Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).
Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. We present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. Self-reported occupations were coded using the Standard Occupational Classification (1991) system. Analyses were restricted to employed persons aged 25-74 years at baseline (N = 2,051,315), with follow-up until December 31, 2010. Hazard ratios (HR) and 95% confidence intervals (CI) were modeled using Cox proportional hazards for all workers in agricultural occupations (n = 70,570; 70.8% male), stratified by sex, and adjusted for age at cohort entry, province of residence, and highest level of education. A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.


How to assess and manage cardiovascular risk associated with lipid alterations beyond LDL.
The maintenance of clinically recommended levels of low-density lipoprotein cholesterol (LDL-C) through a statin therapy is a gold standard in the management of patients with dyslipidaemia and cardiovascular disease (CVD). However, even when LDL-C levels are at or below clinically recommended target levels, residual cardiovascular (CV) risk still remains. Therefore, assessing lipoproteins beyond LDL-C in managing CV risk is imperative. A working group of clinical experts have assessed the role of lipoproteins other than LDL-C in identifying the CV risk in patients with dyslipidaemia and CVD and in the management of atherogenic dyslipidaemia associated with a number of other diseases. The recommendations, in line with the European guidelines, are presented. A thorough evaluation of clinical data by the expert working group resulted in recommendations to consider non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), remnant cholesterol and lipoprotein(a) (Lp[a]) as biomarkers of residual CV risk in patients with CVD. Elevated Lp(a) levels were also suggested to be a causal factor. The experts highlighted the significance of non-HDL-C and triglycerides (TG) in atherogenic dyslipidaemia associated with type 2 diabetes, metabolic syndrome, chronic kidney disease (CKD) and familial combined hyperlipidaemia (FCH). The working group recommended combinatorial therapeutic approaches in high-risk patients, including agents impacting on TG and HDL-C levels. Evaluation of a lipoprotein landscape when LDL-C levels remain low strongly supports the role of non-HDL-C, Lp(a) and TGs in identifying patients with increased residual risk of CV and in selecting their treatment strategy.


Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats.
Acute administration of gamma-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA(B) receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA(B) receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA(B) receptor-positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA(B) receptor agonist (3-amino-2[S]-hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotine- and food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine-induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine self-administration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine self-administration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine- but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA(B) receptor-positive modulators, similarly to GABA(B) receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA(B) receptor agonists. Thus, GABA(B) receptor-positive modulators may be useful antismoking medications.


Isolation and characterization of complement receptor type 1 (CR1) storage vesicles from human neutrophils using antibodies to the cytoplasmic tail of CR1.
Neutrophil (PMN) activation is associated with increased surface expression of several membrane proteins that are translocated from intracellular pools. Indirect evidence suggests that the intracellular storage pools of complement receptor type 1 (CR1) in resting PMN are distinct from traditional granules and may be the secretory vesicles in which albumin is also stored, but it is not known if this compartment is homogeneous or heterogeneous. To isolate and characterize the CR1-containing vesicles, we used antibodies against unique sequences in the cytoplasmic tail of CR1. Affinity-purified IgG was used to adsorb CR1 storage vesicles from the light membrane fraction (gamma-band) of nitrogen cavitates of resting PMN. The immunoadsorbent could quantitatively remove the CR1-containing vesicles, whereas control adsorbents with nonimmune IgG showed no specific binding of CR1. Immunoblots of specifically isolated vesicles also showed enrichment of albumin, decay-accelerating factor, Fc gammaRIII, and CR3; whereas HLA class I was not detectable in these vesicles. Enzyme assay of specifically isolated vesicles after treatment with Triton X-100 showed that these vesicles contained most of the cells' latent alkaline phosphatase. An additional population of vesicles containing albumin, but not CR1, and that did not bind to anti-CR1 adsorbent was also identified. Immunoelectron microscopy showed that the specifically isolated vesicles had mean diameters of 0.086 to 0.1 microm and stained positive for CR1 and albumin. These results indicate that CR1 storage vesicles can be isolated with antibodies against the cytoplasmic tail of CR1 and show that these vesicles also contain albumin as well as glycosylphosphatidyl inositol-anchored proteins. These results are most compatible with the hypothesis that CR1-containing vesicles have arisen by endocytic retrieval of proteins that had been on the plasma membrane.


How does surfactant really work?
Although administration of exogenous surfactant to the neonate with RDS often relieves hypoxia rapidly, it is events occurring some 18-48 h later that determine the ultimate clinical outcome, indicating a vital second stage to 'rescue'. It is proposed that, whereas a reduction in surface tension facilitates the initial penetration of the lungs by air, the second stage is provided by surface-active phospholipid (SAPL) slowly adsorbing (binding) to alveolar epithelium to displace water in the same way that surfactants are widely used industrially as 'de-watering' agents. In the normal newborn, this de-watering lining of SAPL is already in place, explaining the extremely rapid expulsion of fluid from the lungs at birth. The selection or formulation of a surfactant for rescue should thus take both stages into consideration.


Endoscopic polypectomy of a symptomatic antral polyp.
After the introduction of fiberoptic endoscopy and its fully accepted use as an instrument of great diagnostic ability, we are now in an era where the same instrument is providing us with a route for a mode of therapy. Colonic polypectomies are now being performed by a majority of the endoscopists. There have only been three instances reported in the literature, however, where the polypectomies have been performed for the removal of symptomatic polyps in the stomach and duodenum. This communication describes the removal of such a pedunculated distal antral polyp which not only caused intermittent pyloric obstruction but also a moderately severe iron deficiency anemia in an 82-year old female. The benign procedure of endoscopic polypectomy, which took only 25 minutes to perform, was a means of total cure for this patient. To the best of our knowledge, this case represents the second reported one from this country of the endoscopic polypectomy of a symptomatic benign gastric polyp.


A new method for evaluating the rock mass damage index based on the field point load strength.
The damage index is a crucial controlling parameter for rock mass strength and deformation in civil, geological and mining engineering projects. In this study, a new method was proposed for computing the damage index of a rock mass based on the field point load strength. This method provides a strength ratio whose numerator is the point load strength (PLS) of splitting along the pre-existing joint and whose denominator is the PLS of intact rock failure. To validate this method, the authors derived a relationship between the damage index and the integrality coefficient using an empirical relation. Moreover, numerous experimental tests were conducted, including P-wave testing and on-site point load testing. Finally, linear regression analysis was performed to analyse the correlation between the new damage index D R and the integrality coefficient K V . This study demonstrates that the presented new method is sensitive to both plasticity and damage in estimating the damage degree of rock masses in underground excavation and tunnel engineering.


Two-Stage Structural and Slowing-Down Percolation Transitions in the Densifying Cancer Cell Monolayer.
We experimentally demonstrate the two-stage structural and slowing-down percolating transitions, followed by the confluent transition in the densifying cancer cell monolayers from the dilute state, and investigate their impacts on collective cell dynamics. It is found that cells aggregate into clusters at low cell density. With increasing cell number density, the structural percolation through the formation of a large cell cluster percolating through the space precedes the dynamical percolation transition of forming a percolating cluster of slow cell elements. Both percolating transitions exhibit scale-free scaling behaviors of cluster size distributions and fractal structures, similar to those of the universality class of 2D nonequilibrium systems governed by percolation theory. Dynamically, at low cell density, cell aggregation enhances cooperative motion. The structural percolation leads to slower motion, especially with stronger suppression for the high-frequency modes in the turbulent-like velocity power spectra. The following slowing-down percolation associated with the onset of cell crowding in regions occupied by cells further enhances dynamical slowing-down, and suppresses the increasing trend of dynamical heterogeneity and the steepening of the power spectrum of motion, until their reversions after the confluent transition.


Whole body structural vascular adaptation to prolonged hypoxia in chick embryos.
We studied the role of hypoxia in the development of the blood vascular system using functional measurements of whole body and hindlimb structural vascular resistance in the chick embryo. The method is based on a newly developed whole body perfusion technique in which the maximally dilated blood vasculature of 14- to 15-day chick embryos is perfused through the extraembryonic blood vessels. Embryos were grown in 12% oxygen (Po2 65 mmHg, n = 18) or 16% oxygen (Po2 96 mmHg, n = 19) for the last 7 days of incubation and were compared with weight-matched (n = 17) and age-matched (n = 18) normoxic control groups (Po2 134 mmHg). Pressure-flow curves were generated for all embryos by increasing and decreasing the aortic pressure along 1-mmHg steps over a pressure range of 0-6 mmHg. Venous pressure was held at 0 mmHg by allowing the perfusate to flow freely from severed extraembryonic veins. The hydraulic resistance of the maximally dilated vascular bed, called the "structural vascular resistance," was decreased in a dose-related manner in the hypoxic groups to greater than 50% of control in the whole body and hindlimbs of the 12% oxygen group. The vessels of the 12% oxygen group were able to carry two and three times as much flow to the whole body and hindlimb tissues, respectively, as compared with the weight-matched normoxic control group. Therefore, the results support the hypothesis that prolonged exposure to hypoxia causes the blood vascular system to adapt its structure to allow greater amounts of blood to flow to the tissues at any given perfusion pressure gradient.


