Properties of volume-sensitive Cl- channels in a human epithelial cell line.
A regulatory volume decrease is accomplished by parallel activation of Ca(2+)-dependent K+ channels and Ca(2+)-independent Cl- channels in cultured human intestinal epithelial cells (Intestine 407). The anion selectivity of whole-cell currents recorded in osmotically swollen cells falls into the Eisenman type I sequence corresponding to a low-field anion channel. The volume-sensitive Cl- channel has an intermediate unitary conductance. Both the whole-cell and single-channel Cl- currents exhibit unique voltage-dependency. The Cl- current can be maintained in the activated state in the physiological voltage range. However, at very large depolarizations (over +50 mV), the current is quickly inactivated. The Cl- current shows moderate outward rectification. The whole-cell Cl- current is sensitive to Cl- channel blockers such as SITS and NPPB as well as to cis unsaturated fatty acids such as arachidonic acid and oleic acid. The whole-cell current is totally independent of Ca2+ and cyclic AMP, but inhibited by increases in cytosolic free Mg2+ ions. Removal of intracellular ATP, but not Mg2+, abolishes the Cl- current. The ATP role can be substituted for non-hydrolyzable ATP analogs. Therefore, it is likely that intracellular ATP maintains the channel activity through non-hydrolytic binding.


On the blistering of thermo-sensitive hydrogel: the volume phase transition and mechanical instability.
This paper explores the physical mechanisms responsible for the appearance of small blisters on the surface of temperature sensitive hydrogels as they deswell rapidly during their volume phase transition. For this, we develop a numerical model that couples the processes of hydrogel deswelling and blister growth due to the existence of a thin quasi-impermeable layer on its surface. The model points out that blister inflation originates at defects point under the gel's surface, under the effect of the increasing osmotic pressure in the gel as it undergoes its phase transition. Due to their large deformation, these blisters often experience a mechanical instability that triggers a sudden increase in their growth rate at the expense of their closest neighbors. Using a simple computational model, we then show that blisters are able to communicate via internal pressure and that these interactions are mediated by two characteristic time scales related to solvent transport within and between adjacent blisters. Our study finally indicates that these mechanisms can be controlled by temperature and the gel's cross-link density to achieve diversity of blister patterns on the gel's surface. The proposed analysis provides predictions that agree well with experimental observations of NiPAm gels which deswell in various conditions.


Effects of newly developed chemotherapy regimens, comorbidities, chemotherapy-related toxicities on the changing patterns of the leading causes of death in elderly patients with colorectal cancer.
Abundant evidences have shown that newly developed chemotherapy regimens improved 5-year survival rate of colorectal cancer (CRC) patients over the past two decades. However, their impact on risk of death from leading causes among elderly patients is still poorly understood. A retrospective cohort study of 69 718 elderly CRC patients with their first primary tumors in 1992-2009, identified from the 12 areas of Surveillance, Epidemiology, and End Results-Medicare linked database with their Medicare claims up to 2010. Multivariate Cox regression models were used to assess the effect of newly developed chemotherapy regimens, comorbidities, and chemotherapy related toxicities on cause-specific death and their temporal patterns among elderly CRC patients. The leading causes of death among CRC patients were CRC, circulation disorders, and secondary cancers, which accounted for 51.4%, 25%, and 4.6% of all-cause death, respectively. Patients diagnosed in more recent diagnostic time periods were significantly less likely to die of CRC [period 2: 5-year hazard ratio = 0.94, 95% confidence interval (CI) 0.90-0.97; period 3: 0.86, 0.83-0.90], circulation disorders (period 2: 0.94, 0.88-1.00; period 3: 0.80, 0.75-0.87), and more likely to die of secondary cancer (period 3: 1.42, 1.20-1.68) compared with those diagnosed in period 1. Charlson comorbidities index and the selected pre-existing comorbidities were significantly associated with increased 5-year risk of death from all three leading causes. Both hematological and gastric toxicity were associated with reduced risk of death from CRC and circulation disorders. The association between diagnostic time period and risk reduction in death from CRC depended on chemotherapy treatment (P < 0.0001). Subgroup analyses showed that the chemotherapy-dependent significant risk reduction was seen in patients with stage II-III CRC, patients without comorbidities, and patients without toxicities (P < 0.0001 for all). The newly developed chemotherapy regimens were associated with the decreased risk of mortality from CRC.


Influence of oral verapamil on glucoregulatory hormones in man.
We evaluated the effect of treatment with placebo or verapamil (320 mg/day) for 2 weeks on glucose-induced insulin secretion and hypoglycemia-stimulated counterregulatory hormone secretion in hypertensive patients. Verapamil treatment was associated with a significant reduction in diastolic blood pressure (P = 0.02 vs. placebo). During a hyperglycemic clamp (plasma glucose raised 125 mg/dl above basal level) maintained for 90 min, plasma insulin increased 4- to 5-fold (early) and then to values 8- to 10-fold above baseline (late). These increments were identical during placebo or verapamil treatment. The rates of glucose metabolized during each study also were similar, suggesting that no significant change in insulin action occurred during drug treatment. When plasma glucose was allowed to decline precipitously from hyperglycemic levels (220 mg/dl) to nadirs ranging from 42-77 mg/dl, plasma concentrations of glucagon, cortisol, epinephrine, and norepinephrine all increased; however, no consistent differences in the counter-regulatory hormone responses could be attributed to verapamil therapy. We conclude that physiologically effective drug concentrations of verapamil capable of influencing blood pressure do not have a significant effect on secretion of glucoregulatory hormones in man.


Abduction nystagmus in internuclear ophthalmoplegia.
We tested the hypothesis that abnormalities of the abducting eye in internuclear ophthalmoplegia reflect an adaptive process that helps overcome the adduction weakness of the opposite eye. This response operates under the constraints of Hering's law of equal innervation: any attempt to increase the innervation to a weak muscle in one eye must be accompanied by a commensurate increase in innervation to the yoke muscle in the other eye. In 4 patients with internuclear ophthalmoplegia, we patched one eye for 1 to 5 days to allow time for the central nervous system to optimize innervation for the habitually viewing eye. We predicted that there would be a conjugate adjustment of innervation that would diminish the abduction overshoot and backward postsaccadic drift made by the habitually viewing eye. This was the case in 3 of our 4 patients. Our findings show that the abduction nystagmus is a manifestation of a normal adaptive response in some patients with INO.


NH2-Ni-MOF electrocatalysts with tunable size/morphology for ultrasensitive C-reactive protein detection via an aptamer binding induced DNA walker-antibody sandwich assay.
Here we report a general approach for synthesizing size/morphology-controlled NH2-Ni-MOFs by optimizing the solvent composition in the reaction system, and their correlating catalytic performances are clearly explored for the first time. Interestingly, the electrocatalytic performance was found to increase 2.7 fold when the particle size is reduced from 1.5 μm for NH2-Ni-MOF(a) to 300 nm for NH2-Ni-MOF(c). Subsequently, this work exhibits an example of a high-performance NH2-Ni-MOF(c) electrocatalyst for application in constructing an electrochemical aptasensor to achieve sensitive C-reactive protein (CRP) detection based on an aptamer binding induced DNA walker-antibody sandwich assay. The proposed aptasensor shows a wide linear range from 0.1 pg mL-1 to 100 ng mL-1 with a low detection limit of 0.029 pg mL-1. The work presented here can thus offer an atypical approach to size- and morphology-controlled MOFs in electrocatalysis and biosensing.


Simplification of vector ray tracing by the groove function.
Tracing rays through arbitrary diffraction gratings (including holographic gratings of the second generation fabricated on a curved substrate) by the vector form is somewhat complicated. Vector ray tracing utilizes the local groove density, the calculation of which highly depends on how the grooves are generated. Characterizing a grating by its groove function, available for almost arbitrary gratings, is much simpler than doing so by its groove density, essentially being a vector. Applying the concept of Riemann geometry, we give an expression of the groove density by the groove function. The groove function description of a grating can thus be incorporated into vector ray tracing, which is beneficial especially at the design stage. A unified explicit grating ray-tracing formalism is given as well.


Defining the role of primary health care nurse practitioners in rural Nova Scotia.
This article reports on a mixed methods study to define the role of nurse practitioners (NPs) in rural Nova Scotia, Canada, by collecting the perceptions of rural health board chairpersons and health-care providers. Qualitative data were collected in telephone interviews with health board chairpersons. Quantitative data were collected in a survey of NPs, family physicians, public health nurses, and family practice nurses.The authors describe participants' perspectives on the health needs of rural communities, the gaps in the current model of primary health care services, the envisaged role of NPs in rural communities, and the facilitators of and barriers to NP role implementation. Optimizing the benefits of the NP role for residents of rural communities requires attention to the barriers that impede deployment and integration of the role.


