were greatest in midlife; for example, in men aged 45–54 years the odds ratio of receiving psychiatric medication in the lowest income group compared with the highest was 7.50 [95% confidence interval (CI) 4.24–13.27] and in women aged 45–54 years the odds ratio of reporting mental illness was 10.25 (95% CI 6.16–17.05).ConclusionsAn increased prevalence of psychological distress, common mental disorder diagnoses and treatment in midlife is not a universal phenomenon but is found only in those in low-income households. This implies the phenomenon is not inevitable but is potentially manageable or preventable. [ABSTRACT FROM PUBLISHER]

The aim of this, study was to investigate whether dietary protein intake during gestation less than or greater than recommendations affects guts growth and body composition, gestation outcome, and colostrum composition. German Landrace guts were fed gestation diets (13.7 MJ of ME/kg) containing a low (n = 18; LP, 6.5% CP), an adequate (n = 20; AP, 12.1%), or a high (n = 16; HP, 30%) protein content corresponding to a protein:carbohydrate ratio of 1:10.4, 1:5, and 1:1.3, respectively, from mating until farrowing. Gilts were inseminated by semen of pure German Landrace boars and induced to farrow at 114 d postcoitum (dpc; Exp. 1). Energy and protein intake during gestation were 33.3, 34.4, and 35.8 MJ of ME/d (P < 0.001) and 160, 328, and 768 g/d, respectively, in LP, AP, and HP gilts (P < 0.001). From insemination to 109 dpc, BW gain was least in LP (42.1 kg), intermediate in HP (63.1 kg), and greatest in AP gilts (68.3 kg), whereas increase of backfat thickness was least in gilts fed the HP diet compared with LP and AP diets (3.8, 5.1, 5.0 mm; P = 0.01). Litter size, % stillborn piglets, and mummies were unaffected (P > 0.28) by the gestation diet. Total litter weight tended to be l~ess in the offspring of LP and HP gilts (14.67, 13.77 vs. 15.96 kg; P = 0.07), and the percentage of male piglets was greater in litters of HP guts (59.4%; P < 0.01). In piglets originating from LP and HP guts, individual birth weight was less (1.20, 1.21 vs. 1.40 kg; P = 0.001) and birth weight/crown-rump length ratio was reduced (45.3, 46.4 vs. 50.7 g/cm; P = 0.003). Colostrum fat (7.8, 7.4 vs. 8.1%) and lactose concentrations (2.2, 2.1 vs. 2.6%) tended to be reduced in LP and HP gilts (P = 0.10). In Exp. 2, 28 guts (LP, 10; AP, 9; HP, 9) were treated as in Exp. 1 but slaughtered at 64 dpc. At 64 dpc, LP guts were 7% lighter than AP guts (P = 0.03), whereas HP gilts were similar to AP guts. Body composition was markedly altered in response to LP and HP feeding with less lean (P < 0.01) and greater fat content (P = 0.02 to 0.04) in LP and less fat content (P = 0.02 to 0.04) in HP gilts. Fetal titter weight and number, and embryonic survival at 64 dpc were not affected by the diets. These results indicated that gestation diets containing protein at 50 and 250% of recommendations and differing in protein:carbohydrate ratio led to marked changes in protein and fat metabolism in guts resulting in fetal growth retardation of 15%, which mainly occurred during the second half of gestation. [ABSTRACT FROM AUTHOR]

Objective:To compare childhood obesity prevalence in England and the United States using different criteria.Subjects/Methods:Participants included 2- to 17-year olds in the Health Survey for England (HSE, n=33 563) and the US National Health and Nutrition Examination Survey (NHANES, n=14 540) 1999 through 2006. Mean body mass index (BMI) and prevalence of obesity were compared using the UK 1990, US 2000 Centers for Disease Control and International Obesity Task Force (IOTF) criteria.Results:English children at ages 2-5 years had a higher mean BMI than US children (mean difference (English minus US)=0.41 kg/m2, 95% confidence intervals (CI) 0.31-0.52). At age 8 years, mean BMI was lower in England (for ages 8-11 years, mean difference=−1.00 kg/m2, 95% CI −1.26 to −0.75; for ages 12-17 years, mean difference=−1.37 kg/m2, 95% CI −1.59 to −1.14). The IOTF criteria produced the lowest estimates of obesity prevalence. The 2000 Centre for Disease Control and Prevention (CDC) criteria produced the highest estimates in younger children and the UK 1990 criteria produced the highest in adolescents. Children aged 2-5 years in England had higher prevalence of obesity than those in the United States when using the 2000 CDC and UK 1990 criteria. US adolescents had the highest prevalence of obesity by age group using each of the three criteria.Conclusion:The 2000 CDC and UK 1990 criteria give a higher prevalence of obesity in England than in the United States at ages 2-5 years; however, at age 8 years, the reverse is true. Estimates of childhood obesity prevalence rely on the criteria used, which has implications for surveillance and clinical practice. [ABSTRACT FROM AUTHOR]