Regulation of tissue inhibitor of metalloproteinase-1 in fibroblasts and acute phase proteins in hepatocytes in vitro by mouse oncostatin M, cardiotrophin-1, and IL-6.
Mouse oncostatin M (mOSM) has been recently cloned; however, its full spectrum of biologic functions has not been defined. To assess its potential role in inflammation, we have tested the activity of mOSM in vitro in regulation of fibroblasts and hepatic cells. At concentrations of 10 and 20 ng/ml, mOSM stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in NIH-3T3 mouse embryonic fibroblasts, rat lung fibroblasts, and rat synovial fibroblasts, whereas mouse cardiotrophin-1 (mCT-1) or human OSM (hOSM) did not. Similarly, only mOSM was able to induce transcription of chloramphenicol acetyl-transferase (CAT) in NIH-3T3 cells transfected with a minimal TIMP-1 promoter/CAT construct. Mouse OSM had strong action inducing primary rat hepatocyte cultures to produce acute phase proteins; however, mOSM was very weak in its ability to stimulate acute phase protein synthesis in rat H35 cells or human HepG2 cells, which was consistent with weak STAT activation in H35 cells and HepG2 cells. Binding studies showed that NIH-3T3 cells possessed high affinity binding sites for mOSM, but rat H35 cells did not. On the other hand, mCT-1 and mouse IL-6 induced strong STAT activation as well as marked increases in acute phase protein production by H35 cells. These results indicate that mOSM does not share a functional receptor with mCT-1 or hOSM in mouse and rat cells and that hOSM does not activate the putatively specific OSM receptor on mouse or rat cells. These results also suggest that mOSM is an important cytokine in inflammation, through modulation of fibroblast function as well as hepatocyte responses.


Prevalence of respiratory symptoms and diseases associated with gastroesophageal reflux disease.
Investigation of the prevalence of respiratory symptoms and diseases associated with gastroesophageal reflux disease (GERD). 299 subjects with GERD were submitted to upper gastrointestinal endoscopy and 24-hour esophageal pH monitoring and a symptom analysis. Chronic respiratory symptoms or diseases were present in 18% (56/299). Chronic cough was observed in 42/56 patients, while typical reflux symptoms such as heartburn and acid regurgitation were observed in 30/56 and 24/56 cases, respectively. The prevalence of airway diseases was chronic bronchitis 12/56, asthma 10/56, recurrent pneumonia 10/56, chronic sinusitis 7/56 and chronic laryngitis 1/56. In patients with respiratory complications pathologic acid reflux was established in 29/51 cases on the basis of the DeMeester score, while 17/51 had pathologic postprandial, nocturnal or diurnal reflux events. Upper gastrointestinal endoscopy revealed a normal esophageal mucosa in 6/56, Savary-Miller stage I esophagitis in 23/56, stage II in 15/56, stage III in 5/56 and stage IV in 6/56 patients. These investigations have demonstrated an abnormal 24-hour pH score in about half of the patients with GERD-associated respiratory complications, and indicated that short reflux events are characteristic of the reflux activity in one third of this population.


Couple-based interventions for psychopathology: a renewed direction for the field.
This article provides a rationale and empirical support for providing couple-based interventions when one partner in a relationship is experiencing individual psychopathology. Several investigations indicate that relationship distress and psychopathology are associated and reciprocally influence each other, such that the existence of relationship distress predicts the development of subsequent psychopathology and vice versa. Furthermore, findings indicate that for several disorders, individual psychotherapy is less effective if the client is in a distressed relationship. Finally, even within happy relationships, partners often inadvertently behave in ways that maintain or exacerbate symptoms for the other individual. Thus, within both satisfied and distressed relationships, including the partner in a couple-based intervention provides an opportunity to use the partner and the relationship as a resource rather than a stressor for an individual experiencing some form of psychological distress. The authors propose that a promising approach to including the partner in treatment involves (a) integrating intervention principles from empirically supported interventions for individual therapy for specific disorders with (b) knowledge of how to employ relationships to promote individual and dyadic change. Based on this logic, the article includes several examples to demonstrate how couple-based interventions can be focused on a specific type of psychopathology, including encouraging empirical findings for these interventions. The article concludes with recommendations for how clinicians and researchers can adapt their knowledge of couple therapy to assist couples in which one partner is experiencing notable psychological distress or diagnosable psychopathology.


Interspecies scaling of excretory amounts using allometry - retrospective analysis with rifapentine, aztreonam, carumonam, pefloxacin, miloxacin, trovafloxacin, doripenem, imipenem, cefozopran, ceftazidime, linezolid for urinary excretion and rifapentine, cabotegravir, and dolutegravir for fecal excretion.
1. Interspecies allometry scaling for prediction of human excretory amounts in urine or feces was performed for numerous antibacterials. Antibacterials used for urinary scaling were: rifapentine, pefloxacin, trovafloxacin (Gr1/low; <10%); miloxacin, linezolid, PNU-142300 (Gr2/medium; 10-40%); aztreonam, carumonam, cefozopran, doripenem, imipenem, and ceftazidime (Gr3/high; >50%). Rifapentine, cabotegravir, and dolutegravir was used for fecal scaling (high; >50%). 2. The employment of allometry equation: Y = aW(b) enabled scaling of urine/fecal amounts from animal species. Corresponding predicted amounts were converted into % recovery by considering the respective human dose. Comparison of predicted/observed values enabled fold difference and error calculations (mean absolute error [MAE] and root mean square error [RMSE]). Comparisons were made for urinary/fecal data; and qualitative assessment was made amongst Gr1/Gr2/Gr3 for urine. 3. Average correlation coefficient for the allometry scaling was >0.995. Excretory amount predictions were largely within 0.75- to 1.5-fold differences. Average MAE and RMSE were within ±22% and 23%, respectively. Although robust predictions were achieved for higher urinary/fecal excretion (>50%), interspecies scaling was applicable for low/medium excretory drugs. 4. Based on the data, interspecies scaling of urine or fecal excretory amounts may be potentially used as a tool to understand the significance of either urinary or fecal routes of elimination in humans in early development.


Echocardiographic detection of left main coronary artery obstruction.
Advances in two-dimensional echocardiography have improved the prospects of using this technique to detect left main coronary artery (LMCA) obstruction. Using an echocardiograph that had digital gray scale, a 3-MHz transducer and strobe freeze-frame capability and reviewing recordings on an off-line videotape-videodisc analyzer, we retrospectively examined the LMCA in 72 patients who underwent coronary cineangiography. Angiography showed 50% or greater LMCA obstruction in seven patients. All seven had high-intensity echoes in the walls of the LMCA. The high-intensity echoes were irregularly located in the artery and partially occluded it. The LMCA could frequently be recorded proximal and distal to the obstruction. A blinded observer reviewed 28 randomly selected patients from this group and correctly identified the four patients with LMCA obstruction. There was one true and two questionable false-positive diagnoses. In a prospective study of 31 patients, two independent observers correctly identified the three patients with LMCA obstruction. There were no false negatives, and one observer had one false positive. All of the false positives were in patients with proximal left anterior descending coronary artery obstructions. Echocardiography may be a practical means of identifying patients with the LMCA obstruction.


Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer.
Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. Eighteen patients were treated with escalating doses of CTL102 (range, 10(8)-5 x 10(11) virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 x 10(11) virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.


Volatile Constituents and Biological Properties of Essential Oils from Aerial Parts of Gentiana gelida BIEB.
This work reports the chemical composition, antimicrobial and antioxidant activities of essential oils from the aerial parts of Gentiana gelida BIEB. for the first time in literature. The oils from the aerial parts (flower, leaf and stem) were obtained by Clevenger-type apparatus and characterized by GC-FID and GC-MS. While tricosane (21.67%) was the main component of flower oil, hexadecanoic acid was the most abundant component of leaf and stem oils in ratios 26.46% and 31.89%, respectively. Additionally, all essential oils of G. gelida were investigated for their antimicrobial activity against eight Gram negative bacteria, four Gram positive bacteria and five fungi, using agar dilution method and antioxidant activities by using 2,2-diphenyl-1-picrylhydrazyl radical scavenging and Folin-Ciocalteu assays. The flower oil of G. gelida showed stronger antimicrobial and antioxidant activities than those of stem and leaf. The amount of total phenolic content and scavenging activity of the flower oil were found 525.35±8.24 mg GAE/L and 49.30±1.25%, respectively.