A Preoperative Planning Tool: Aggregate Anterior Approach to the Humerus With Quantitative Comparisons.
Extensile approaches to the humerus are often needed when treating complex proximal or distal fractures that have extension into the humeral shaft or in those fractures that occur around implants. The 2 most commonly used approaches for more complex fractures include the modified lateral paratricipital approach and the deltopectoral approach with distal anterior extension. Although the former is well described and quantified, the latter is often associated with variable nomenclature with technical descriptions that can be confusing. Furthermore, a method to expose the entire humerus through an anterior extensile approach has not been described. Here, we illustrate and quantify a technique for connecting anterior humeral approaches in a stepwise fashion to form an aggregate anterior approach (AAA). We also describe a method for further distal extension to expose 100% of the length of the humerus and compare this approach with both the AAA and the lateral paratricipital in terms of access to critical bony landmarks, as well as the length and area of bone exposed.


Outcome of Youth with Early-Phase Schizophrenia-Spectrum Disorders and Psychosis Not Otherwise Specified Treated with Second-Generation Antipsychotics: 12 Week Results from a Prospective, Naturalistic Cohort Study.
The purpose of this study was to assess differences in the outcomes of youth with schizophrenia-spectrum disorders (SCZ-S) and psychotic disorder not otherwise specified (PsyNOS) during early antipsychotic treatment. The study was a prospective, naturalistic, inception cohort study of youth ≤19 years old with SCZ-S (schizophrenia, schizoaffective disorder, schizophreniform disorder) or PsyNOS (PsyNOS, brief psychotic disorder) and ≤24 months of lifetime antipsychotic treatment receiving clinician's choice antipsychotic treatment. Baseline demographic, illness and treatment variables, and effectiveness outcomes were compared at 12 weeks last-observation-carried-forward across SCZ-S and PsyNOS patients, adjusting for significantly different baseline variables. Altogether, 130 youth with SCZ-S (n=42) or PsyNOS (n=88), mostly antipsychotic naïve (76.9%), were prescribed risperidone (47.7%), olanzapine (19.2%), aripiprazole (14.6%), quetiapine (11.5%), or ziprasidone (6.9%). Compared with those with PsyNOS, SCZ-S youth were older (16.4±2.1 vs. 14.8±3.2, p=0.0040), and less likely to be Caucasian (19.1% vs. 42.5%, p=0.009). At baseline, SCZ-S patients had significantly higher Clinical Global Impressions-Severity (CGI-S) scores (6.0±0.9 vs. 5.5±0.8, p=0.0018) and lower Children's Global Assessment Scale (CGAS) scores (29.6±9.2 vs. 36.1±8.9, p=0.0002) and were more likely to be in the severely ill CGAS group (i.e., CGAS≤40). SCZ-S and PsyNOS patients did not differ regarding all-cause discontinuation (40.5 vs. 40.3%. p=0.49), discontinuation because of adverse effects (12.2% vs. 12.4%, p=0.97), or nonadherence (29.3% vs. 30.9%, p=0.88), but somewhat more SCZ-S patients discontinued treatment for inefficacy (19.5% vs. 7.4%, p=0.063). CGI-S and CGAS scores improved significantly in both diagnostic groups (p=0.0001, each). Adjusting for baseline differences, PsyNOS patients experienced significantly better CGI-I improvement (CGI-I) scores (p=0.012) and more frequently reached higher categorical CGAS group status (p=0.021) than SCZ-S patients. Both youth with SCZ-S and those with PsyNOS experienced significant improvements with clinician's choice antipsychotic treatment. However, treatment discontinuation was common within 12 weeks, with greater inefficacy-related discontinuation in the SCZ-S group, whereas CGI-I and CGAS score-based improvements were greater in the PsyNOS group.


A Theoretical Approach for the Electrochemical Characterization of Ciliary Epithelium.
The ciliary epithelium (CE) is the primary site of aqueous humor (AH) production, which results from the combined action of ultrafiltration and ionic secretion. Modulation of ionic secretion is a fundamental target for drug therapy in glaucoma, and therefore it is important to identify the main factors contributing to it. As several ion transporters have been hypothesized as relevant players in CE physiology, we propose a theoretical approach to complement experimental methods in characterizing their role in the electrochemical and fluid-dynamical conditions of CE. As a first step, we compare two model configurations that differ by (i) types of transporters included for ion exchange across the epithelial membrane, and by (i) presence or absence of the intracellular production of carbonic acid mediated by the carbonic anhydrase enzyme. The proposed model configurations do not include neurohumoral mechanisms such as P2Y receptor-dependent, cAMP, or calcium-dependent pathways, which occur in the ciliary epithelium bilayer and influence the activity of ion transporters, pumps, and channels present in the cell membrane. Results suggest that one of the two configurations predicts sodium and potassium intracellular concentrations and transmembrane potential much more accurately than the other. Because of its quantitative prediction power, the proposed theoretical approach may help relate phenomena at the cellular scale, that cannot be accessed clinically, with phenomena occurring at the scale of the whole eye, for which clinical assessment is feasible.


Synaptosomal transport of radiolabel from N-acetyl-aspartyl-[3H]glutamate suggests a mechanism of inactivation of an excitatory neuropeptide.
This study was undertaken to explore in synaptosomal preparations the disposition of N-acetyl-aspartyl-glutamate (NAAG), an endogenous acidic dipeptide neurotransmitter candidate. Radiolabel from N-acetyl-aspartyl[3H]glutamate was taken up rapidly into an osmotically sensitive compartment by rat brain synaptosomal preparations in a sodium-, temperature-, and time-dependent manner. HPLC analysis of the accumulated radiolabel indicated that the bulk of the tritium cochromatographed with glutamic acid and not with NAAG. In contrast, [14C]NAAG, labeled on the N-terminal acetate, was not taken up by the synaptosomal preparation. All effective inhibitors of synaptosomal, Na+-dependent [3H]glutamate uptake were found to exhibit similar potency in inhibiting uptake of tritium derived from [3H]NAAG. However, certain alpha-linked acidic dipeptides, structurally similar to NAAG, as well as the potent convulsant quisqualic acid inhibited synaptosomal transport of [3H]NAAG but were ineffective as inhibitors of [3H]glutamate transport. Together with a demonstration of disparities between the regional accumulation of radiolabel from [3H]NAAG and high-affinity [3H]glutamate uptake, these data suggest the presence in brain of a specific peptidase targeting carboxy-terminal glutamate-containing dipeptides that may be coupled to the Na+-dependent glutamate transporter. These findings provide a possible mechanism for NAAG inactivation subsequent to its release from nerve endings.


Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells.
Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS.


Acupuncture-Analgesia Following a Single Treatment Session in Chronic Whiplash is Unrelated to Autonomic Nervous System Changes: A Randomized Cross-over Trial.
An acupuncture treatment can reduce pain sensitivity in patients with chronic whiplash associated disorders (WAD). But it has been hypothesized that many of the experimental results in acupuncture research could be interpreted as stress-induced analgesia. The present study aimed at examining whether acupuncture has an effect on the autonomic nervous system response in patients with chronic WAD and if this response is related to the pain inhibition after an acupuncture session. Randomized crossover trial with blinded assessor. Two private practices. Thirty-nine patients with chronic WAD received 2 treatment sessions of identical duration, with acupuncture and relaxation therapy randomly crossed over in the 2 visits. The primary outcome measurement was the registration of autonomic nervous system parameters (heart rate, skin conductance, and heart rate variability parameters) during the administration of experimental pain. Endogenous analgesia was the secondary outcome. Following one acupuncture treatment session, there was a significant change for 2 parameters: the heart rate was slightly reduced and the skin conductance was raised. Comparing the effects of acupuncture and relaxation, no differences were found with respect to the change in any of the autonomic parameters. Further, the reduction in pain sensitivity in response to acupuncture treatment was unrelated to any of the changes in autonomic measurements. The results were observed after only one session of acupuncture. In patients with chronic WAD, in response to a single treatment session, no acupuncture specific effects on the autonomic response to pain assessment were present and the analgesia after one session of acupuncture is not caused by stress-induced analgesia but is more likely the result of an acupuncture specific reaction.