A semiclassical method is proposed for the theoretical description of elastic light scattering by arbitrary semiconductor quantum dots under conditions of size quantization. This method involves retarded potentials and allows one to dispense with boundary conditions for electric and magnetic fields. Exact results for the Umov-Poynting vector at large distances from quantum dots in the case of monochromatic and pulsed irradiation and formulas for differential scattering cross sections are obtained. [ABSTRACT FROM AUTHOR]

Atrial fibrillation is a common arrhythmia in an intensive care unit. We performed a prospective observational study over a period of three months, to study the incidence, risk factors and outcome of patients who develop atrial fibrillation in a multidisciplinary intensive care unit. All patients above the age of 50 years were eligible. Exclusion criteria were: cardiac or oesophageal surgery during current hospitalisation, atrial fibrillation at admission, implanted pacemaker and expected intensive care unit stay of less than 24 hours. Sixty-one patients were included in the study. Eighteen patients (29.5%, confidence interval 18-40) developed atrial fibrillation. Incidence of atrial fibrillation was 4.02 episodes per 100 patient days. Patients who developed atrial fibrillation had higher age (71.3 years vs. 63.2 years, P=0.001), severity of illness (APACHE II 25.4 vs. 20.0, P=0.005) and sepsis at admission (9/18 vs. 9/43, P=0.01). They also had higher in-hospital mortality (Risk ratio 2.7, 95% confidence interval 1.3-5.4). Standardised mortality ratio was higher in patients who developed atrial fibrillation (1.08 vs. 0.63). Patients who developed atrial fibrillation required a longer period of mechanical ventilation and inotropic support. Multivariate logistic regression analysis showed age >75 years, APACHE II score >20 and sepsis at admission were independent predictors for development of atrial fibrillation in critically ill patients. Although atrial fibrillation by itself is unlikely to be the cause of higher mortality, it is likely to be a marker for increased mortality and resource utilisation in the intensive care unit. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether there is a relationship between smoking and levels of overall quality of life, or with the pleasure domain of quality of life, in Lower socio-economic groups (SES). Study design: Cohort study involving 9176 individuals aged 50 years and over who participated in the Health Survey for England and were followed up in Wave 1 of the English Longitudinal Study of Ageing in 2002. Methods: We classified smokers as never-smokers, ex-smokers and current smokers, and used household wealth as a marker for socio-economic position. Pleasure was assessed using the pleasure subscale of the CASP-19 instrument, a 19-point measure of quality of life that covers four theoretical domains: control, autonomy, self-realization and pleasure. Results: We found that the odds ratio for experiencing lower than median levels of pleasure for smokers with low SES was 1.42 (95% Cl 1.16-1.74), and for all smokers was 1.33 (95% Cl 1.17-1.51). The same pattern of associations was found when the outcome was total CASP-19 score or positive GHQ-12 score. Conclusions: We found no evidence to support a claim that smoking is associated with heightened levels of pleasure, either in people with low SES or in the general population. In fact, our results suggest the opposite: that smoking is associated with lower levels of pleasure and poorer overall quality of life. Policy decisions on smoking should consider its potentially harmful effect on quality of life and pleasure as well as on other aspects of health. [ABSTRACT FROM AUTHOR]

Isolated salivary glands of Periplaneta americana were used to measure secretion rates and, by quantitative capillary electrophoresis, Na+, K+, and Cl− concentrations in saliva collected during dopamine (1 μM) and serotonin (1 μM) stimulation in the absence and presence of ouabain (100 μM) or bumetanide (10 μM). Dopamine stimulated secretion of a NaCl-rich hyposmotic saliva containing (mM): Na+ 95 ± 2; K+ 38 ± 1; Cl- 145 ± 3. Saliva collected during serotonin stimulation had a similar composition. Bumetanide decreased secretion rates induced by dopamine and serotonin; secreted saliva had lower Na+, K+ and Cl− concentrations and osmolarity. Ouabain caused increased secretion rates on a serotonin background. Saliva secreted during dopamine but not serotonin stimulation in the presence of ouabain had lower K+ and higher Na+ and Cl− concentrations, and was isosmotic. We concluded: The Na+-K+-2Cl− cotransporter is of cardinal importance for electrolyte and fluid secretion. The Na+/K+-ATPase contributes to apical Na+ outward transport and Na+ and K+ cycling across the basolateral membrane in acinar P-cells. The salivary ducts modify the primary saliva by Na+ reabsorption and K+ secretion, whereby Na+ reabsorption is energized by the basolateral Na+/K+-ATPase which imports also some of the K+ needed for apical K+ extrusion. [Copyright &y& Elsevier]

A quantum theory of conductivity is constructed for semiconductor objects such as quantum wells, wires, and dots. The mean values of current and charge densities induced by a weak electromagnetic field are calculated. It is shown that the mean values of current and charge densities consist of two parts, the first of which is expressed in terms of the electric field and the second is expressed in terms of derivatives of the electric field with respect to spatial coordinates. Appropriate expressions are derived for the conductivity tensor that depends on coordinates; these expressions can be applied to any spatially inhomogeneous systems. The results obtained can be used in the theory of secondary radiation from objects of reduced dimension in the cases of monochromatic or pulsed irradiation. [ABSTRACT FROM AUTHOR]

Features the German Arthroplasty Register. Creation of the register as a result of the Health Reform Act of 1989; Set up and structure of the Register; Use of the register to assess the quality of joint implants; Requirements for the register.