Characteristics of youth who report early sexual experiences in Sweden.
Early timing of first sex is a common risk factor for adverse sexual and reproductive health (SRH) outcomes. This study explored characteristics and circumstances associated with early sexual experience (at or below age 14) among Swedish youth. Data were drawn from UngKAB09, a national study of youth SRH in Sweden. 24,000 youth 16-28 years were randomly selected for a web-based survey with a response rate of 24%. Post-stratification weights were used to correct for over- and underrepresentation in response. Adjusted logistic regression was used to model associations with early sexual experience, by gender. In the final sample (N = 5,321, 49% girls), 9 in 10 were sexually experienced, of whom 21% reported early first sex. In multivariate analysis, early sex was significantly associated with 7 of the 9 predictor variables selected for the model among boys and 14 of 15 selected factors among girls. Early sex was positively associated with low educational attainment, early pubertal onset, bisexual identity and (girls only) rural residence. For girls, first generation immigrant status, greater religiosity, conservative sexual attitudes and low Chlamydia knowledge decreased the odds of early sex. Early experience was more common if youth had older partners and, among girls, felt that sex was expected. Being in love, feelings of intimacy, alcohol use at first sex, and (girls only) causal sexual partner and wantedness of first sex were inversely associated with early first sex. The findings and implications are discussed in relation to the European and global literature on early sexual experiences.


Smartphone-controlled optogenetically engineered cells enable semiautomatic glucose homeostasis in diabetic mice.
With the increasingly dominant role of smartphones in our lives, mobile health care systems integrating advanced point-of-care technologies to manage chronic diseases are gaining attention. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. A custom-designed home server SmartController was programmed to process wireless signals, enabling a smartphone to regulate hormone production by optically engineered cells implanted in diabetic mice via a far-red light (FRL)-responsive optogenetic interface. To develop this wireless controller network, we designed and implanted hydrogel capsules carrying both engineered cells and wirelessly powered FRL LEDs (light-emitting diodes). In vivo production of a short variant of human glucagon-like peptide 1 (shGLP-1) or mouse insulin by the engineered cells in the hydrogel could be remotely controlled by smartphone programs or a custom-engineered Bluetooth-active glucometer in a semiautomatic, glucose-dependent manner. By combining electronic device-generated digital signals with optogenetically engineered cells, this study provides a step toward translating cell-based therapies into the clinic.


Bidirectional effect of CD200 on breast cancer development and metastasis, with ultimate outcome determined by tumor aggressiveness and a cancer-induced inflammatory response.
CD200 acts through its receptor (CD200R) to inhibit excessive inflammation. The role of CD200-CD200R1 interaction in tumor immunity is poorly understood. In this study, we examined the role of CD200-CD200R1 interaction in the progression and metastasis of highly aggressive 4THM murine-breast carcinoma using CD200 transgenic (CD200(tg)) and CD200R1 knock-out (CD200R1(-)(/-)) BALB/c mice. 4THM cells induce extensive visceral metastasis and neutrophil infiltration in affected tissues. CD200 overexpression in the host was associated with decreased primary tumor growth and metastasis, whereas lack of CD200R1 expression by host cells was associated with enhanced visceral metastasis. Absence of CD200R1 expression led to decreased tumor-infiltrating-cytotoxic T cells and increased the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. In contrast, CD200 overexpression led to increased tumor-induced interferon-γ and IL-10 response and decreased TNF-α and IL-6 release. Neutrophil infiltration of tissues was markedly decreased in CD200(tg) animals and increased in CD200R1(-/-) mice. These findings are contradictory to what has been reported in the EMT6 mouse breast-cancer model. Other distinguishing features of tumor elicited by EMT6 and 4THM cell injections were also examined. Visceral tissues from mice bearing EMT6 tumors showed a lack of neutrophil infiltration and decreased IL-6 release in CD200R1(-/-) mice. EMT6 and 4THM cells also differed in vimentin expression and in vitro migration rate, which was markedly lower in EMT6 tumors. These results support the hypothesis that CD200 expression can alter immune responses, and can inhibit metastatic growth of tumor cells that induce systemic and local inflammatory response. Increasing CD200 activity/signaling might be an important therapeutic strategy for treatment of aggressive breast carcinomas.


The (AAT)n repeat of the cannabinoid CB1 receptor gene influences disease progression in relapsing multiple sclerosis.
Genetic and pharmacological inactivation of cannabinoid CB(1) receptors (CB(1)Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB(1)Rs might play a role in the neurodegenerative damage associated with multiple sclerosis (MS). To see whether CNR1 gene polymorphism could influence disease progression in relapsing-remitting MS. The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression. MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥ 2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤-0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity. The results of the present investigation point to CB(1)R as an important modulator of disease severity in relapsing MS subjects.


17beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease.
Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17beta-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease. We studied 20 women; 14 received estrogen (mean age 65+/-2 years) and 6 served as ethanol control subjects (age 63+/-3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17beta-estradiol or 0.2 microL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO(2)/NO(3)) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12+/-0.18 versus 0.86+/-0.17 pmol/L baseline2 versus estradiol, P:=0.05). Endothelin-1 levels to SP decreased after 17beta-estradiol (1.29+/-0. 18 versus 1.04+/-0.15 and 1.3+/-0.16 versus 0.99+/-0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both P:<0.05). NO(2)/NO(3) levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol. Short-term intracoronary 17beta-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.


The complete nucleotide sequence of bacteriophage HP1 DNA.
The complete nucleotide sequence of the temperate phage HP1 of Haemophilus influenzae was determined. The phage contains a linear, double-stranded genome of 32 355 nt with cohesive termini. Statistical methods were used to identify 41 probable protein coding segments organized into five plausible transcriptional units. Regions encoding proteins involved in recombination, replication, transcriptional control, host cell lysis and phage production were identified. The sizes of proteins in the mature HP1 particle were determined to assist in identifying genes for structural proteins. Similarities between HP1 coding sequences and those in databases, as well as similar gene organizations and control mechanisms, suggest that HP1 is a member of the P2-like phage family, with strong similarities to coliphages P2 and 186 and some similarity to the retronphage Ec67.


Sedation and Afternoon Placement of the 48-Hour Wireless Ambulatory pH Capsule Results in More Reflux on the First Day.
A 48-hour wireless capsule results often vary from the first to second day. Previous investigations comparing discrepant acid reflux readings have yielded variable results. In this study we investigated differences in data obtained on day 1 versus day 2, and the effect of time of capsule placement on discrepancies. We performed a retrospective cohort study. Patients undergoing a 48-hour wireless capsule study between January 2012 through November 2013 were eligible for inclusion. We collected reflux data for each patient and calculated the proportion of patients in four groups based on abnormal DeMeester score groups (+/+, -/+, +/-, -/-). We placed patients into morning placement or afternoon placement categories and calculated the proportions of patients with various DeMeester score discrepancies. This study evaluated 229 patients. The mean day 1 DeMeester score was 28.38 and the mean day 2 DeMeester score was 23.24 (P<0.0001). The mean day 1 DeMeester score in the morning group was 24.9 and 31.7 in the afternoon group (P<0.05). The mean total DeMeester score in the morning placement group was 23.1 and 30.6 in the afternoon group (P<0.05). Twenty-five percent of afternoon patients had a +day 1/-day 2 DeMeester discordance, whereas only 12% of morning placement patients had this discordance (P=0.26). Afternoon capsule placement is associated with a significantly increased amount of acid reflux on day 1. Approximately 10% of 48-hour esophageal wireless monitoring studies may falsely overestimate reflux when the capsule is placed in the afternoon. Capsule placement should ideally be performed in the morning.


Synaptic plasticity, metaplasticity and memory effects in hybrid organic-inorganic bismuth-based materials.
Since the discovery of memristors, their application in computing systems utilizing multivalued logic and a neuromimetic approach is of great interest. A thin film device made of methylammonium bismuth iodide exhibits a wide variety of neuromorphic effects simultaneously, and is thus able to mimic synaptic behaviour and learning phenomena. Standard learning protocols, such as spike-timing dependent plasticity and spike-rate dependent plasticity might be further modulated via metaplasticity in order to amplify or alter changes in the synaptic weight. Moreover, transfer of information from short-term to long-term memory is observed. These effects show that the diversity of functions of memristive devices can be strongly affected by the pre-treatment of the sample. Modulation of the resistive switching amplitude is of great importance for the application of memristive elements in computational applications, as additional sub-states might be utilized in multi-valued logic systems and metaplasticity and memory consolidation will contribute to the development of more efficient bioinspired computational schemes.


Chymotryptic digestion of Tetrahymena ciliary dynein. II. Pathway of the degradation of 22S dynein heavy chains.
As shown in the preceding paper (Toyoshima, Y. Y., 1987, J. Cell Biol., 105:887-895) three-headed Tetrahymena 22S dynein consists of three heavy chains (HCs) and is decomposed into two-headed (H) and one-headed (L) fragments by chymotryptic digestion. To accurately determine the presence of multiple ATPases and ultimately the location of various domains, it is necessary to determine the identity of each HC fragment relative to the original HCs in 22S dynein. The degradation pathway of each HC was determined by peptide mapping and immunoblotting. The three HCs (A alpha, A beta, and A gamma) were immunologically different; although SDS-urea gel electrophoresis showed that A gamma HC was apparently resistant to the digestion, actually three distinct HCs contributed to the same band alternately. H fragment was derived from A beta and A gamma HCs, whereas L fragment originated from A alpha HC. Since both fragments were associated with ATPase activity, these results directly demonstrate the presence of multiple ATPase sites in Tetrahymena 22S dynein.