Sexuality in individuals with traumatic brain injury and their partners.
Whilst previous research has detailed the impact of TBI on an individual's sexuality, few studies have investigated couples' sexuality where one partner has sustained a TBI. The study assessed sexual function in individuals with TBI and their partners. Fifty five individuals who had sustained TBI and their partners completed the Derogatis Interview for Sexual Function-Self Report (DISF-SR). All participants scored below the 50th percentile in relation to norms. Whilst participants with TBI obtained lower T-scores than partners on all subscales (except for sexual behaviour/experiences where scores were equivalent), as well as the total score, none of these differences was significant. Item analysis indicated that female participants with TBI reported significantly lower scores than female partners on frequency of having normal lubrication. Normative comparisons revealed that approximately one-third of individuals with TBI and one-fifth of their partners scored below the second percentile. Given the high frequency of sexual problems in individuals with TBI, which also impact their partners, addressing sexual problems should be a priority in rehabilitation and beyond.


Hypoxia-Related Marker GLUT-1, CAIX, Proliferative Index and Microvessel Density in Canine Oral Malignant Neoplasia.
For various types of tumor therapy, it is suggested that co-targeting of tumor microenvironment, mainly tumor vasculature, mediates tumor response mechanisms. Immunohistochemistry for glucose transporter-1 (GLUT-1), carbonic anhydrase-IX (CAIX), Ki-67, and von Willebrand factor VIII for microvessel density (MVD) were performed on formalin-fixed paraffin-embedded samples of canine oral malignant neoplasms. Polarographic oxygen measurements (median pO2) and perfusion data via contrast-enhanced power Doppler ultrasound (median vascularity, median blood volume) provided additional information. Ninety-two samples were analyzed: sarcomas (n = 32), carcinomas (n = 30), and malignant melanomas (n = 30). Polarographic oxygen and perfusion data was available in 22.8% (sarcomas n = 9, carcinomas n = 7, melanomas n = 5), and 27.1% (sarcomas n = 10, carcinomas n = 8, melanomas n = 7) of cases, respectively. GLUT-1 expression was detected in 46.7% of all samples, and was generally weak. CAIX expression was found in 34.8% of all samples. Median Ki-67 score and MVD count was 19% and 17, respectively. The evaluation of the GLUT-1 score and continuous data showed significantly lower GLUT-1 levels in sarcomas (mean 5.1%, SD 6.2) versus carcinomas and melanomas (mean 16.5%/ 19.0%, SD 17.3/ 20.9, p = 0.001). The expression of CAIX correlated mildly positively with GLUT-1 (p = 0.018, rho = 0.250) as well as with Ki-67 (p = 0.014, rho = 0.295). MVD showed a significantly lower level in melanomas (mean 12.6, SD 7.7) versus sarcomas and carcinomas (mean 21.8/ 26.9, SD 13.0/20.4, p = 0.001). Median vascularity and blood volume were significantly lower in sarcomas (mean 10.4%, SD 11.0, and mean 6.3%, SD 6.5, respectively) versus carcinomas (mean 39.2%, SD 16.4 and mean 33.0%, SD 25.6, respectively) and melanomas (mean 36.0%, SD 18.3, and 31.5%, SD 24.5). Between the 3 histological groups, there was neither a significant difference in the GLUT-1 and CAIX score and continuous data, nor the Ki67 score, or polarographic oxygen measurements. GLUT-1 continuous data and Ki-67 (p<0.001, rho = 0.403), as well as Ki-67 and MVD (p = 0.029, rho = 0.228) correlated positively and a mild correlation was found between vascularity and GLUT-1 (p = 0.043, rho = 0.408). GLUT-1, CAIX, proliferative index and MVD levels were established as microenvironmental descriptors with the purpose of creating a baseline in order to follow changes seen in the tumor microenvironment after hypofractionated radiation with high doses.


Impact of new diagnostic criteria for diabetes on different populations.
For epidemiological purposes, it has now been recommended that a fasting plasma glucose value of 7.0 mmol/l can be used to diagnose diabetes, instead of a 2-h value of 11.1 mmol/l. This study assesses the impact of making this change on the prevalence of diabetes and on the phenotype of individuals identified. Data were collated from nine population based southern hemisphere studies in which a 75-g oral glucose tolerance test was performed. Comparisons were made between the prevalence derived from fasting values only and the prevalence derived from 2-h values only. Cardiovascular risk was assessed in all individuals. There were 20,624 subjects in the nine surveys of whom 1,036 had previously diagnosed diabetes and 1,714 had newly diagnosed diabetes, according to either fasting or 2-h glucose. The differences in prevalence within each population resulting from changing the diagnostic criteria ranged from +30 to -19% (relative difference) and +4.1 percentage points to -2.8 percentage points (absolute difference). BMI was the most important determinant of disagreement in classification. A total of 31% of those individuals who were diabetic on the fasting value were not diabetic on the 2-h value, and 32% of those with diabetes on the 2-h value were not diabetic on the fasting value. Apart from obesity, there were no differences in cardiovascular risk between those identified by the fasting and the 2-h values. Changing the diagnostic criteria is likely to have variable and sometimes quite large effects on the prevalence of diabetes in different populations. Furthermore, the fasting criterion identifies different people as being diabetic than those identified by the 2-h criterion.


Adolescent and Young Adult Cancer Survivors: Development of an Interprofessional Survivorship Clinic.
Adolescent and young adult (AYA) cancer survivors experience unique needs and challenges, including the long-term risk of adverse treatment and disease effects. In addition, consequences of the cancer experience may profoundly affect their quality of life. This article describes the development of an interprofessional survivorship clinic established to meet the unique needs of AYA cancer survivors aged 18-39 years.


The Evolution of Health Care Utilisation and Costs for Inflammatory Bowel Disease Over Ten Years.
Inflammatory bowel disease [IBD] places an economic strain on health systems due to expensive pharmaceutical therapy, risk of hospitalisation and surgery, and long-term monitoring. The evolving treatment guidelines advocate rapid scale-up to biologic agents in order to improve health outcomes and quality of life. This study evaluated changes in health care utilisation and expenditures for IBD in Switzerland over time. We extracted clinical, patient, and resource consumption data from the Swiss IBD Cohort Study between 2006 and 2016. Average unit costs for IBD-related events were derived from Swiss claims data and pharmaceutical price lists. We used multivariate regression, controlling for patient-level characteristics, to estimate trends and determinants of direct and indirect costs and resource utilisation. We included 2365 adults diagnosed with Crohn's disease [CD; N = 1353] and ulcerative colitis [UC; N = 1012]. From 2006-16, mean health care expenditures per patient per year were 9504 euros [70% drugs, 23% inpatient, 7% outpatient] for CD and 5704 euros [68% drugs, 22% inpatient, 10% outpatient] for UC. Health care costs increased by 7% [CD] and 10% [UC] per year, largely due to rising pharmaceutical expenditures driven by increased biologic agent use. Inpatient, outpatient, and indirect costs fluctuated and did not offset increased pharmaceutical costs. Disease characteristics were important predictors of costs. Increased expenditure for IBD was marked by a shift towards greater pharmaceutical management over the past decade. This study highlights the need to identify cost-effective treatment strategies in the face of increased uptake and expenditures associated with innovative treatments.