Abstract. A variety of growth factors promote the complex multistep process of angiogenesis. The mitogenic activity of vascular endothelial growth factors (VEGFs) and placental growth factors (PlGFs), known as cytokines acting predominantly on endothelial cells, was tested on human umbilical vein endothelial cells (HUVEC) and microvascular endothelial cells (MIEC) and compared with the potency of the universally acting basic fibroblast growth factor (FGF-2). The cells were seeded at different cell numbers and incubated with various doses of growth factors for a period of 24–72 h in culture medium ± serum. Proliferation was determined by measuring the optical density after staining the cells with the tetrazolium salt WST-1. VEGF 121 and VEGF 165 increased the number of HUVEC and MIEC at low and high seeding densities various doses and incubation times. The efficiency of FGF-2 was less pronounced at high seeding densities of the cells under serum-free conditions. PlGF-1 and PlGF-2 stimulated mitogenesis on HUVEC only at low cell numbers and after a short incubation time by 125 ± 3% and 102 ± 5% (P < 0.001), respectively. Longer incubation times with the lower seeding density in the absence of FCS did not induce a significant stimulatory effect of the PlGFs. MIEC responded stronger to all growth factors. In particular under serum free conditions, PlGF-1 and PlGF-2 effectively stimulated cell proliferation by 247 ± 54% (P < 0.01) and 288 ± 40% (P < 0.05) at low cell numbers, and by 81 ± 13% (P < 0.05) and 49 ± 13% (P < 0.01), respectively, at high cell numbers. The addition of fetal calf serum caused a reduced proliferative response of all growth factors on both cell types related to the controls. In conclusion, MIEC and HUVEC differ in their proliferative response to VEGFs, PlGFs and FGF-2. [ABSTRACT FROM AUTHOR]

An analysis is made of the influence of the spatial dispersion of LO phonons and the exciton effect on the energy spectrum of magnetopolarons in a quantum well. It is shown that in optical experiments where light is incident normally on the plane of the quantum well, a discrete spectrum of magnetopolarons is observed. Both the phonon dispersion and the Coulomb attraction of an electron and a hole may lead to a shift of the discrete magnetopolaron energy levels and additional contributions to the broadening of various levels. [ABSTRACT FROM AUTHOR]

Combined polaron states in a rectangular quantum well in a strong magnetic field perpendicular to the well plane are discussed. These states are due to interaction between two discrete electron levels with different Landau quantum numbers (n and n[sub 1]) and different sizequantization quantum numbers (m and m[sub 1]) on the one hand and a confined LO phonon on the other under conditions of low temperature when the energy difference between the electronic levelsis equal or close to the energy of the confined LO phonon. The expression for the resonant magnetic field H[sub res] at which a combined polaron is formed contains the energy difference between size-quantized levels, so it is a function of quantum well parameters. The separation ΔE[sub res] between branches in the energy spectrum of a combined polaron and H[sub res] has been calculated as a function of the quantum well width d. The resonant field H[sub res] can be reduced dramatically in comparison with the case m=m[sub 1]. The case of size-quantization with n = n[sub 1] has been analyzed. The energy difference ΔE[sub res] is in the range (1 - 5) ·10[sup -3] eV. The damping of combined polaron states due to the effect of anharmonicity on the LO phonon has been studied. Interband absorption and features in the reflection spectrum due to interband transitions have been calculated for an arbitrary ratio between the radiative and "phonon" lifetime of a combined polaron have been investigated. [ABSTRACT FROM AUTHOR]

Analyzes the energy splitting in double magnetopolaron energy spectrum in rectangular quantum wells. Capacity of interaction leading to resonant coupling between electrons and phonons; Cyclotron and phonon frequency in the quantum well; Frolich's coupling constant.

The spatial correlation of light-generated electrons and holes in a quasi-two-dimensional electron gas in a strong magnetic field is investigated in an approximation linear in the intensity of the exciting light. The correlation is due to the interaction of the electrons and holes with longitudinal optical (LO) phonons. The theory permits calculating, on the basis of a special diagrammatic technique, two distribution functions of an electron-hole pair with respect to the distance between the electron and the hole after the emission of N phonons: first, the function determining the total number of pairs which have emitted N phonons and, second, the function related to the rank-4 light-scattering tensor in interband resonance Raman scattering of light. A special feature of the system is that the electron and hole energy levels are discrete. The calculation is performed for a square quantum well with infinitely high barriers. The distribution function and the total number of electron-hole pairs before the emission of phonons as well as the distribution function corresponding to two-phonon resonance Raman scattering are calculated. The theory predicts the appearance of several close-lying peaks in the excitation spectrum under resonance conditions. The number of peaks is related to the number of the Landau level participating in the optical transition. The distance between peaks is determined by the electron-phonon coupling constant. Far from resonance there is one peak, which is much weaker than the peaks obtained under resonance conditions. [ABSTRACT FROM AUTHOR]