Dynein light chain LC8 promotes assembly of the coiled-coil domain of swallow protein.
LC8 is a highly conserved light-chain subunit of cytoplasmic dynein that is thought to play a fundamental role in both the assembly of the motor complex and the recruitment of cargo. An interaction between LC8 and the Drosophila protein swallow has been previously characterized and supports a role for dynein in the localization of maternal morphogens during oogenesis. Swallow is required for the proper localization of bicoid mRNA, the anterior determinant that plays a critical role in establishment of the Drosophila embryonic axis. In this work, we prepared constructs of swallow, each containing a predicted coiled-coil domain and variable surrounding segments that lie within the domain proposed to interact with LC8. The interaction between LC8 and swallow domains was characterized by glutathione S-transferase (GST) pull-down assays, limited proteolysis followed by mass spectrometry, and circular dichroic spectroscopy. Hydrodynamic measurements, covalent cross-linking, and circular dichroic spectroscopy show that this domain of swallow is an unstable dimeric coiled-coil. Upon LC8 binding, however, the coiled-coil becomes significantly more stable. A possible general role for LC8 in macromolecular assembly is discussed.


Early Left-Planum Temporale Asymmetry in newborn monkeys (Papio anubis): A longitudinal structural MRI study at two stages of development.
The "language-ready" brain theory suggests that the infant brain is pre-wired for language acquisition prior to language exposure. As a potential brain marker of such a language readiness, a leftward structural brain asymmetry was found in human infants for the Planum Temporale (PT), which overlaps with Wernicke's area. In the present longitudinal in vivo MRI study conducted in 35 newborn monkeys (Papio anubis), we found a similar leftward PT surface asymmetry. Follow-up rescanning sessions on 29 juvenile baboons at 7-10 months showed that such an asymmetry increases across the two ages classes. These original findings in non-linguistic primate infants strongly question the idea that the early PT asymmetry constitutes a human infant-specific marker for language development. Such a shared early perisylvian organization provides additional support that PT asymmetry might be related to a lateralized system inherited from our last common ancestor with Old-World monkeys at least 25-35 million years ago.


[Hygienic and medicosocial problems in the training of pupils at vocational colleges].
The authors studied the specific features of adaptation in a heterogeneous cohort of pupils (final-year pupils of common, compensating education classes and those of auxiliary schools) to the conditions of varying-level vocational training in building professions. The physiological cost of a learning process, which was associated with the volume and nature of a training load, was shown to be high. The functional capacities of different cohorts of pupils were comparatively assessed on the basis of the common integral index of mental performance, which offered more objective possibilities of hygienically substantiating the volume of an educational load. There was evidence that it was necessary to correct the total educational load in all forms of training, by taking into account a 5-day schooling week, the age of pupils and their capabilities. It was established that there was a need for improving work on pupils' health care, having regard to great differences available in the health status of final-year pupils from different types of educational establishments, contraindications to profession familiarization, the high spread of social and behavioral risk factors, and the influence of schooling and training factors.


Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady-state.
The aim of the study was to describe the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs when investigated as a single dose and at steady-state. Five healthy adult dogs were used in the study in a crossover design receiving either 5 mg/kg of cyclosporin A (CsA) alone or 5 mg/kg of fluconazole with 2.5 mg/kg of cyclosporin A (CsA/Flu) for 35 days. Pharmacokinetic curves were performed on day 1 and day 35 in addition to sampling trough and suspected peak concentrations (C2) twice weekly with LC/MS/MS. There was no statistically significant difference noted in any pharmacokinetic value (AUC0-inf. [day 1, P = 0.225], AUCtau [day 35, P = 0.225], t½ [day 1, P = 0.279; day 35, P = 0.686], and Cmax [day 1, P = 0.225; day 35, P = 0.225]) between the treatment groups by sampling day. There was a statistically significant increase in AUC (CsA P = 0.043; CsA/Flu P = 0.043) and t½ (CsA P = 0.042, CsA/Flu P = 0.042) over time within each group. There were no significant differences in the Cmax (CsA P = 0.08; CsA/Flu P = 0.08) when comparing day 1 vs. day 35. Steady-state cyclosporine concentrations were achieved by day 10 in both groups. Subjectively, individual variability was noted among the dogs and a much larger sample size would be beneficial in a future study.


pH and Thrombin Concentration Are Decisive in Synthesizing Stiff, Stable, and Open-Porous Fibrin-Collagen Hydrogel Blends without Chemical Cross-Linker.
Fibrin-collagen hydrogel blends exhibit high potential for tissue engineering applications. However, it is still unclear whether the underlying cross-linking mechanisms are of chemical or physical nature. It is here hypothesized that chemical cross-linkers play a negligible role and that instead pH and thrombin concentration are decisive for synthetizing blends with high stiffness and hydrolytic stability. Different fibrin-collagen formulations (pure and with additional transglutaminase) are used and the blends' compaction rate, hydrolytic stability, compressive strength, and hydrogel microstructure are investigated. The effect of thrombin concentration on gel compaction is examined and the importance of pH control during synthesis observed. It is revealed that transglutaminase impairs gel stability and it is deduced that fibrin-collagen blends mainly cross-link by mechanical interactions due to physical fibril entanglement as opposed to covalent bonds from chemical cross-linking. High thrombin concentrations and basic pH during synthesis reduce gel compaction and enhance stiffness and long-term stability. Scanning electron microscopy reveals a highly interpenetrating fibrous network with unique, interconnected open-porous microstructures. Endothelial cells proliferate on the blends and form a confluent monolayer. This study reveals the underlying cross-linking mechanisms and presents enhanced fibrin-collagen blends with high stiffness, hydrolytic stability, and large, interconnected pores; findings that offer high potential for advanced tissue engineering applications.


Age-Specific Reference Intervals for Plasma Free Thyroxine and Thyrotropin in Term Neonates During the First Two Weeks of Life.
Background: Congenital hypothyroidism (CH) is a common and preventable cause of mental retardation, which is detected in many neonatal screening programs. Upon suspicion of CH, plasma free thyroxine (fT4) and thyrotropin (TSH) concentrations are measured. CH can be of thyroidal or central origin (CH-T and CH-C, respectively). While CH-T diagnosis is based on an elevated TSH with a low fT4, CH-C diagnosis is based on a low fT4 without a clearly elevated TSH. Currently, reliable neonatal reference intervals (RIs) for plasma fT4 and TSH are lacking. Age-specific RIs would greatly improve the diagnostic process for CH, especially for CH-C. Our aim was to establish neonatal RIs for plasma fT4 and TSH in term neonates at day 3-7 (t = 1) and day 13-15 (t = 2). The study was particularly designed to provide a reliable fT4 lower limit of the RI to facilitate the diagnosis of CH-C. In the Netherlands, neonates are screened at day 3-7 of life. After a screening result suggestive for CH-C, pediatric consultation takes place on average at day 14. Thus, the time points were chosen accordingly. Methods: Venous blood was collected from 120 healthy neonates at each time point (94 participants provided blood samples at two time points; 52 participants provided a sample at t = 1 or t = 2). fT4 and TSH were measured using an immunoassay (Cobas; Roche Diagnostics). RIs were calculated using the 95% confidence interval for normally distributed data and the nonparametric percentile method if data were not normally distributed. Results: From 146 participants (49% female), ≥1 measurement was available. Ninety-five percent RIs for fT4 were 20.5-37.1 pmol/L (day 3-7) and 15.3-26.5 pmol/L (day 13-15). Ninety-five percent RIs for TSH were 1.0-8.4 mU/L (day 3-7) and 1.4-8.6 mU/L (day 13-15). Conclusions: Our results indicate an fT4 lower limit of the RI of 20.5 pmol/L at day 3-7 and 15.3 pmol/L at day 13-15. These lower limits are considerably higher than this assay's lower limit of the adult RI for fT4. In case CH is suspected, we recommend measuring fT4 and TSH using an assay with an established neonatal RI, taking into account the child's age in days.


Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation.
Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.


Protective effect of sitagliptin against renal ischemia reperfusion injury in rats.
This study was designed to investigate the protective effects of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in rats. For this, rats were randomly divided into four groups (n = 8): (1) sham group, in which the rats only underwent right nephrectomy; (2) right nephrectomy and left kidney ischemia (1 h) and reperfusion (24 h) group (I/R); (3) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks; (4) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks before left kidney I/R (n = 8). Sitagliptin-treated rats that underwent renal I/R demonstrated significant decrease in the serum urea nitrogen and creatinine and also, lipid peroxidation, total oxidant status and malondialdehyde level in the renal tissue when compared to the renal I/R group. Additionally, reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase and total antioxidative capacity were significantly increased after renal I/R in sitagliptin-treated rats. Our histopathological findings were in accordance with these biochemical results. In sum, in the current study all of our results indicated that sitagliptin treatment ameliorated renal damage induced by renal I/R in rats.