Platelet autophagic machinery involved in thrombosis through a novel linkage of AMPK-MTOR to sphingolipid metabolism.
Basal macroautophagy/autophagy has recently been found in anucleate platelets. Platelet autophagy is involved in platelet activation and thrombus formation. However, the mechanism underlying autophagy in anucleate platelets require further clarification. Our data revealed that LC3-II formation and SQSTM1/p62 degradation were noted in H2O2-activated human platelets, which could be blocked by 3-methyladenine and bafilomycin A1, indicating that platelet activation may cause platelet autophagy. AMPK phosphorylation and MTOR dephosphorylation were also detected, and block of AMPK activity by the AMPK inhibitor dorsomorphin reversed SQSTM1 degradation and LC3-II formation. Moreover, autophagosome formation was observed through transmission electron microscopy and deconvolution microscopy. These findings suggest that platelet autophagy was induced partly through the AMPK-MTOR pathway. In addition, increased LC3-II expression occurred only in H2O2-treated Atg5f/f platelets, but not in H2O2-treated atg5-/- platelets, suggesting that platelet autophagy occurs during platelet activation. atg5-/- platelets also exhibited a lower aggregation in response to agonists, and platelet-specific atg5-/- mice exhibited delayed thrombus formation in mesenteric microvessles and decreased mortality rate due to pulmonary thrombosis. Notably, metabolic analysis revealed that sphingolipid metabolism is involved in platelet activation, as evidenced by observed several altered metabolites, which could be reversed by dorsomorphin. Therefore, platelet autophagy and platelet activation are positively correlated, partly through the interconnected network of sphingolipid metabolism. In conclusion, this study for the first time demonstrated that AMPK-MTOR signaling could regulate platelet autophagy. A novel linkage between AMPK-MTOR and sphingolipid metabolism in anucleate platelet autophagy was also identified: platelet autophagy and platelet activation are positively correlated.Abbreviations: 3-MA: 3-methyladenine; A.C.D.: citric acid/sod. citrate/glucose; ADP: adenosine diphosphate; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ANOVA: analysis of variance; ATG: autophagy-related; B4GALT/LacCS: beta-1,4-galactosyltransferase; Baf-A1: bafilomycin A1; BECN1: beclin 1; BHT: butylate hydrooxytoluene; BSA: bovine serum albumin; DAG: diacylglycerol; ECL: enhanced chemiluminescence; EDTA: ethylenediamine tetraacetic acid; ELISA: enzyme-linked immunosorbent assay; GALC/GCDase: galactosylceramidase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/GluSDase: glucosylceramidase beta; GPI: glycosylphosphatidylinositol; H2O2: hydrogen peroxide; HMDB: human metabolome database; HRP: horseradish peroxidase; IF: immunofluorescence; IgG: immunoglobulin G; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPV: mean platelet volume; MTOR: mechanistic target of rapamycin kinase; ox-LDL: oxidized low-density lipoprotein; pAb: polyclonal antibody; PC: phosphatidylcholine; PCR: polymerase chain reaction; PI3K: phosphoinositide 3-kinase; PLS-DA: partial least-squares discriminant analysis; PRP: platelet-rich plasma; Q-TOF: quadrupole-time of flight; RBC: red blood cell; ROS: reactive oxygen species; RPS6KB/p70S6K: ribosomal protein S6 kinase B; SDS: sodium dodecyl sulfate; S.E.M.: standard error of the mean; SEM: scanning electron microscopy; SGMS: sphingomyelin synthase; SM: sphingomyelin; SMPD/SMase: sphingomyelin phosphodiesterase; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; UGT8/CGT: UDP glycosyltransferase 8; UGCG/GCS: UDP-glucose ceramide glucosyltransferase; ULK1: unc-51 like autophagy activating kinase 1; UPLC: ultra-performance liquid chromatography; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; WBC: white blood cell; WT: wild type.


A Case of Solitary Well-Differentiated Papillary Mesothelioma with Invasive Foci in the Pleura.
Well-differentiated papillary mesothelioma (WDPM) is a rare, distinct tumor consisting of mesothelial cells with a papillary architecture, bland cytological features, and a tendency toward superficial spread without invasion. Rare cases with superficial invasion are termed WDPM with invasive foci. We report a case of solitary WDPM with invasive foci in the pleura. A 61-year-old woman presented with a lung adenocarcinoma. A small papillary lesion measuring 29 × 10 × 8 mm was incidentally found in the parietal pleura during a lobectomy for the lung adenocarcinoma. The fibrovascular core of the small papillary lesion was surrounded by a single layer of cuboidal cells with mild to moderate atypia and large nucleoli. Atypical mesothelial cells focally invaded the submesothelial layer. The cells of the papillary lesion were positive for cytokeratins and mesothelial markers. The Ki67 index was <1 %. The lesion did not show p16 loss on fluorescence in situ hybridization. We could not detect atypical mesothelial cells in the specimen from an extrapleural pneumonectomy. WDPM with invasive foci is prone to multifocality; however, our case represents a solitary case in the pleura.


Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma.
The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3) in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90). Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17-demethoxygeldanamycin (17-AAG) had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of downstream signaling intermediates (AKT, mitogen-activated protein kinase, and S6); upregulated the p53, p21, and p27 cell cycle checkpoints; induced G(2) phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G(1) apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma.


Independent component and pathway-based analysis of miRNA-regulated gene expression in a model of type 1 diabetes.
Several approaches have been developed for miRNA target prediction, including methods that incorporate expression profiling. However the methods are still in need of improvements due to a high false discovery rate. So far, none of the methods have used independent component analysis (ICA). Here, we developed a novel target prediction method based on ICA that incorporates both seed matching and expression profiling of miRNA and mRNA expressions. The method was applied on a cellular model of type 1 diabetes. Microarray profiling identified eight miRNAs (miR-124/128/192/194/204/375/672/708) with differential expression. Applying ICA on the mRNA profiling data revealed five significant independent components (ICs) correlating to the experimental conditions. The five ICs also captured the miRNA expressions by explaining > 97% of their variance. By using ICA, seven of the eight miRNAs showed significant enrichment of sequence predicted targets, compared to only four miRNAs when using simple negative correlation. The ICs were enriched for miRNA targets that function in diabetes-relevant pathways e.g. type 1 and type 2 diabetes and maturity onset diabetes of the young (MODY). In this study, ICA was applied as an attempt to separate the various factors that influence the mRNA expression in order to identify miRNA targets. The results suggest that ICA is better at identifying miRNA targets than negative correlation. Additionally, combining ICA and pathway analysis constitutes a means for prioritizing between the predicted miRNA targets. Applying the method on a model of type 1 diabetes resulted in identification of eight miRNAs that appear to affect pathways of relevance to disease mechanisms in diabetes.


Heat shock protein gp96 and NAD(P)H oxidase 4 play key roles in Toll-like receptor 4-activated apoptosis during renal ischemia/reperfusion injury.
Ischemia/reperfusion injury (IRI) causes inflammation and cell injury as a result of activating innate immune signaling. Toll-like receptor 4 (TLR4) has a key role in mediating kidney damages during IRI, but the downstream signaling pathway(s) stimulating apoptosis remains debated. In this study we show that TLR4 mediates MyD88-dependent activation of TNF receptor-associated factor 2, apoptosis signal-regulating kinase 1 (ASK1), and Jun N-terminal kinase (JNK) and p38 MAP kinases in ischemic-reperfused kidneys and posthypoxic renal tubule epithelial cells (RTECs). Hypoxia stimulated the expression of the endoplasmic-resident gp96, which co-immunoprecipitated TLR4, whereas silencing gp96 mRNA expression impaired hypoxia-induced apoptosis in TLR4-expressing RTECs. NAD(P)H oxidase 4 (NOX4) was shown to interact with TLR4 and to be required in lipopolysaccharide-induced production of reactive oxygen species (ROS). IRI stimulated the expression of a 28-kDa NOX4 spliced isoform abundantly expressed in wild-type RTECs, which co-immunoprecipitated with TLR4, but not with gp96 in TLR4-deficient RTECs. Silencing NOX4 mRNA expression impaired hypoxia-induced activation of ASK1 and both JNK and p38, leading to the inhibition of ROS production and apoptosis in posthypoxic TLR4-expressing RTECs. These findings show that, concomitantly to the activation of p38, the gp96/TLR4 interaction is required for activation of ASK1/JNK signaling in posthypoxic mouse RTECs, and that the 28-kDa NOX4 has a key role in TLR4-mediated apoptosis during renal IRI.


The effect of pH on the acute toxicity of phenanthrene in a marine microalgae Chlorella salina.
Phenanthrene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) found in continental shelf environment of China and is on the EPA's Priority Pollutant list. In this study, the effects of phenanthrene on marine algal growth rate were determined after 96-h exposure at pH 6.0, 7.0, 8.0, 9.0, and 10.0 in seawater of salinity 35. Two measuring techniques to assess growth inhibition were also compared using prompt fluorescence and microscopic cell count. The results showed that the toxicity of phenanthrene increased significantly (p < 0.05) with decreasing pH, with the nominal concentration required to inhibit growth rate by 50%, EC50, decreasing from 1.893 to 0.237 mg L-1 as pH decreased from 9.0 to 6.0, with a decrease higher than 55% from 10.0 to 9.0. In addition, the nominal EC50 values calculated in this study were at the same range of some environmental concentrations of phenanthrene close to areas of crude oil exploration. Based on the two measuring techniques, the results showed that cell count and fluorescence measurement were significantly different (p < 0.05), and the nominal EC50 values calculated with cell count measurement were significantly higher than fluorescence measurement at pH 8.0, 9.0 and 10.0. In conclusion, the present studies confirmed that acidification of seawater could affect the toxicity of phenanthrene to this species of microalgae, and which encouraged further studies involving responses of marine organisms to ocean acidification.