Fluorescein conjugated Vicia villosa (Vv) lectin was used for direct staining of the surface of viable cells of various mouse lymphocyte populations. A varying proportion of polyclonally-activated T cells expressed Vv receptor although leas strongly than cells of an influenza virus-specific cytotoxic T lymphocyte (CTL) clone and blasts generated in the mixed lymphocyte reaction. Cyclosporin A (CyA) treatment markedly reduced the expression of Vv receptor following concanavalin A (Con A) stimulation by between 66% and 93% with a concurrent inhibition of blastogenesis and complete abrogation of cytolytic function. Resting mouse lymphocytes and B-cell blasts were always Vv-negative. However, non-specific suppressor factor producing non-cytotoxic T-cell lines also expressed Vv receptor as shown by the weak, but specific, surface fluorescence of EL4 and BW5147 cells stained with Vv. Vv-positive cells were not restricted to a particular Ly phenotype, Vv-positive cells being found among both Lyt 1+ and Lyt 2+ MLC stimulated lymphocytes. Our data suggest that the receptor for Vv lectin cannot be regarded as an exclusive differential marker for CTL. [ABSTRACT FROM AUTHOR]

It is predicted that resonance coupling between two discrete electron energy levels corresponding to different size-quantization quantum numbers and different Landau quantum numbers can occur in a quantum well in a quantizing magnetic field. The resonance coupling is due to the interaction of an electron with LO phonons and results in the formation of polaron states of a new type. It is shown that for a certain value of the magnetic field, which depends on the splitting of the electron size-quantization levels, the absorption peak and the two-phonon resonance Raman scattering peak split into two components, the separation between which is determined by the electron–phonon coupling constant. The resonance coupling between size-quantization levels with the same Landau quantum numbers is also studied. The splitting of the peaks in this case is virtually independent of the magnetic field and can be observed in much weaker fields. The experimental observation of the effect will make it possible to determine the relative position of the electronic levels and the electron–phonon coupling constant. © 1997 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Describes the features of the clavicular fractures on the shoulder and system of radiological interpretation of the injury. Variation on the type of injuries; Importance of the anatomical considerations of the injury; Indication of common injury arising from trauma.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) with multigrees, vessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown. METHODS: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year. RESULTS: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCL A primary end-point event occurred in 35 patients (8.590) in the immediate group as compared with 68 patients (16.396) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P< 0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.090) and 17 patients (4.1°6), respectively, in the immediate group and in 22 patients (5.3°6) and 39 patients (9.3°6), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event. CONCLUSIONS: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. [ABSTRACT FROM AUTHOR]

Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain. Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5 mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation. Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409). Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain. Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities. [ABSTRACT FROM AUTHOR]

Background: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years.Methods: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods.Discussion: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns.Trial Registration: ISRCTN17325135 . Registration date 27 November 2019. [ABSTRACT FROM AUTHOR]

Background- Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results- The international registry included 679 newly diagnosed (<=6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%- 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension-targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions- Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension-targeted treatments. [ABSTRACT FROM AUTHOR]

Impaired clearance of cerebral amyloid-β (Aβ) across the blood-brain barrier (BBB) may facilitate the onset and progression of Alzheimer's disease (AD). Additionally, experimental evidence suggests a central role for cellular cholesterol in amyloid-β protein precursor (AβPP) processing. The present study investigated whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous AβPP synthesis and whether and to what extent AβPP synthesis and processing is under control of cellular cholesterol homeostasis. Intracellular cholesterol metabolism was pharmacologically manipulated by using natural and synthetic liver-X receptor (LXR) agonists. Using an in vitro model of the BBB consisting of primary porcine BCEC (pBCEC), we demonstrate that endogenous full-length AβPP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aβ oligomers is decreased in response to 24(S)-hydroxycholesterol (24OH-C) or 27OH-C, TO901317, cholesterol, or simvastatin treatment. Oxysterols, as well as simvastatin, enhanced the secretion of non-amyloidogenic sAβPPα up to 2.5-fold. In parallel, LXR agonists reduced cholesterol biosynthesis by 30-80% while stimulating esterification (up to 2.5-fold) and efflux (up to 2.5-fold) of cellular cholesterol by modifying hydroxymethylglutaryl-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-CoA: cholesterol acyltransferase 2 (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAβPPα preferentially to the basolateral compartment. In summary endothelial cells of the BBB actively synthesize AβPP, Aβ oligomers, and secrete AβPPα in a polarized manner. AβPP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models. [ABSTRACT FROM AUTHOR]

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successlisted ful TAVR. The primary efficacy outcome was a composite of adverse events conavailable sisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1. 38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P=0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and ZO per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P= 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.). [ABSTRACT FROM AUTHOR]