The discovery of glycogenin and the priming mechanism for glycogen biogenesis.
The biogenesis of glycogen in skeletal muscle requires a priming mechanism that has recently been elucidated. The first step is catalysed by a protein tyrosine glucosyltransferase and involves the formation of a novel glycosidic linkage, namely the covalent attachment of glucose to a single tyrosine residue (Tyr194) on a priming protein, termed glycogenin. The next stage is the extension of the glucan chain from Tyr194 and involves the sequential addition of up to seven further glucosyl residues. This reaction is brought about autocatalytically by glycogenin itself, which is a Mn2+/Mg(2+)-dependent UDP-Glc-requiring glucosyltransferase. The glucan primer is elongated by glycogen synthase, but only when glycogenin and glycogen synthase are complexed together. Glycogen synthase dissociates from glycogenin during the synthesis of a glycogen molecule, enabling glycogen molecules to reach their maximum theoretical size. Each mature glycogen beta particle in muscle contains one molecule of glycogenin attached covalently, and an average one glycogen synthase catalytic subunit bound non-covalently. As evidence accumulates that a priming protein may be a fundamental property of polysaccharide synthesis in general, the molecular details of mammalian glycogen biogenesis may serve as a useful model for other systems.


Changing resident test ordering behavior: a multilevel intervention to decrease laboratory utilization at an academic medical center.
Hospital laboratory test volume is increasing, and overutilization contributes to errors and costs. Efforts to reduce laboratory utilization have targeted aspects of ordering behavior, but few have utilized a multilevel collaborative approach. The study team partnered with residents to reduce unnecessary laboratory tests and associated costs through multilevel interventions across the academic medical center. The study team selected laboratory tests for intervention based on cost, volume, and ordering frequency (complete blood count [CBC] and CBC with differential, common electrolytes, blood enzymes, and liver function tests). Interventions were designed collaboratively with residents and targeted components of ordering behavior, including system changes, teaching, social marketing, academic detailing, financial incentives, and audit/feedback. Laboratory ordering was reduced by 8% cumulatively over 3 years, saving $2 019 000. By involving residents at every stage of the intervention and targeting multiple levels simultaneously, laboratory utilization was reduced and cost savings were sustained over 3 years.


A Two-Locus System with Strong Epistasis Underlies Rapid Parasite-Mediated Evolution of Host Resistance.
Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome-wide association study, we built a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.


Autism: alterations in auditory perception.
Investigations made in previous decades about irregularities in auditory perception in individuals with autism are reviewed and revised clinical and theoretical implications are provided. Emphasis is placed on the fact that these auditory perception irregularities of people with autism are very important for the understanding of the symptoms, for the search of its etiology, for the implementation of an adequate treatment program, and for the formulation of an adequate theoretical explanation of the syndrome.


A native chromatin purification system for epigenomic profiling in Caenorhabditis elegans.
High-resolution mapping of chromatin features has emerged as an important strategy for understanding gene regulation and epigenetic inheritance. We describe an in vivo tagging system coupled to chromatin purification for genome-wide epigenetic profiling in Caenorhabditis elegans. In this system, we coexpressed the Escherichia coli biotin ligase enzyme (BirA), together with the C. elegans H3.3 gene fused to BioTag, a 23-amino-acid peptide serving as a biotinylation substrate for BirA, in vivo in worms. We found that the fusion BioTag::H3.3 was efficiently biotinylated in vivo. We developed methods to isolate chromatin under different salt extraction conditions, followed by affinity purification of biotinylated chromatin with streptavidin and genome-wide profiling with microarrays. We found that embryonic chromatin is differentially extracted with increasing salt concentrations. Interestingly, chromatin that remains insoluble after washing in 600 mM salt is enriched at 5' and 3' ends, suggesting the presence of large protein complexes that render chromatin insoluble at transcriptional initiation and termination sites. We also found that H3.3 landscapes from these salt fractions display consistent features that correlate with gene activity: the most highly expressed genes contain the most H3.3. This versatile two-component approach has the potential of facilitating genome-wide chromatin dynamics and regulatory site identification in C. elegans.


Cervical musculoskeletal impairments and temporomandibular disorders.
The study of cervical muscles and their significance in the development and perpetuation of Temporomandibular Disorders has not been elucidated. Thus this project was designed to investigate the association between cervical musculoskeletal impairments and Temporomandibular Disorders. A sample of 154 subjects participated in this study. All subjects underwent a series of physical tests and electromyographic assessment (i.e. head and neck posture, maximal cervical muscle strength, cervical flexor and extensor muscles endurance, and cervical flexor muscle performance) to determine cervical musculoskeletal impairments. A strong relationship between neck disability and jaw disability was found (r = 0.82). Craniocervical posture was statistically different between patients with myogenous Temporomandibular Disorders (TMD) and healthy subjects. However, the difference was too small (3.3º) to be considered clinically relevant. Maximal cervical flexor muscle strength was not statistically or clinically different between patients with TMD and healthy subjects. No statistically significant differences were found in electromyographic activity of the sternocleidomastoid or the anterior scalene muscles in patients with TMD when compared to healthy subjects while executing the craniocervical flexion test (P = 0.07). However, clinically important effect sizes (0.42 - 0.82) were found. Subjects with TMD presented with reduced cervical flexor as well as extensor muscle endurance while performing the flexor and extensor muscle endurance tests when compared to healthy individuals. Subjects with Temporomandibular Disorders presented with impairments of the cervical flexors and extensors muscles. These results could help guide clinicians in the assessment and prescription of more effective interventions for individuals with Temporomandibular Disorders.


Menopausal hormone therapy trends before versus after 2002: impact of the Women's Health Initiative Study Results.
To better understand how to educate patients and providers about study findings relevant to treatment guidelines, we assessed pre- versus post-Women's Health Initiative (WHI) differences in menopausal hormone therapy (MHT) initiation and continuation and their correlates, and in women's reasons for initiation and discontinuation. We analyzed survey data from up to 14 approximately annual visits over 17 years (1996-2013) from 3,018 participants in the Study of Women's Health Across the Nation, a prospective cohort study. We used logistic regression to compare pre- versus post-WHI associations of covariates with MHT initiation and continuation, and to compare pre- versus post-WHI reasons for initiation and continuation. MHT initiation dropped from 8.6% pre-WHI to 2.8% post-WHI (P < 0.0001), and the corresponding decrease in MHT continuation was 84.0% to 62.0% (P < 0.0001). Decreases in MHT initiation and continuation occurred across a range of participant subgroups, consistent with wide dissemination of post-WHI recommendations. However, contrary to current guidelines, we found large declines in MHT use in subgroups for whom MHT is often recommended, that is, younger women and those with more vasomotor symptoms. Post-WHI, women's reasons for MHT initiation and discontinuation reflected concerns highlighted by WHI results. The largest declines in initiation reasons were for reducing risks of osteoporosis and heart disease, whereas the largest increases in discontinuation reasons were for media reports and provider advice. Immediate post-WHI recommendations for MHT use were widely adopted. MHT risks documented in older women, however, may have led younger symptomatic women to forgo MHT for symptom relief.


Cloning, mapping and expression analysis of barley MADS-box genes.
Six MADS-box cDNA clones were isolated by heterologous screening from a barley inflorescence cDNA library. Based on sequence comparison to known MADS-box genes, the barley MADS-box (BM) genes were grouped into three distinct phylogenetic subclasses of the MADS-box gene family. The three MADS-box genes BM3, BM5 and BM8 share similarities with genes of the SQUAMOSA (SQUA) subgroup, while BM7 and BM9 belong to the AGAMOUS-LIKE 2 (AGL2) subgroup. BM1 resembles MADS-box genes described as solitary sequences or orphan genes. Expression analysis of the barley MADS-box genes revealed expression patterns that are not characteristic of the barley MADS-box genes of the SQUA subgroup. while expression of BM7 and BM9 was largely as expected for the AGL2 subgroup. BM1 is mainly expressed in vegetative tissues and its primary transcript undergoes alternative splicing such that the corresponding mRNAs differ by two codons. The genes BM1, BM3 and BM8 were mapped by analysis of single-nucleotide polymorphisms onto barley chromosomes 4, 2 and 7, respectively.


Design, production, and reverse engineering of two-octave antireflection coatings.
We deal with design and production of optimal two-component antireflection (AR) coatings for an ultra broadband spectral range from 450 nm to 1800 nm. We demonstrate the whole design-production chain including design selection, choosing monitoring technique, coating production, and reverse engineering of the deposited coatings. At each step of this chain we provide thorough analysis on the basis of theoretical results and adequate computational manufacturing experiments. In order to produce the designed AR coatings we use magnetron sputtering deposition technique and accurate time monitoring.