The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease.
E5555 is a potent protease-activated receptor (PAR-1) antagonist targeting the G-coupled receptor and modulating thrombin-platelet-endothelial interactions. The drug is currently being tested in phase II trials in patients with coronary artery disease (CAD) and has potential antithrombotic and anti-inflammatory benefits. We investigated the in-vitro effects of E5555 on platelet function beyond PAR-1 blockade in healthy volunteers and CAD patients treated with aspirin (ASA) with or without clopidogrel. Conventional aggregation induced by 5 microM ADP, 1 microg/ml collagen, 10 microM TRAP, whole blood aggregation with 1 microg/ml collagen, and expression of 14 intact, and TRAP-stimulated receptors by flow cytometry were utilised to assess platelet activity after preincubation with escalating concentrations of E5555 (20 ng/ml, 50 ng/ml, and 100 ng/ml) in healthy volunteers, CAD patients treated with ASA, and CAD patients treated with ASA and clopidogrel combination (n=10, for each group). E5555 inhibited a number of platelet biomarkers. Platelet inhibition was usually moderate, present already at 20 ng/ml, and was not seemingly dose-dependent without TRAP stimulation. E5555 caused 10-15% inhibition of ADP- and collagen-induced platelet aggregation in plasma, but not in whole blood. TRAP-induced aggregation was inhibited almost completely. PECAM-I, GP IIb/IIIa antigen, and activity with PAC-1, GPIb, thrombospondin, vitronectin receptor expression, and formation of platelet-monocyte aggregates were also significantly reduced by E5555. TRAP stimulation caused dose-dependent effects between 20 and 50 ng/ml E5555 doses. P-selectin, LAMP-1, LAMP, and CD40-ligand were not affected by E5555. In conclusion, E5555 in vitro moderately but significantly inhibits platelet activity beyond PAR-1 blockade. Antiplatelet potency of ASA alone, and the combination of ASA and clopidogrel may be enhanced by E5555 providing rationale for their synergistic use. Selective blockade of platelet receptors suggests unique antiplatelet properties of E5555 as a potential addition to current antithrombotic regimens.


Proportion of patients without mental disorders being treated in mental health services worldwide.
Previous research suggests that many people receiving mental health treatment do not meet criteria for a mental disorder but are rather 'the worried well'. To examine the association of past-year mental health treatment with DSM-IV disorders. The World Health Organization's World Mental Health (WMH) Surveys interviewed community samples of adults in 23 countries (n = 62 305) about DSM-IV disorders and treatment in the past 12 months for problems with emotions, alcohol or drugs. Roughly half (52%) of people who received treatment met criteria for a past-year DSM-IV disorder, an additional 18% for a lifetime disorder and an additional 13% for other indicators of need (multiple subthreshold disorders, recent stressors or suicidal behaviours). Dose-response associations were found between number of indicators of need and treatment. The vast majority of treatment in the WMH countries goes to patients with mental disorders or other problems expected to benefit from treatment.


PI4KIIIβ Activity Regulates Lateral Root Formation Driven by Endocytic Trafficking to the Vacuole.
Lateral roots (LRs) increase the contact area of the root with the rhizosphere and thereby improve water and nutrient uptake from the soil. LRs are generated either via a developmentally controlled mechanism or through induction by external stimuli, such as water and nutrient availability. Auxin regulates LR organogenesis via transcriptional activation by an auxin complex receptor. Endocytic trafficking to the vacuole positively regulates LR organogenesis independently of the auxin complex receptor in Arabidopsis (Arabidopsis thaliana). Here, we demonstrate that phosphatidylinositol 4-phosphate (PI4P) biosynthesis regulated by the phosphatidylinositol 4-kinases PI4KIIIβ1 and PI4KIIIβ2 is essential for the LR organogenesis driven by endocytic trafficking to the vacuole. Stimulation with Sortin2, a biomodulator that promotes protein targeting to the vacuole, altered PI4P abundance at both the plasma membrane and endosomal compartments, a process dependent on PI4K activity. These findings suggest that endocytic trafficking to the vacuole regulated by the enzymatic activities of PI4KIIIβ1 and PI4KIIIβ2 participates in a mechanism independent of the auxin complex receptor that regulates LR organogenesis in Arabidopsis. Surprisingly, loss-of-function of PI4KIIIβ1 and PI4KIIIβ2 induced both LR primordium formation and endocytic trafficking toward the vacuole. This LR primordium induction was alleviated by exogenous PI4P, suggesting that PI4KIIIβ1 and PI4KIIIβ2 activity constitutively negatively regulates LR primordium formation. Overall, this research demonstrates a dual role of PI4KIIIβ1 and PI4KIIIβ2 in LR primordium formation in Arabidopsis.


[Influence of ganciclovir and astragalus membranaceus on proliferation of hematopoietic progenitor cells of cord blood after cytomegalovirus infection in vitro].
Cytomegalovirus (CMV) infection was greatly common in the world. CMV infection produces usually mild or asymptomatic infections in individuals with normal immune responses, whereas it may cause serious disease in immunosuppressive patients. Clinical manifestations include suppression of myelopoiesis, a mononucleosis like syndrome, hepatosplenomegaly, lymphadenopathy, thrombocytopenia, and hemolytic anemia. In patients undergoing bone marrow transplantation CMV remains the most common infectious causes of morbidity and mortality. But the treatment drugs with specific effect for CMV was fewer at the present. This study was to investigate the effect of CMV on proliferation of colony forming unit granulocyte-macrophage (CFU-GM), CFU-erythroid (CFU-E), brust forming unit-erythroid (BFU-E), CFU-multipotential (CFU-Mix) and CFU-megakaryocyte (CFU-Mk) progenitor cells of cord blood (CB) with the presence of ganciclovir (GCV) and astragalus membranaceus in vitro. Twenty CB samples were collected from fetal umbilical vein of normal term spontaneous delivery neonates. The colony forming unit-assay was applied to observe the suppression effect of CMV-AD169 strain on CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk of CB with the presence of GCV and astragalus membranaceus in vitro. The technique of PCR was used to demonstrate the existence of CMV-AD169 DNA in the colony cells of cultured CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk. (1) The numbers of CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk colonies in CMV infection groups were significantly less than those in blank and mock group, respectively. The last time of colonies in groups with CMV infection was significantly shorten compared with the blank and mock group. (2) CMV-DNA was positively detected in the colony cells of CMV infection groups by PCR, while negative in the control groups. (3) The lasting time of CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk colonies infected with CMV extended significantly with the presence of astragalus membranaceus and GCV, and the numbers of those increased significantly compared with the CMV infection group, respectively. The increasing rate of colonies was 27.2%, 45.2%, 49.1%, 39.0% and 11.9% with astragalus membranaceus group, 37.4%, 74.2%, 71.7%, 67.4% and 38.9% with GCV group, 53.6%, 83.8%, 88.7%, 87.8% and 61.5% with astragalus membranaceus and GCV group, respectively. The differentiation and proliferation of CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk were significantly inhibited after infected with CMV-AD169 strain. The suppression effect of CMV-AD169 on CFU-GM, CFU-E, BFU-E, CFU-Mix and CFU-Mk was inhibited with the presence of GCV and astragalus membranaceus in vitro. This suggested that CMV-AD169 may be inhibited or killed by GCV and Astragalus Membranaceus in vitro.


Fast algorithms for designing optical phase-only filters (POFs) and binary phase-only filters (BPOFs).
Very efficient suboptimal algorithms for the design of phase-only filters and binary phase-only filters are presented. A reduction of 2- to 3-orders of magnitude in computer time is obtained over previous algorithms. The loss in signal-to-noise ratio is negligible (<0.001 dB).


Does telomerase reverse transcriptase induce functional de-differentiation of human endothelial cells?
By counteracting the shortening of chromosome telomeres, telomerase reverse transcriptase (hTERT) prevents senescence and age-related cell death. Embryonic cells display a high telomerase activity that declines rapidly with cell differentiation. Conversely, de-differentiated tumor cells tend to re-express telomerase. In view of the controversial data on the reciprocal correlation between cell proliferation and differentiation, we questioned whether telomerase overexpression and the resulting immortalization would affect the functional phenotype of human endothelial cells. Our comparative analysis addressed (1) distinct cell adhesion to different ECM-proteins analyzed on miniaturized multisubstrate arrays (MSA), (2) protein expression of diverse markers, (3) the uptake of DiI-Ac-LDL, (4) the inflammatory response based on upregulation of ICAM-1, (5) tube formation, and (6) the barrier properties of cell monolayers in transfilter cultures. Our results, based on some 40 data sets, demonstrate that immortalization of primary endothelial cells by hTERT maintains the typical endothelial characteristics without any sign of functional de-differentiation.