The upper esophageal sphincter (UES) is composed of the cricopharyngeus (CP), thyropharyngeus (TP; inferior pharyngeal constrictor [IPC] in humans), and cranial cervical esophagus. All 3 muscles may at times function to maintain tone in the UES, but only the CP contracts and relaxes in all physiologic states consistent with the UES. The CP is a striated muscle composed of variable-sized small (25-35 microm) muscle fibers that are primarily type I (slow twitch), highly oxidative, and contain abundant (40%) endomysial elastic connective tissue. The fibers may attach to the connective tissue framework, forming a muscular net. In humans and rats, but not other animals, the CP has no median raphe. The optimum length of the CP for development of active tension is about 1.7 times resting length; therefore, in some respects the CP acts more like cardiac than striated muscle. A passive tone in the CP is present and increases through all degrees of stretch. The high compliance of the CP allows it to be opened by distraction of other muscles (e.g., geniohyoideus) or increased intraluminal pressure. The CP is innervated by branches of the vagus nerves: pharyngoesophageal (PE), superior laryngeal (SLN), and recurrent laryngeal (RLN); glossopharyngeal (GPN); and cervical sympathetics. Only the PE and SLN provide motor fibers to the CP. The GLN may be sensory; the sympathetics may innervate the mucosa, blood vessels, and glands; but no functional innervation by the RLN has been identified. Parasympathetic ganglia and various peptides (galanin, cGRP, VIP, neuropeptide Y, substance P, tyrosine hydroxylase) have been found in the CP, but their role in control of the CP is unknown. The motoneurons of the CP are found in the nucleus ambiguus, and the innervation is ipsilateral for animal species in which the CP has a median raphe. These motoneurons are topographically organized with other pharyngeal and laryngeal muscles and the striated muscle esophagus. Pharyngeal motoneurons often have a respiratory rhythm, but not a spontaneous background discharge. Therefore, the CP motoneurons may not generate CP tone. Various reflexes control the tone of the CP. Distension of the esophagus causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. Pressure on the pharyngeal mucosa contracts the CP and UES and is mediated by a glossopharyngo-vagal reflex. Inflation of the lungs causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. The pharyngo-UES and pulmonary-UES reflexes may generate the respiratory rhythm often observed on UES pressure or electromyographic activity. The UES or CP also contracts with arousal or with changes in posture. All of these reflexes and responses and the passive elastic properties of the CP may contribute to the generation of tone in the CP and UES. [ABSTRACT FROM AUTHOR]

Evolutionary theories of senescence, such as the 'disposable soma' theory, propose that natural selection trades late survival for early fecundity. 'Frailty', a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a 'parity-frailty trade-off', there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes. [ABSTRACT FROM AUTHOR]

Many have argued that the development of evidence-based policing (EBP) depends on those in law enforcement agencies receiving appropriate training in research methodologies and data analysis. Despite this, there are few detailed accounts of such training and its delivery. This paper describes and evaluates the contribution of training workshops for police officers and staff in driving forward EBP. The workshops, developed based on a model used in healthcare, sought to provide attendees with the knowledge, skills, and confidence to engage with research evidence during their work, and sat within a wider plan for organisational change within one force in England. We outline the development and delivery of the workshops, which were undertaken using an action research approach, and assess their impact including subsequent changes to practice. Finally, we consider the role these workshops played within organisational change, and reflect on how EBP can be promoted within academic-police collaborations. [ABSTRACT FROM AUTHOR]

Objectives: In children, radiography is performed to diagnose vertebral fractures and dual energy x-ray absorptiometry (DXA) to assess bone density. In adults, DXA assesses both. We aimed to establish whether DXA can replace spine radiographs in assessment of paediatric vertebral fractures.Methods: Prospectively, lateral spine radiographs and lateral spine DXA of 250 children performed on the same day were independently scored by three radiologists using the simplified algorithm-based qualitative technique and blinded to results of the other modality. Consensus radiograph read and second read of 100 random images were performed. Diagnostic accuracy, inter/intraobserver and intermodality agreements, patient/carer experience and radiation dose were assessed.Results: Average sensitivity and specificity (95 % confidence interval) in diagnosing one or more vertebral fractures requiring treatment was 70 % (58-82 %) and 97 % (94-100 %) respectively for DXA and 74 % (55-93 %) and 96 % (95-98 %) for radiographs. Fleiss' kappa for interobserver and average kappa for intraobserver reliability were 0.371 and 0.631 respectively for DXA and 0.418 and 0.621 for radiographs. Average effective dose was 41.9 μSv for DXA and 232.7 μSv for radiographs. Image quality was similar.Conclusion: Given comparable image quality and non-inferior diagnostic accuracy, lateral spine DXA should replace conventional radiographs for assessment of vertebral fractures in children.Key Points: • Vertebral fracture diagnostic accuracy of lateral spine DXA is non-inferior to radiographs. • The rate of unreadable vertebrae for DXA is lower than for radiographs. • Effective dose of DXA is significantly lower than radiographs. • Children prefer DXA to radiographs. • Given the above, DXA should replace radiographs for paediatric vertebral fracture assessment. [ABSTRACT FROM AUTHOR]