Information acquisition from audio-video-data sources: an experimental study on remote diagnosis. The LOTAS Group.
To determine what information sources are used during a remote diagnosis task. Experienced trauma care providers viewed segments of videotaped initial trauma patient resuscitation and airway management. Experiment 1 collected responses from anesthesiologists to probing questions during and after the presentation of recorded video materials. Experiment 2 collected the responses from three types of care providers (anesthesiologists, nurses, and surgeons). Written and verbal responses were scored according to detection of critical events in video materials and categorized according to their content. Experiment 3 collected visual scanning data using an eyetracker during the viewing of recorded video materials from the three types of care providers. Eye-gaze data were analyzed in terms of focus on various parts of the videotaped materials. Care providers were found to be unable to detect several critical events. The three groups of subjects studied (anesthesiologists, nurses, and surgeons) focused on different aspects of videotaped materials. When the remote events and activities are multidisciplinary and rapidly changing, experts linked with audio-video-data connections may encounter difficulties in comprehending remote activities, and their information usage may be biased. Special training is needed for the remote decision-maker to appreciate tasks outside his or her speciality and beyond the boundaries of traditional divisions of labor.


Understanding primary parotid squamous cell carcinoma - A systematic review.
The true incidence of primary parotid squamous cell carcinoma (SCC) is unknown and likely overestimated in the literature. The aim of this systematic review is to examine the diagnosis, aetiology and incidence of parotid SCC by analysing studies evaluating primary parotid SCC. A systematic search of Medline, EMBASE and Cochrane library was performed. A narrative synthesis was done. A total of 14 observational retrospective studies on primary parotid SCC were included. There are currently no standard criteria for ascertainment of primary parotid SCC. Primary parotid SCC is thought to be due to squamous metaplasia within the ductal epithelium and subsequent invasive squamous carcinoma. Histological features that favour primary disease includes SCC confined to parotid parenchyma with no direct communication to the skin and the absence of mucin. Incidence of primary parotid SCC varied from 1.54 to 2.8 cases per million person-years. Around 30%-86% of patients recorded to have primary parotid SCC on clinical records, when scrutinised, were in fact secondary to parotid lymph node involvement following regional advancement from skin or upper aerodigestive tract SCC. Primary parotid SCC is rare and it is currently a diagnosis of exclusion. Thorough clinical assessment including endoscopy, preoperative imaging and the scrutiny of histopathological findings allow for differentiation between primary and secondary SCC within the parotid. This thus affects both initial treatment and subsequent follow-up.


An investigation of experiential avoidance, emotion dysregulation, and distress tolerance in young adult outpatients with borderline personality disorder symptoms.
In this study we investigated 3 domains of emotional functioning--emotion dysregulation, distress tolerance, and experiential avoidance--in young adult outpatients with borderline personality disorder (BPD) symptoms. Participants were 40 young adult outpatients at a university counseling center who reported current suicidal ideation and met diagnostic criteria for BPD or experienced subthreshold BPD symptoms (i.e., met diagnostic criteria for 3 or 4 symptoms). Participants completed 3 self-report measures of emotional functioning-experiential avoidance (Acceptance and Action Questionnaire-2; Bond et al., 2011; Hayes et al., 2004), emotion dysregulation (Difficulties in Emotion Regulation Scale; Gratz & Roemer, 2004), and distress tolerance (Distress Tolerance Scale; Simons & Gaher, 2005)-and a behavioral measure of distress tolerance (Paced Auditory Serial Addition Task-Computerized; Lejuez, Kahler, & Brown, 2003), in addition to self-report measures of depression and BPD symptom severity. Partial correlations demonstrated that both emotion dysregulation and experiential avoidance were significantly associated with BPD symptom severity after accounting for depression. However, neither the self-report nor behavioral measure of distress tolerance were related to BPD symptom severity. A regression analysis with emotion dysregulation and experiential avoidance as independent variables revealed that only experiential avoidance was significantly associated with BPD symptom severity after controlling for depression symptoms. The current findings suggest that experiential avoidance may be a central process in BPD symptom severity. Future research directions are discussed.


Current ocular drug delivery challenges for N-acetylcarnosine: novel patented routes and modes of delivery, design for enhancement of therapeutic activity and drug delivery relationships.
This review article explores the functional activity and development aspects of N-acetylcarnosine for the visual system as revealed by the use of a variety of biophysical, physiological and therapeutic ophthalmic methods. It is designed for pharmacists and more advanced ophthalmology, optometry and pharmacology researchers who wish to gain a basic understanding of the biological effects of N-acetylcarnosine for vision and to share in the excitement of the latest developments in this field. Topics under the consideration include: ophthalmic drug delivery of N-acetylcarnosine eye drops and challenging endeavors facing the pharmaceutical scientist; clinical and functional types of activity of the developed and patented N-acetylcarnosine lubricant eye drops designed as 1% N-acetylcarnosine prodrug of L-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in a drug delivery system; management of age-related serious or disabling eye diseases in humans with N-acetylcarnosine eye drop therapeutic platform (age-related cataracts, ocular inflammation, age-related macular degeneration , macular dystrophies, ocular manifestations of diabetes , hypertonic retinopathy, primary open angle glaucoma, vitreous lesions) ; development and molecular mechanisms of ocular therapeutic activities of carnosine derivatives in the visual system. Through this article we can perceive some helpful recent patents according to the title of the issue. The biologically significant applications of carnosine mimetics including those in ophthalmology were patented by Dr. Babizhayev and the alliance Groups (WO 2004/028536 A1; WO 94/19325; WO 95/12581; WO 2004/064866 A1).


Learning impairment and allergic rhinitis.
Allergic rhinitis is underestimated as a cause of suffering and diminished quality of life in children and adolescents. If nasal symptoms such as itching, sneezing, rhinorrhea, and congestion are not well controlled during the day, they may contribute to learning problems during school hours. If these symptoms are not well controlled during the night, they may contribute to nocturnal sleep loss, secondary daytime fatigue and learning impairment. Even uncomplicated seasonal allergic rhinitis may be associated with reduced ability to learn, and the likelihood of learning problems may increase in severe perennial rhinitis or in rhinitis associated with complications such as sinusitis or eustachian tube dysfunction and conductive hearing loss. Also, many of the medications used to treat allergic rhinitis may cause central nervous system adverse effects and contribute to learning impairment. For some medications, such as inhaled glucocorticoids and decongestants, the potential effect on central nervous system function and learning has not been tested. For others such as H1-receptor antagonists (antihistamines), well-designed, prospective studies have been performed. The newer relatively nonsedating medications such as terfenadine, astemizole, loratadine, cetirizine, and fexofenadine have less potential to impair central nervous system function and learning than their predecessors.


A reversible epigenetic memory of inflammatory injury controls lineage plasticity and tumor initiation in the mouse pancreas.
Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.


Characterizing virus-induced gene silencing at the cellular level with in situ multimodal imaging.
Reverse genetic strategies, such as virus-induced gene silencing, are powerful techniques to study gene function. Currently, there are few tools to study the spatial dependence of the consequences of gene silencing at the cellular level. We report the use of multimodal Raman and mass spectrometry imaging to study the cellular-level biochemical changes that occur from silencing the phytoene desaturase (pds) gene using a Foxtail mosaic virus (FoMV) vector in maize leaves. The multimodal imaging method allows the localized carotenoid distribution to be measured and reveals differences lost in the spatial average when analyzing a carotenoid extraction of the whole leaf. The nature of the Raman and mass spectrometry signals are complementary: silencing pds reduces the downstream carotenoid Raman signal and increases the phytoene mass spectrometry signal. Both Raman and mass spectrometry imaging show that the biochemical changes from FoMV-pds silencing occur with a mosaic spatial pattern at the cellular level, and the Raman images show carotenoid expression was reduced at discrete locations but not eliminated. The data indicate the multimodal imaging method has great utility to study the biochemical changes that result from gene silencing at the cellular spatial level of expression in many plant tissues including the stem and leaf. Our demonstrated method is the first to spatially characterize the biochemical changes as a result of VIGS at the cellular level using commonly available instrumentation.


Club practice.
There were many forms of club or contract practice in the nineteenth century, but the friendly societies were the most important. A brief history of the friendly societies is given. As they grew in numbers and importance so did the dissatisfaction of the doctors who worked with them. Discontent among the doctors led at the end of the century to a battle between the medical profession and the clubs. The issues which divided the clubs and the doctors were clearly defined but, although the battle was protracted, the doctors did not win or manage to change the system of medical provision for the poor. The club system was ended by Lloyd George when he introduced his National Insurance Act, 1911.