Prevalence of extra-articular manifestations in psoriatic arthritis: a systematic review and meta-analysis.
To describe the prevalence of extra-articular manifestations-enthesitis, dactylitis, nail disease, uveitis and IBD-in PsA, and their impact on longitudinal disease outcomes. We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies using imaging to define extra-articular manifestations (EAMs) were excluded. Where possible, we performed meta-analyses of prevalence estimates, reported as percentages (95% CI). Heterogeneity (I2 statistic) was examined according to study characteristics. We identified 65 studies amounting to a total of 163 299 PsA patients. Enthesitis was assessed in 29 studies with an average prevalence of 30% (95% CI: 24%, 38%). Dactylitis was reported in 35 studies with an average prevalence of 25% (95% CI: 20%, 31%). Nail disease was present in 60% (95% CI: 52%, 68%) across 26 studies, but definitions were often unclear. Uveitis (3.2%; 95% CI: 1.9%, 5.3%) and IBD (3.3%; 95% CI: 1.5%, 7.1%) were less common. Heterogeneity was high (>95%) in all meta-analyses, but could not be explained by study characteristics. No studies examined the impact of EAMs on longitudinal disease outcomes, except that dactylitis increases radiographic progression. Enthesitis, dactylitis and nail disease are highly prevalent in PsA, but not uveitis and IBD. EAM patterns differ from axial SpA despite their shared disease mechanisms, which may help further understand differences between spondyloarthritides. More studies are needed on the impact of EAMs on disease outcomes such as response to treatment.


Chorionic gonadotropin up-regulates long pentraxin 3 expression in myeloid cells.
Pentraxin 3 (PTX3) is an acute-phase response protein that initiates innate immunity against diverse microorganisms. It is produced in response to proinflammatory stimuli by many cell types including myeloid cells. Increased serum levels of PTX3 are found in pregnancy, a condition characterized by increased serum levels of the pregnancy hormone human chorionic gonadotropin (hCG). As myeloid cells bear the receptor for hCG, we hypothesized that hCG can promote innate immunity by affecting the PTX3 production by myeloid cells. In this paper, we demonstrate that hCG increases PTX3 expression by human monocytes, mouse dendritic cells, and mouse macrophages in vitro. This increased PTX3 expression by hCG is mediated via the protein kinase A signaling pathway. hCG injection in mice also increases the PTX3 serum levels. This serum PTX3 is produced mainly by blood monocytes, which from pregnant women, express more PTX3 compared with nonpregnant controls. The hCG-induced hormones progesterone and estrogen also increase the PTX3 production by human monocytes. In conclusion, hCG increases innate immunity via induction of PTX3 in myeloid cells.


Mimivirus relatives in the Sargasso sea.
The discovery and genome analysis of Acanthamoeba polyphaga Mimivirus, the largest known DNA virus, challenged much of the accepted dogma regarding viruses. Its particle size (>400 nm), genome length (1.2 million bp) and huge gene repertoire (911 protein coding genes) all contribute to blur the established boundaries between viruses and the smallest parasitic cellular organisms. Phylogenetic analyses also suggested that the Mimivirus lineage could have emerged prior to the individualization of cellular organisms from the three established domains, triggering a debate that can only be resolved by generating and analyzing more data. The next step is then to seek some evidence that Mimivirus is not the only representative of its kind and determine where to look for new Mimiviridae. An exhaustive similarity search of all Mimivirus predicted proteins against all publicly available sequences identified many of their closest homologues among the Sargasso Sea environmental sequences. Subsequent phylogenetic analyses suggested that unknown large viruses evolutionarily closer to Mimivirus than to any presently characterized species exist in abundance in the Sargasso Sea. Their isolation and genome sequencing could prove invaluable in understanding the origin and diversity of large DNA viruses, and shed some light on the role they eventually played in the emergence of eukaryotes.


Study of middle ear disease using tympanometry in general practice.
Tympanometry was used to provide evidence of middle ear effusions in a prospective study of middle ear disease in 264 children aged 3 months to 6 years in general practice. Adequate measurements on both ears were obtained in 220 children, of whom 68 (31%) had evidence of middle ear effusion in one ear (29 children) or both ears (39 children) at entry to the study. In 28 (42%) of the 68 children persistence of the tympanometric findings was recorded for at least three months. Children of European descent were more likely to have evidence of middle ear effusion at the initial examination compared with African and West Indian children, as were those children whose siblings had a positive history of otitis media compared with those whose siblings had no such history. Children under 3 years were more likely to have evidence of an effusion than older children. Middle ear effusion as shown by tympanometry was not associated with a previous history of otitis media in the child but was associated with recent symptoms of respiratory infection or otalgia. A previous consultation for otitis media was, however, strongly associated with a greater likelihood of a consultation for otitis media during the follow up period. Comparing evidence of effusion by tympanometry with that by pneumatic otoscopy showed that using the appearance of the eardrum alone the sensitivity of otoscopy was 55%; the addition of mobility improved the sensitivity to 76% with little reduction in specificity. Further studies on populations using tympanometry are needed to determine the natural history, aetiology, and indications for referring children with middle ear effusion.


Substance abuse in outpatients attending rural and urban health centres in Kenya.
To estimate the prevalence and pattern of substance use among patients attending primary health centres in urban and rural areas of Kenya. A descriptive cross-sectional prevalence survey. Urban health centres of Jericho and Kenyatta University (KU) and rural health centres in Muranga district. One hundred and fifty adult patients (seventy eight males and seventy two females) were included in the study. Semi-structured questionnaires and the DSM IV diagnostic criteria were used to record the socio-demographic data and to determine substance dependence or abuse. The substances commonly used in descending order of frequency were alcohol, tobacco, khat and cannabis. Only alcohol and tobacco were extensively used. Lifetime prevalence rates of alcohol use for the two urban health centres were 54% and 62% compared to 54% for the rural health centres. For tobacco the lifetime prevalence rates were 30% for Jericho, 28% for KU and 38% for Muranga. The differences between the rural and urban samples were not statistically significant. More males than females had used alcohol (average lifetime use 80.8% for males compared to 30.6% for females: p<0.05) and tobacco (average lifetime use 56.4% for males compared to 5.6% for females p<0.05). The rates of substance abuse were generally low with the exception of alcohol and tobacco. Socio-cultural factors might be responsible for the differences noted. It is suggested that preventive measures and education should be emphasised at the primary care level.


Selective nonoperative management of penetrating thoracic injury.
Thoracic penetrating injury is a cause for up to one-fifth of all non-natural deaths. The aim of this study was to determine the success of selective nonoperative management (SNOM) of patients presenting with a penetrating thoracic injury (PTI). This was a prospective study of patients with PTI who presented to a level 1 Trauma Center between April 2012 and August 2012. A total of 248 patients were included in the study, with 5.7% (n=14) requiring immediate emergency surgery. Overall, five of these 248 patients died, resulting in a mortality rate of 2.0%. Primarily 221 patients (89.1%) were managed with SNOM, of whom 15 (6.8%) failed conservative management. Failure of SNOM was primarily caused by complications of chest tube drainage (n=12) (e.g. retained clot, empyema) and delayed development of cardiac tamponade (n=3). The survival rate in the SNOM group was 100%. PTI has a low in-hospital mortality rate. Only 16.5% (41/248) of the patients presenting with PTI will need surgical treatment. The other patients are safe to be treated conservatively according to a protocolized SNOM approach for PTI without any additional mortality. Conservative treatment of patients who were selected for this nonoperative treatment strategy with repeated clinical reassessment was successful in 93.2%.


Isolation, characterization, and complementation of a paralyzed flagellar mutant of Rhodobacter sphaeroides WS8.
A paralyzed Rhodobacter sphaeroides mutant strain (PARA1) was isolated by a motility screening procedure following mutagenesis of wild-type R. sphaeroides WS8-N with the transposable element TnphoA (Tn5 IS50L::phoA). PARA1 synthesized a wild-type level of flagellin, as detected by Western immunoblotting with antiflagellar antiserum. Flagellar staining showed that flagellin was assembled into apparently normal external flagellar filaments. Electron micrographs of basal body structures from PARA1 showed that some ring structures that were present were similar to those in wild-type R. sphaeroides WS8-N. PARA1 cells were nonmotile under all growth conditions. No pseudorevertants to motility were seen when PARA1 was grown in the presence of kanamycin to select for the presence of the transposon. The presence of the single copy of TnphoA in the PARA1 chromosome was demonstrated by Southern blotting. Western blotting of cytoplasmic, periplasmic, and membrane fractions of PARA1 with anti-alkaline phosphatase antiserum showed that the transposon had been inserted in-frame into a gene encoding a membrane protein. A SalI restriction endonuclease fragment was cloned from the chromosome of PARA1; this fragment contained a portion of the transposon and R. sphaeroides DNA sequence 5' of the site of insertion. This flanking R. sphaeroides DNA sequence was used to probe an R. sphaeroides WS8 cosmid library. A cosmid designated c19 hybridized to the probe, and a SalI restriction endonuclease fragment derived from this cosmid restored wild-type motility to PARA1 when introduced into this mutant strain by conjugation. The significance of this finding in a bacterium with unidirectionally rotating flagella is discussed.