Introduction: The risk of developing distant metastasis is elevated in patients (pts) who experience isolated locoregional recurrences (ILRR) after initial breast cancer treatment. Surgical resection of ILRR, radiation therapy (RT), and adjuvant hormonal therapy are common practice strategies. However, the role of chemotherapy (C) is unknown. Pts with complete excision of an ILRR were randomly assigned to C or no C. We report treatments, estrogen (ER) and progesterone receptor (PR) status in primary tumors and ILRR, incidence of second-ILRR failure events, and deaths. Methods: 162 pts were enrolled in IBCSG 27-02, BIG 1-02, NSABP B-37. RT was recommended but not required if a completion/salvage mastectomy was performed after an ipsilateral breast tumor recurrence. Hormonal therapy was required for ER+ and/or PR+ tumors and anti-HER2 therapy was given at investigator discretion. Stratification criteria were hormone receptor status of recurrence, site of recurrence (breast, mastectomy scar/chest, regional lymph nodes), and use of prior C. Results: Primary surgery was breast conserving: 98 (60%) and mastectomy: 64 (40%). Types of nodal surgery for primary cancer included sentinel node resection: 20 (12%), axillary node (AN) sampling: 37 (23%), AN dissection: 88 (54%), more extensive nodal surgery: 6 (4%), and no nodal surgery: 8 (5%). The sites of first ILRR were breast: 88 (54%), mastectomy scar/chest wall: 53 (33%), and regional lymph nodes: 21 (13%), and were similarly distributed by treatment arms. Of the 98 pts who originally had a lumpectomy, 92 (94%) received RT. Among these 92, ILRR were in-breast: 83 (90%), chest wall: 1 (1 %), and regional node: 8 (9%). Salvage mastectomy was performed in 76/98 (78%) with prior lumpectomy. Of the other 22 pts, 17 had repeat lumpectomies and 5 had AN resection. Of the 64 who originally had mastectomy, 52 (81%) recurred in the scar/chest wall, 12 (19%) in the regional nodes and 15 pts (23%) received post-mastectomy RT, 4 of whom had regional nodal recurrences. Of the 143 pts who had ER status reported for the primary tumor, 21 (15%) had a different ER status reported for the ILRR (table). PR expression was discordant in 35 (26%) of the patients with known values. Average time from surgery for ILRR to surgery for second ILRR was 1.6 yrs (range: 0.08 -4.8). The average pt age for second LRR was 58.9 yrs versus 54.6 yrs for those who developed distant failures. At median follow up of 4.9 yrs, 15 pts developed a second ILRR (10 local, 5 regional), 7 (47%) of whom have died. Of the 37 (23%) pts who developed a distant failure 19 (51%) have died. Conclusions Similar to the effect observed in distant failure rates, a second ILRR following multimodality therapy for an ILRR is a strong prognostic indicator of subsequent death in this population. [ABSTRACT FROM AUTHOR]

Background: This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. Patients and methods: Post-menopausal women aged ≥l18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity. Results: The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXErelated or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported nonhematologic AEs were (overall%, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. [ABSTRACT FROM AUTHOR]

Background: The impact of levosimendan treatment on clinical outcome in patients undergoing extracorporeal membrane oxygenation (ECMO) support after cardiovascular surgery is unknown. We hypothesized that the beneficial effects of levosimendan might improve survival when adequate end-organ perfusion is ensured by concomitant ECMO therapy. We therefore studied the impact of levosimendan treatment on survival and failure of ECMO weaning in patients after cardiovascular surgery.Methods: We enrolled a total of 240 patients undergoing veno-arterial ECMO therapy after cardiovascular surgery at a university-affiliated tertiary care centre into our observational single-centre registry.Results: During a median follow-up period of 37 months (interquartile range 19-67 months), 65% of patients died. Seventy-five per cent of patients received levosimendan treatment within the first 24 h after initiation of ECMO therapy. Cox regression analysis showed an association between levosimendan treatment and successful ECMO weaning [adjusted hazard ratio (HR) 0.41; 95% confience interval (CI) 0.22-0.80; P=0.008], 30 day mortality (adjusted HR 0.52; 95% CI 0.30-0.89; P=0.016), and long-term mortality (adjusted HR 0.64; 95% CI 0.42-0.98; P=0.04).Conclusions: These data suggest an association between levosimendan treatment and improved short- and long-term survival in patients undergoing ECMO support after cardiovascular surgery. [ABSTRACT FROM AUTHOR]