Serum Copeptin Levels Predict the Return of Spontaneous Circulation and the Short-Term Prognosis of Patients with Out-of-Hospital Cardiac Arrest: A Randomized Control Study.
Early and accurate prediction of survival to hospital discharge following resuscitation after cardiac arrest (CA) is a major challenge. Biomarkers can be used for early and accurate prediction of survival and prognosis following resuscitation after CA, but none of those identified so far are sufficient by themselves. The goal of this study was to investigate the predictive power of the serum copeptin level for determining the return of spontaneous circulation (ROSC) and prognosis of patients with non-traumatic out-of-hospital cardiac arrest (OHCA) who underwent cardiopulmonary resuscitation (CPR). A total of 76 consecutive consenting adult patients who were diagnosed as non-traumatic OHCA and 63 age- and sex-matched healthy controls were enrolled. The patients were divided into two groups based on whether or not they had ROSC. The ROSC group was divided into two sub-groups according to whether death occurred within 24 hours or after 24 hours following ROSC. Serum copeptin, high-sensitivity cardiac troponin (hs-cTnI), creatine kinase-muscle/brain (CK-MB), glucose, and blood gas values were compared between the groups. Serum copeptin levels were significantly higher in the patient group than control group (P <.001). Receiving operator characteristic analysis revealed a cut-off copeptin level of 27.29pmol/L, with 98.7% sensitivity and 100.0% specificity, for distinguishing patients from controls. Serum copeptin levels were significantly lower in the ROSC group than non-ROSC group (P = .018). Additionally, the mean serum hs-cTnI level was significantly higher in the ROSC group than non-ROSC group (P = .032). However, there were no significant differences in the mean serum glucose level and CK-MB levels or arterial blood gas levels between the ROSC and non-ROSC groups (all P >.05).Ten (38.5%) of the patients died within the first 24 hours after ROSC, whereas 16 (61.5%) survived longer than 24 hours. Serum copeptin levels were significantly lower in patients who survived longer than 24 hours compared with those who died within the first 24 hours. Moreover, the mean CPR duration was significantly lower in patients surviving more than 24 hours compared with less than 24 hours. The serum copeptin level may serve as a guide in diagnostic decision making to predict ROSC in patients undergoing CPR and determining the short-term prognosis of patients with ROSC.


Sequential stimulation of cellular RNA synthesis in polyoma-infected mouse kidney cell cultures.
Lytic infection with polyoma virus leads in Go-arrested primary mouse kidney cell cultures to a mitotic host response. In the present work we focused our attention on cellular RNA synthesis shortly after onset of polyoma T-antigen synthesis. Onset of polyoma-induced stimulation of 45S pre-rRNA synthesis was determined by hybridization of total cellular RNA with a plasmid (pMrSalB) containing the 5'-end of the mouse ribosomal gene and of the other cellular RNA species by standard biochemical analysis of cellular fractions. The results showed that polyoma-induced stimulation of cellular hnRNA (hnRNP) synthesis, the earliest presently known host cell reaction, preceded onset of stimulated 45S pre-rRNA synthesis and that the latter was paralleled by polyoma-induced stimulation of 5S RNA, tRNA and overall protein synthesis. The polyoma-induced mitotic response is similar to that triggered by simian virus 40 and by certain nonviral mitogens.


Possible prevalence and transmission of acute respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae among the internally displaced persons in tsunami disaster evacuation camps of Sri Lanka.
The objective of this prospective study was to investigate the status of acute respiratory tract infections caused by Haemophilus influenzae and Streptococcus pneumoniae in tsunami disaster evacuation camps. Nasopharyngeal swabs (NP) of 324 internally displaced persons (IDP) in 3 different tsunami disaster evacuation camps of Sri Lanka were collected between March 18th and 20th, 2005, and analyzed for MIC, beta-lactamase production, serotypes, PCR and pulsed-field gel electrophoresis (PFGE). Many IDP had respiratory symptoms and the prevalence of cough and/or sputum was 84%, 70.5% and 64.7% in the three camps. Twenty-one H. influenzae from 20 IDP and 25 S. pneumoniae from 22 IDP were isolated from the NP. All H. influenzae isolates were nontypeable, and 5 were beta-lactamase producing. Seventeen pneumococci were susceptible, 5 showed intermediate resistance and 3 were fully resistant to penicillin G. Molecular analysis showed the 21 H. influenzae strains had 13 PFGE patterns and 25 pneumococci had 16 PFGE patterns. All 4 different PFGE patterns of H. influenzae strains were detected in a few IDP in camps 1 and 3, and 5 different PFGE patterns of serotype 3, 22A, 9A, 10A and 11A pneumococci were detected in a few IDP in camps 1 and 3. Our data indicate acute respiratory tract infections caused by various types of H. influenzae and S. pneumoniae appear to have been prevalent, some of which were potentially transmitted from person to person in tsunami disaster evacuation camps.


Epidemiological, Serological, and Entomological Investigation of New Visceral Leishmaniasis Foci in Nepal.
The aim of this study was to explore epidemiological, serological, entomological, and social aspects of visceral leishmaniasis (VL) in new foci in Nepal. The study was conducted in 11 villages of five districts that had been previously free of VL but that reported new cases between 2019 and 2021. We screened 1,288 inhabitants using rK39 tests and investigated the epidemiological and clinical characteristics of 12 recent VL cases. A total of 182 community members were interviewed about knowledge, attitude, and practices regarding VL. They then underwent an awareness training; 40 of them had a second interview at 6 months to assess the training impact. Vector surveys were conducted in six houses per village to assess sandfly density and infection rates. The prevalence of VL infection was 0.5% and 3.2% among screened populations in Dolpa and Kavre districts, respectively, while the other districts had no rK39-positive cases. No association between travel history and VL infection was found. Phlebotomus argentipes sandflies were collected in three districts at high altitudes (from 1,084 to 4,450 m). None of the sandflies captured had Leishmania donovani DNA. People in new foci were not aware of VL symptoms, vectors, or preventive measures. The training significantly improved their knowledge and practice in seeking medical care in case of illness. The epidemiological, serological, and entomological investigations suggest indigenous focal transmission of VL. An integrated package of strategic interventions should be implemented by the national VL elimination program in districts with new VL foci.


Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study.
Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown. We studied 13,893 first-born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Västerbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population-based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable poisson and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N = 135). Offspring participants of women with HDP (N = 383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2-hour 75 g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses. Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period.


Analysis of Body-wide Unfractionated Tissue Data to Identify a Core Human Endothelial Transcriptome.
Endothelial cells line blood vessels and regulate hemostasis, inflammation, and blood pressure. Proteins critical for these specialized functions tend to be predominantly expressed in endothelial cells across vascular beds. Here, we present a systems approach to identify a panel of human endothelial-enriched genes using global, body-wide transcriptomics data from 124 tissue samples from 32 organs. We identified known and unknown endothelial-enriched gene transcripts and used antibody-based profiling to confirm expression across vascular beds. The majority of identified transcripts could be detected in cultured endothelial cells from various vascular beds, and we observed maintenance of relative expression in early passage cells. In summary, we describe a widely applicable method to determine cell-type-specific transcriptome profiles in a whole-organism context, based on differential abundance across tissues. We identify potential vascular drug targets or endothelial biomarkers and highlight candidates for functional studies to increase understanding of the endothelium in health and disease.


Restless Legs Syndrome in Patients with Behçet's Disease and Multiple Sclerosis: Prevalence, Associated Conditions and Clinical Features.
To investigate the prevalence and characteristics of Restless Legs Syndrome (RLS) in patients with Behçet's Disease (BD) and Multiple Sclerosis (MS). Consecutive patients with BD and MS seen in the outpatient clinic were included in the study. As a control group, volunteer subjects without a known peripheral or central nervous system disorder were included. The BD group was divided into two sub-groups as BD with neurological involvement [Neuro-Behçet's Disease (NBD)] and BD without any neurological involvement (other BD) for further evaluation. Data on demographic characteristics, medical history and family history were collected, and all patients underwent neurological examination. The patients were evaluated for the presence of diagnostic criteria for RLS. The features and severity of RLS were evaluated in patients with RLS using Restless Legs Syndrome Identification Form, and the International Restless Legs Syndrome Study Group (IRLSSG) Rating Scale. The clinical and radiological findings of patients with BD and MS were retrieved from their medical files. The study included a total of 96 patients with BD (mean age 39.9±11.8; 51 males; 41 patients with NBD) and 97 patients with MS (mean age 34.97±4.1 years; 24 males). There were 100 healthy control subjects (mean age 36.18±11.10 years; 46 males). RLS was more prevalent in MS (22.8%) and NBD (22%) groups compared to the control group (10%; p=0.004 and 0.029, respectively) with a statistically significant difference. The prevalence of RLS was higher in MS patients with less disability. Most severe RLS symptoms were observed in the MS group. The rate of sleep disorders was also higher in MS group. Although stress appeared to be a factor worsening RLS in all groups, its prevalence was higher in the MS group (p=0.011). There was no correlation between the distribution of magnetic resonance imaging lesions and RLS in both MS and NBD groups. It is well established that RLS can accompany disorders involving the peripheral and central nervous systems such as all types of peripheral neuropathy, myelopathy, and Parkinson's disease. The present study showed that MS and NBD also seem to be a risk factor for RLS, being associated with more severe symptoms.


Psychotropic medications in children with autism spectrum disorders: a systematic review and synthesis for evidence-based practice.
This paper presents a systematic review, rating and synthesis of the empirical evidence for the use of psychotropic medications in children with autism spectrum disorders (ASD). Thirty-three randomized controlled trials (RCTs) published in peer-reviewed journals qualified for inclusion and were coded and analyzed using a systematic evaluative method specific to autism research (Reichow et al. in Journal of Autism and Developmental Disorders 38:1311-1319, 2008). Results are presented by agent and primary target symptom(s). The findings suggest established evidence for relatively few agents, with preliminary and promising evidence for a larger group. Challenges and opportunities in the developing field of ASD psychopharmacology are identified, and recommendations for further research are provided.