Polarization multiplexing of diffractive elements with metal-stripe grating pixels.
Diffractive elements with polarization multiplexing for the visible spectral region are demonstrated. The polarization-multiplexing property of the element is based on the polarization-dependent transmission characteristics of metal-stripe subwavelength period gratings. The proper dimensions of these gratings are estimated by rigorous calculations. The principle of polarization multiplexing by use of metal-stripe subwavelength period gratings is described for a diffractive element that has a binary amplitude transmission per polarization channel and is demonstrated by experimental results.


Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish.
Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters. Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.


Effects of potato-cotton cropping systems and nematicides on plant-parasitic nematodes and crop yields.
Belonolaimus longicaudatus has been reported as damaging both potato (Solanum tuberosum) and cotton (Gossypium hirsutum). These crops are not normally grown in cropping systems together in areas where the soil is infested with B. longicaudatus. During the 1990s cotton was grown in a potato production region that was a suitable habitat for B. longicaudatus. It was not known how integrating the production of these two crops by rotation or double-cropping would affect the population densities of B. longicaudatus, other plant-parasitic nematodes common in the region, or crop yields. A 3-year field study evaluated the viability of both crops in monocropping, rotation, and double-cropping systems. Viability was evaluated using effects on population densities of plant-parasitic nematodes and yields. Rotation of cotton with potato was found to decrease population densities of B. longicaudatus and Meloidogyne incognita in comparison with continuous potato. Population densities of B. longicaudatus following double-cropping were greater than following continuous cotton. Yields of both potato and cotton in rotation were equivalent to either crop in monocropping. Yields of both crops were lower following double-cropping when nematicides were not used.


Adjunctive naturopathic care for type 2 diabetes: patient-reported and clinical outcomes after one year.
Several small, uncontrolled studies have found improvements in self-care behaviors and reductions in clinical risk in persons with type 2 diabetes who received care from licensed naturopathic physicians. To extend these findings and determine the feasibility and promise of a randomized clinical trial, we conducted a prospective study to measure the effects of adjunctive naturopathic care (ANC) in primary care patients with inadequately controlled type 2 diabetes. Forty patients with type 2 diabetes were invited from a large integrated health care system to receive up to eight ANC visits for up to one year. Participants were required to have hemoglobin A1c (HbA1c) values between 7.5-9.5 % and at least one additional cardiovascular risk factor (i.e., hypertension, hyperlipidemia or overweight). Standardized instruments were administered by telephone to collect outcome data on self-care, self-efficacy, diabetes problem areas, perceived stress, motivation, and mood. Changes from baseline scores were calculated at 6- and 12-months after entry into the study. Six and 12-month changes in clinical risk factors (i.e., HbA1c, lipid and blood pressure) were calculated for the ANC cohort, and compared to changes in a cohort of 329 eligible, non-participating patients constructed using electronic medical records data. Between-cohort comparisons were adjusted for age, gender, baseline HbA1c, and diabetes medications. Six months was pre-specified as the primary endpoint for outcome assessment. Participants made 3.9 ANC visits on average during the year, 78 % of which occurred within six months of entry into the study. At 6-months, significant improvements were found in most patient-reported measures, including glucose testing (P = 0.001), diet (P = 0.001), physical activity (P = 0.02), mood (P = 0.001), self-efficacy (P = 0.0001) and motivation to change lifestyle (P = 0.003). Improvements in glucose testing, mood, self-efficacy and motivation to change lifestyle persisted at 12-months (all P < 0.005). For clinical outcomes, mean HbA1c decreased by -0.90 % (P = 0.02) in the ANC cohort at 6-months, a -0.51 % mean difference compared to usual care (P = 0.07). Reductions at 12-months were not statistically significant (-0.34 % in the ANC cohort, P = 0.14; -0.37 % difference compared to the usual care cohort, P = 0.12). Improvements were noted in self-monitoring of glucose, diet, self-efficacy, motivation and mood following initiation of ANC for patients with inadequately controlled type 2 diabetes. Study participants also experienced reductions in blood glucose that exceeded those for similar patients who did not receive ANC. Randomized clinical trials will be necessary to determine if ANC was responsible for these benefits.


Early discontinuation of antidepressant treatment and suicide risk among persons aged 50 and over: a population-based register study.
As many as 47% of adults over age 50 discontinue treatment with antidepressants after redeeming only one prescription. The study aim was to assess the risk of suicide in adults aged 50+ who discontinue antidepressants at an early stage of treatment. Case control study of all individuals aged 50+ living in Denmark and who initiated antidepressant treatment between July 1st 1995 and December 31st 2000 (N=217,123). Hazard ratios were calculated using Cox regression analyses, propensity score matching techniques, and marginal structural models. During the study period, 78,594 men and 138,529 women aged 50+ began treatment with an antidepressant medication, of whom 309 men and 229 women died by suicide. Men aged 50+ who discontinued treatment early had a suicide rate of 167 per 100,000 compared with 175 per 100,000 in those who continued refilling prescriptions; hazard ratio=0.98 [CI-95%: 0.78-1.23]. The suicide rate in women who discontinued treatment was 52 per 100,000 compared with 74 per 100,000 in those who continued refilling; hazard ratio=0.72 [CI-95%: 0.55-0.94]. Although people with previous psychiatric hospitalizations had greater risk of suicide than those without past hospital admissions, the difference was not significant in the adjusted model. Prescriptions redeemed at pharmacies are our only indicator of treatment adherence. Also, information on severity of depression was not available. We did not find a lower suicide risk among people over age 50 who seemingly follow treatment in comparison with those who discontinued treatment with antidepressants at an early stage.


Paleo-oncology: the role of ancient remains in the study of cancer.
Paleo-oncology is the study of carcinomas and sarcomas in ancient human populations and their hominid precursors. These populations are informative concerning the possible influences on cancer of morphologic and functional evolution, diet, lifestyle, and other environmental factors. The prevalence of cancer in ancient populations might have differed from that in modern humans, because of substantial differences in tobacco and alcohol use, diet, life expectancy, and the availability of treatment. The available physical data concerning cancer in antiquity includes evidence of its existence in animal fossils and ancient humans and their precursors. The difficulties of paleo-oncologic research include a limited soft tissue record. In evaluating cancer in ancient remains, one must also deal with the problem of pseudopathology: whether an observed tissue change is all antemortem pathologic lesion or a postmortem artifact. Future archeological discoveries and the application of improved diagnostic techniques may enable paleo-oncology to make further contributions to our understanding of cancer.


The use of tobacco is a modifiable risk factor for poor outcomes and readmissions after shoulder arthroplasty.
The impact of tobacco use on readmission and medical and surgical complications has been documented in hip and knee arthroplasty. However, there remains little information about the effect of smoking on the outcome after total shoulder arthroplasty (TSA). We hypothesized that active smokers are at an increased risk of poor medical and surgial outcomes after TSA. Data for patients who underwent arthroplasty of the shoulder in the USA between January 2011 and December 2015 were obtained from the National Readmission Database, and 90-day readmissions and complications were documented using validated coding methods. Multivariate regression analysis was performed to quantify the risk of smoking on the outcome after TSA, while controlling for patient demographics, comorbidities, and hospital-level confounding factors. A total of 196,325 non-smokers (93.1%) and 14,461 smokers (6.9%) underwent TSA during the five-year study period. Smokers had significantly increased rates of 30- and 90-day readmission (p = 0.025 and 0.001, respectively), revision within 90 days (p < 0.001), infection (p < 0.001), wound complications (p < 0.001), and instability of the prosthesis (p < 0.001). They were also at significantly greater risk of suffering from pneumonia (p < 0.001), sepsis (p = 0.001), and myocardial infarction (p < 0.001), postoperatively. Smokers have an increased risk of readmission and medical and surgical complications after TSA. These risks are similar to those found for smokers after hip and knee arthroplasty. Many surgeons choose to avoid these elective procedures in patients who smoke. The increased risks should be considered when counselling patients who smoke before undertaking TSA.