Background: Identification of osteoporotic vertebral fractures allows treatment opportunity reducing future risk. There is no agreed standardised method for diagnosing paediatric vertebral fractures.Objective: To evaluate the precision of a modified adult algorithm-based qualitative (ABQ) technique, applicable to children with primary or secondary osteoporosis.Materials and Methods: Three radiologists independently assessed lateral spine radiographs of 50 children with suspected reduction in bone mineral density using a modified ABQ scoring system and following simplification to include only clinically relevant parameters, a simplified ABQ score. A final consensus of all observers using simplified ABQ was performed as a reference standard for fracture characterisation. Kappa was calculated for interobserver agreement of the components of both scoring systems and intraobserver agreement of simplified ABQ based on a second read of 29 randomly selected images.Results: Interobserver Kappa for modified ABQ scoring for fracture detection, severity and shape ranged from 0.34 to 0.49 Kappa for abnormal endplate and position assessment was 0.27 to 0.38. Inter- and intraobserver Kappa for simplified ABQ scoring for fracture detection and grade ranged from 0.37 to 0.46 and 0.45 to 0.56, respectively. Inter- and intraobserver Kappa for affected endplate ranged from 0.31 to 0.41 and 0.45 to 0.51, respectively. Subjectively, observers' felt simplified ABQ was easier and less time-consuming.Conclusion: Observer reliability of modified and simplified ABQ was similar, with slight to moderate agreement for fracture detection and grade/severity. Due to subjective preference for simplified ABQ, we suggest its use as a semi-objective measure of diagnosing paediatric vertebral fractures. [ABSTRACT FROM AUTHOR]

Background We recently reported an increase in N-methyl- d-aspartate ( NMDA) receptor subunit expression and CaMKII-dependent phosphorylation of NR2B in the rostral cingulate cortical ( rCC) neurons following esophageal acid exposure in rats. As α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ( AMPA) receptors mediate the fast excitatory transmission and play a critical role in synaptic plasticity, in this study, we investigated the effect of esophageal acid exposure in rats on the expression of AMPA receptor subunits and the involvement of these molecular alterations in acid-induced sensitization of neurons in the anterior cingulate ( ACC) and midcingulate ( MCC) cortices. Methods In molecular study, we examined GluA1 and GluA2 expression and phosphorylation in membrane preparations and in the isolated postsynaptic densities ( PSDs) from rats receiving acute esophageal exposure of either saline (control group) or 0.1 N HCl (experimental group). In electrophysiological study, the effect of selective AMPA receptor ( Ca2+ permeable) antagonist IEM-1460 and CaMKII inhibitor KN-93 was tested on responses of cortical neurons during acid infusion to address the underlying molecular mechanism of acid-induced sensitization. Key Results The acid exposure significantly increased expression of GluA1, pGluA1Ser831, and phosphorylated CaMKIIThr286, in the cortical membrane preparations. In isolated PSDs, a significant increase in pGluA1Ser831 was observed in acid-treated rats compared with controls. Microinjection of IEM-1460 or KN-93 near the recording site significantly attenuated acid-induced sensitization of cortical neurons. Conclusions & Inferences The underlying mechanism of acid-induced cortical sensitization involves upregulation and CaMKII-mediated phosphorylation of GluA1. These molecular changes of AMPA receptors subunit GluA1 in the cortical neurons might play an important role in acid-induced esophageal hypersensitivity. [ABSTRACT FROM AUTHOR]

Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009). Synergistic activity was also observed in vitro when combined with tamoxifen. After determination of the recommended phase 2 dose in combination with letrozole (letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1), a randomized phase 2 study comparing letrozole alone (L) to letrozole plus PD 0332991 (L+P) was initiated. Methods: The phase 2 portion of the study was designed as a two-part study; Part 1 enrolled post- menopausal women with ER+/HER2-- advanced BC; Part 2 in addition to ER+/HER2-- as eligibility criteria, screened for CCND1 amplification and/or loss of p16 by FISH. The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2-- advanced BC were randomized 1:1 to receive letrozole either with or without PD 0332991. Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months. Results: 66 pts were randomized in Part 1 and 99 pts in Part 2. Preliminary results from Part 1 of this study have been previously reported (IMPAKT Breast Cancer Conference, Abstract #292, Finn et al. May 2012) demonstrating a significant improvement in median PFS in the L+P vs. L arm (HR = 0.35; 95% CI, 0.17 to 0.72; p = 0.006). With the additional 99 pts randomized in Part 2 (N = 165), the statistically significant improvement in median PFS (26.2 vs. 7.5 months, respectively) continues to be observed with a HR=0.32 (95% CI, 0.19 to 0.56) with p <0.001. The response rate for the L+P arm (n = 84) was 31% vs. 26% for the L arm (n = 81) and the clinical benefit rate was 68% vs. 44%, respectively. The most commonly reported treatment-related AEs in the combination arm were neutropenia, leukopenia, anemia, and fatigue. The updated results from the combined Part 1 and Part 2 group will be presented in December 2012. Conclusions: The combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ BC to PD 0332991 observed in preclinical models. A phase 3 trial in this setting will commence in 2013. [ABSTRACT FROM AUTHOR]