Beta-glucan, a "specific" biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18).
beta-Glucans were identified 36 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3; known also as Mac-1, CD11b/CD18, or alphaMbeta2-integrin, that functions as an adhesion molecule and a receptor for factor I-cleaved C3b, i.e., iC3b) resulting in the priming of this iC3b receptor for cytotoxicity of iC3b-opsonized target cells. This investigation explored mechanisms of tumor therapy with soluble beta-glucan in mice. Normal mouse sera were shown to contain low levels of Abs reactive with syngeneic or allogeneic tumor lines that activated complement, depositing C3 onto tumors. Implanted tumors became coated with IgM, IgG, and C3, and the absent C3 deposition on tumors in SCID mice was reconstituted with IgM or IgG isolated from normal sera. Therapy of mice with glucan- or mannan-rich soluble polysaccharides exhibiting high affinity for CR3 caused a 57-90% reduction in tumor weight. In young mice with lower levels of tumor-reactive Abs, the effectiveness of beta-glucan was enhanced by administration of a tumor-specific mAb, and in SCID mice, an absent response to beta-glucan was reconstituted with normal IgM or IgG. The requirement for C3 on tumors and CR3 on leukocytes was highlighted by therapy failures in C3- or CR3-deficient mice. Thus, the tumoricidal function of CR3-binding polysaccharides such as beta-glucan in vivo is defined by natural and elicited Abs that direct iC3b deposition onto neoplastic cells, making them targets for circulating leukocytes bearing polysaccharide-primed CR3. Therapy fails when tumors lack iC3b, but can be restored by tumor-specific Abs that deposit iC3b onto the tumors.


Stretch-inducible expression of connective tissue growth factor (CTGF) in human osteoblasts-like cells is mediated by PI3K-JNK pathway.
To explore the possible role for connective tissue growth factor (CTGF) during tooth movement, we evaluated CTGF gene and protein expression in MG-63 cells subjected to cyclic stretch. Cyclic stretch caused a time-dependent increase in CTGF mRNA and protein levels.Inhibition of p38 MAP kinase or ERK activation did not affect cyclic stretch-induced CTGF expression. Specific inhibitors of PI3K suppressed stretch -induced CTGF expression in a time-dependent manner. cyclic stretch activated JNK and ERK, but not p38 MAP kinase in osteoblast-like cells. PI3K inhibitors suppressed cyclic stretch-induced JNK, but not p38 MAP kinase activation. Finally, SP600125, a Specific Inhibitor of JNK, suppressed stretch -induced CTGF Expression. These results suggest that stretch-induced CTGF expression is mediated through the PI3K-JNK -dependent pathway, not by p38 MAP kinase and ERK pathways.


Low-dose bisphenol A induces RIPK1-mediated necroptosis in SH-SY5Y cells: Effects on TNF-α and acetylcholinesterase.
Bisphenol A (BPA) is an endocrine disruptor chemical, which is commonly used in everyday products. Adverse effects of its exposure are reported even at picomolar doses. Effects of picomolar and nanomolar concentrations of BPA on cytotoxicity, nitric oxide (NO) levels, acetylcholinesterase (AChE) gene expression and activity, and tumor necrosis factor-α (TNF-α) and caspase-8 levels were determined in SH-SY5Y cells. The current study reveals that low-dose BPA treatment induced cytotoxicity, NO, and caspase-8 levels in SH-SY5Y cells. We also evaluated the mechanism underlying BPA-induced cell death. Ours is the first report that receptor-interacting serine/threonine-protein kinase 1-mediated necroptosis is induced by nanomolar BPA treatment in SH-SY5Y cells. This effect is mediated by altered AChE and decreased TNF-α levels, which result in an apoptosis-necroptosis switch. Moreover, our study reveals that BPA is an activator of AChE.


High-spectral-resolution Mie Doppler lidar based on a two-stage Fabry-Perot etalon for tropospheric wind and aerosol accurate measurement.
A two-stage Fabry-Perot etalon (FPE)-based high-spectral-resolution (HSR) Mie Doppler lidar technology is proposed that is capable of simultaneously detecting tropospheric wind and aerosol optical properties with high precision. The lidar structure is designed, and the measurement principle is analyzed. A two-channel integrated FPE forming a two-stage FPE ensures the relative stability of the spectra. The HSR first-stage etalon can effectively suppress the contamination of Rayleigh signal. The transmission and reflection spectra of the second-stage etalon can form a double edge (DE) to measure wind speed. Two multimode polarization-insensitive optical circulators are used to achieve high-efficiency utilization for backscattering signals. The parameters of the two-stage FPE are optimized. According to the selected system parameters, the detection performance of the proposed lidar is simulated. Simulation results show that with 150 m range resolution and 1 min total accumulation time for the paired line-of-sight (LOS) measurement, within ±25 m/s LOS wind speed range, the nighttime and daytime LOS wind speed errors are below 0.48 m/s and 2.5 m/s, respectively, for a clear day, and below 0.58 m/s and 5.5 m/s, respectively, for a hazy day from 0.1 km to 8 km altitude; the backscatter ratio relative errors are below 2.7% up to 8 km for a clear day, and below 4.6% up to 5 km for a hazy day. Compared with the traditional dual-FPE-based DE Mie Doppler lidar, the wind speed accuracies are improved by 2.02-3.58 times for a clear day and 2.14-4.31 times for a hazy day.


Comparative bioavailability studies on some brands of ampicillin capsules.
The bioequivalence of two generics of Ampicillin capsules, hitherto untested, were assessed using Penbritin capsules, the innovator's brand, as the reference product. The bioavailability study was carried out in nine healthy volunteers given one capsule (250 mg) of ampicillin in a completely randomized cross-over design. Statistical analysis (ANOVA) of the results indicated that one of the products tested, designated ampicillin (X), was significantly different (p less than 0.05) in its bioavailability compared to Penbritin while the other product, ampicillin (Helm), was not.


The lymphoid liver: considerations on pathways to autoimmune injury.
Immunologic injury in the liver involves immigrant T and B lymphocytes and a resident lymphoid population that comprises distinct lymphocytic cells and accessory cells. The forerunner to autoimmunity is breaching of natural self-tolerance and hence the disruption of a fundamental property of the immune system. Such breaching occurs by processes that include inflammatory activation of immunocytes and macrophages, spillage of intracellular constituents, and epitope mimicry by constituents of microorganisms, with these acting on a genetically conditional phenotype; compounding factors include aberrations of apoptosis, whether insufficient or excess. The downstream end requires specifically directed inflammatory leukocyte traffic as an essential component of autoimmune expressions in the liver. The culmination is an orchestrated attack on hepatocytes or biliary epithelial cells by multiple effector pathways. Progress in type 1 autoimmune hepatitis still requires knowledge of a disease-specific autoantigen(s) involved in T-cell reactivity, although such knowledge in type 2 autoimmune hepatitis, in which the known autoantigen is cytochrome P4502D6, has not yet been integrated into a clearly defined scheme of pathogenesis. For PBC there has been a very promising amalgamation of molecular knowledge of the mitochondrial autoantigens. Future insights require deeper analysis of molecular, genetic, macroenvironmental, and microenvironmental elements in predisposition.


Chemiluminescence in autoxidation of phosphonate carbanions. Phospha-1,2-dioxetanes as the most likely high-energy intermediates.
Autoxidation of the phosphonate carbanions derived from 9-phosphono-10-hydroacridanes provided chemiluminescence ascribed to the excited acridone anion. The intramolecular CIEEL (chemically initiated electron exchange luminescence) mechanism can be applied to this chemiluminescence because of the much higher emission efficiency compared to that of 9-phosphono-10-methylacridanes. The effect of the phosphonate substituents on the emission efficiency and especially on the rates of the chemiluminescence decay can be interpreted to originate from the valence deviation of the phosphorus atoms, which is connected with the substituent effect on the geometrical selectivity in the olefination reaction of the phosphonate carbanions. The enhanced chemiluminescence in the presence of the fluorophores was also detected in autoxidation of the carbanions of diethyl diphenylmethylphosphonate and fluorenylphosphonate. Although the evidence is circumstantial, these results strongly support the belief that phospha-1,2-dioxetane is the most likely high-energy intermediate generating the excited molecules.


[Acute profound thrombocytopenia associated with the use of abciximab: case report].
We present the case-report of a patient with instable angina who submitted to percutaneous coronary intervention and stent place for revascularization who developed purpura and groin hematoma associated to acute profound thrombocytopenia induced by abciximab infusion with nadir platelet counts 1x10⁹/L (1,000 platelets/mm3), his platelet recovery with the instituted treatment and the outcome with subacute intra-stent thrombosis that was associated with functionally platelet counts that required a primary angioplasty and administration of tirofiban, a platelet glycoprotein IIb/IIIa receptor antagonist. Laboratory confirmation to exclude other causes of thrombocytopenia and its association of glycoprotein IIb/IIIa receptor antagonist with heparin, acetylsalicylic acid and clopidogrel were obtained. We perform in literature trials with this complication.