Highlights: [•] Mine drainage decontaminates itself within the historic copper habitat Schwarzwand. [•] Metals are retained by a biofiom dominated by Phormidium and Pohlia. [•] This process offers new possibilities for the remediation of contaminated waters. [Copyright &y& Elsevier]

To assess the bacterial killing rate produced by a combination of cefalexin and kanamycin at two different concentration ratios. Time-kill kinetics of cefalexin and kanamycin, individually and in combination, were determined against one strain each of Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis. The combination was tested using two fixed ratios (cefalexin : kanamycin ratios of 1·25 : 1 and 1 : 2·3) and two concentrations of each ratio. Time-kill curves produced with either ratio were quite similar. Against most bacterial species, higher concentrations produced faster kill. In all cases, the combination of cefalexin and kanamycin showed faster and greater kill at lower antibiotic concentrations than those observed with either drug alone. The combination of cefalexin and kanamycin results in a fast initial killing of major mastitis pathogens at both concentration ratios. The combination of cefalexin and kanamycin achieved rapid bacterial kill at concentrations and ratios that can be achieved in vivo following intramammary infusion of a mastitis treatment. [ABSTRACT FROM AUTHOR]

The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re-exposure to the same antigen, they are rapidly re-stimulated to proliferate and differentiate into antibody-secreting plasma cells (ASC) that secrete high-affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII-specific memory B cells from becoming re-stimulated. We established a 6-day in vitro culture system that enabled us to study the regulation of FVIII-specific murine memory-B-cell re-stimulation. We tested the impact of the blockade of co-stimulatory interactions, of different concentrations of FVIII and of ligands for toll-like receptors (TLR). The blockade of B7-CD28 and CD40-CD40 ligand interactions prevented FVIII-specific murine memory B cells from becoming re-stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re-stimulation of FVIII-specific murine memory B cells. Triggering of TLR7 amplified re-stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re-stimulation of FVIII-specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (3): 233–241 Background Current data appear in favour of thrombectomy for ST-elevation myocardial infarction (STEMI). However, information on long-term outcome after thrombectomy is limited. We performed a retrospective long-term study to assess the risk of cardiac re-hospitalizations and survival after discharge from the index hospitalization for STEMI. Methods Patients originally randomized to percutaneous coronary intervention (PCI) with thrombectomy vs. standard PCI were included in a retrospective long-term observational study. The primary study endpoint was the combined risk for all-cause death or cardiac re-hospitalization after index discharge under optimal medical therapy. The cumulative number of cardiac hospitalization days and ventricular remodelling assessed by echocardiography and plasma biomarkers were secondary endpoints. Results Of 94 STEMI patients who had been randomized between 11/2000 and 03/2003, 89 patients consented to long-term follow-up. A total of 43 patients had been allocated to thrombectomy and 46 to standard primary PCI. The minimum follow-up time was 1115 days. There was a significantly lower risk for death or cardiac re-hospitalization for patients of the thrombectomy group (hazard ratio = 0·69, 95% CI: 0·49–0·98, P = 0·036). The incidence of recurrent myocardial infarction was not different ( P = 0·343). No differences in cardiac remodelling were detected by echocardiography, with the exception that heart-type fatty acid binding protein at 53·2 ± 17 months was lower in the thrombectomy group ( P = 0·045). Conclusion Thrombectomy in STEMI may decrease the long-term risk for death or cardiac re-hospitalization. [ABSTRACT FROM AUTHOR]

Background Device implantation in chronic heart failure (CHF) for cardiac resynchronization therapy (CRT) with or without implantable cardioverter/defibrillator (ICD) is an established treatment option for symptomatic patients under medical baseline therapy. Although recommended, the need for optimization of medical therapy was never proven. As in ‘the real world’, medical therapy is not always up-titrated to the desirable dosages; this provides the opportunity to evaluate the impact of optimizing medical therapy in patients who had received a device therapy with proven effectiveness. Materials and methods This observational cohort study retrospectively assessed the ‘real life’-effect of CRT compared with that of CRT/ICD therapy and the impact of concomitant pharmacotherapy on outcome. Outcome of patients with guideline recommended renin–angiotensin system inhibitor and ß-blocker dosages was compared with that of patients who failed to reach the desired dosages. Mean follow-up for the 205 CHF (95 CRT and 110 CRT/ICD) patients was 16·8 ± 12·4 months. Results In the total study cohort, 83 (41%) reached the combined primary endpoint of all-cause death or cardiac hospitalization [CRT group: 25 (26%), CRT/ICD group: 58 (52·7%), P < 0·001]. Multiple cox regression analysis revealed non-optimized medical therapy at follow-up [HR = 2·080 (1·166–3·710), P = 0·013] and CRT/ICD vs. CRT [HR = 2·504 (1·550–4·045), P < 0·001] as significant predictors of the primary endpoint. Conclusion Our data stress the importance of professional monitoring and titration of pharmacotherapy not only in medically treated CHF patients but also in patients under device therapy by a heart failure unit or a specialized cardiologist. [ABSTRACT FROM AUTHOR]