Prediction of differential adult health burden by conduct problem subtypes in males.
A cardinal feature of the DSM-IV diagnostic criteria for conduct disorder is the distinction between childhood- vs adolescent-onset subtypes. Whether such developmental subtypes exist in the population and have different prognoses should be rigorously tested to inform the DSM-V. To evaluate the epidemiological validity of childhood- vs adolescent-onset conduct problems in a prospective birth cohort, and to assess whether life-course-persistent conduct problems are associated with a greater adult health burden. Our sample includes 526 male study members in the Dunedin Multidisciplinary Health and Development Study, a 1-year birth cohort (April 1, 1972, through March 30, 1973). Developmental trajectories were defined using prospective ratings of conduct problems at 7, 9, 11, 13, 15, 18, 21, and 26 years of age. Health burden was assessed as mental and physical health problems at 32 years of age measured via diagnostic interviews and physical examinations. We identified the following 4 developmental subtypes of conduct problems through general growth mixture modeling: (1) childhood-onset/life-course-persistent, (2) adolescent onset, (3) childhood limited, and (4) low. At 32 years of age, study members with the life-course-persistent subtype experienced the worst health burden. To a lesser extent, those with the adolescent-onset subtype also experienced health problems. A childhood-limited subtype not specified by DSM-IV was revealed; its adult health outcomes were within the range of the cohort norm. Results support the epidemiological validity of the DSM-IV conduct disorder distinction based on age of onset but highlight the need to also consider long-term persistence to refine diagnosis. Preventing and treating conduct problems has the potential to reduce the adult health burden.


Femur rotation and patellofemoral joint kinematics: a weight-bearing magnetic resonance imaging analysis.
Controlled laboratory study using a cross-sectional design. To compare patellofemoral joint kinematics, femoral rotation, and patella rotation between females with patellofemoral pain (PFP) and pain-free controls using weight-bearing kinematic magnetic resonance imaging. Recently, it has been recognized that patellofemoral malalignment may be the result of femoral motion as opposed to patella motion. Fifteen females with PFP and 15 pain-free females between the ages of 18 and 45 years participated in this study. Kinematic imaging of the patellofemoral joint was performed using a vertically open magnetic resonance imaging system. Axial-oblique images were obtained using a fast gradient-echo pulse sequence. Images were acquired at a rate of 1 image per second while subjects performed a single-limb squat. Measures of femur and patella rotation (relative to the image field of view), lateral patella tilt, and lateral patella displacement were made from images obtained at 45 degrees , 30 degrees , 15 degrees , and 0 degrees of knee flexion. Group differences were assessed using a mixed-model analysis of variance with repeated measures. When compared to the control group, females with PFP demonstrated significantly greater lateral patella displacement at all angles evaluated and significantly greater lateral patella tilt at 30 degrees , 15 degrees , and 0 degrees of knee flexion. Similarly, greater medial femoral rotation was observed in the PFP group at 45 degrees , 15 degrees , and 0 degrees of knee flexion when compared to the control group. No group differences in patella rotation were found. Altered patellofemoral joint kinematics in females with PFP appears to be related to excessive medial femoral rotation, as opposed to lateral patella rotation. Our results suggest that the control of femur rotation may be important in restoring normal patellofemoral joint kinematics. J Orthop Sports Phys Ther 2010;40(5):277-285, Epub 12 March 2010. doi:10.2519/jospt.2010.3215.


Behavioral sensitivity to purinergic drugs parallels ethanol sensitivity in selectively bred mice.
Behavioral responses to an adenosine receptor agonist and antagonist were examined in mice genetically selected for differential sensitivity to the soporific effects of ethanol. Both ethanol and the adenosine receptor agonist L-phenylisopropyladenosine had greater sedative and hypothermic effects in ethanol-sensitive "long-sleep" mice than in ethanol-insensitive "short-sleep" mice. Long-sleep mice were also more sensitive to the excitatory behavioral effects of theophylline, an adenosine receptor antagonist. These data suggest that adenosine may be an endogenous mediator of responses to ethanol.


Animal model of fatal human monocytotropic ehrlichiosis.
Human monocytotropic ehrlichiosis caused by Ehrlichia chaffeensis is a life-threatening, tick-borne, emerging infectious disease for which no satisfactory animal model has been developed. Strain HF565, an ehrlichial organism closely related to E. chaffeensis isolated from Ixodes ovatus ticks in Japan, causes fatal infection of mice. C57BL/6 mice became ill on day 7 after inoculation and died on day 9. The liver revealed confluent necrosis, ballooning cell injury, apoptosis, poorly formed granulomas, Kupffer cell hyperplasia, erythrophagocytosis, and microvesicular fatty metamorphosis. The other significant histological findings consisted of marked expansion of the marginal zone and infiltration of the red pulp of the spleen by macrophages, interstitial pneumonitis, and increased numbers of immature myeloid cells and areas of necrosis in the bone marrow. Ehrlichiae were detected by immunohistology and electron microscopy in the liver, lungs, and spleen. The main target cells were macrophages, including Kupffer cells, hepatocytes, and endothelial cells. Apoptosis was detected in Kupffer cells, hepatocytes, and macrophages in the lungs and spleen. This tropism for macrophages and the pathological lesions closely resemble those of human monocytotropic ehrlichiosis for which it is a promising model for investigation of immunity and pathogenesis.


Sirolimus conversion efficacy for graft function improvement and histopathology in renal recipients with mild to moderate renal insufficiency.
This study was designed to evaluate whether sirolimus (SRL) conversion effectively improves renal function and histopathology in calcineurin inhibitor (CNI)-treated renal recipients with mild to moderate renal insufficiency. SRL conversion from CNI was performed in patients who underwent kidney transplantation from 6 months to 5 yr prior to screening. Forty-five patients were enrolled. The effect of SRL conversion on graft function was evaluated, and protocol biopsies were performed preconversion and 1 yr after conversion. Overall graft function after SRL conversion gradually improved, and the improvement in renal function was closely associated with the shorter duration of CNI exposure. When we divided the patients by the duration of CNI exposure, the patients with less than 1 yr of CNI exposure demonstrated significant improvement, but patients with a greater than 1 yr CNI exposure did not exhibit significant improvement. In contrast, protocol biopsies demonstrated no significant improvements in the modified "ah" score or other Banff scores after SRL conversion. Furthermore, the duration of CNI treatment prior to SRL conversion was not associated with histological findings 1 yr after SRL conversion. SRL conversion improved graft function in renal recipients with mild to moderate renal insufficiency, but this effect is not accompanied by histological improvement.


Fine particulate matter and the risk of autism spectrum disorder.
The causes of autism spectrum disorder (ASD) are not well known. Recent investigations have suggested that air pollution, including PM2.5, may play a role in the onset of this condition. The objective of the present work was to investigate the association between prenatal and early childhood exposure to fine particulate matter (PM2.5) and risk for childhood ASD. A population-based case-control study was conducted in children born between January 1, 2005 and December 31, 2009 in six counties in Southwestern Pennsylvania. ASD cases were recruited from specialty autism clinics, local pediatric practices, and school-based special needs services. ASD cases were children who scored 15 or above on the Social Communication Questionnaire (SCQ) and had written documentation of an ASD diagnosis. Controls were children without ASD recruited from a random sample of births from the Pennsylvania state birth registry and frequency matched to cases on birth year, gender, and race. A total of 217 cases and 226 controls were interviewed. A land use regression (LUR) model was used to create person- and time-specific PM2.5 estimates for individual (pre-pregnancy, trimesters one through three, pregnancy, years one and two of life) and cumulative (starting from pre-pregnancy) key developmental time periods. Logistic regression was used to investigate the association between estimated exposure to PM2.5 during key developmental time periods and risk of ASD, adjusting for mother's age, education, race, and smoking. Adjusted odds ratios (AOR) were elevated for specific pregnancy and postnatal intervals (pre-pregnancy, pregnancy, and year one), and postnatal year two was significant, (AOR=1.45, 95% CI=1.01-2.08). We also examined the effect of cumulative pregnancy periods; noting that starting with pre-pregnancy through pregnancy, the adjusted odds ratios are in the 1.46-1.51 range and significant for pre-pregnancy through year 2 (OR=1.51, 95% CI=1.01-2.26). Our data indicate that both prenatal and postnatal exposures to PM2.5 are associated with increased risk of ASD. Future research should include multiple pollutant models and the elucidation of the biological mechanism for PM2.5 and ASD.


Repeatability of Adaptive Radiation Depends on Spatial Scale: Regional Versus Global Replicates of Stickleback in Lake Versus Stream Habitats.
The repeatability of adaptive radiation is expected to be scale-dependent, with determinism decreasing as greater spatial separation among "replicates" leads to their increased genetic and ecological independence. Threespine stickleback (Gasterosteus aculeatus) provide an opportunity to test whether this expectation holds for the early stages of adaptive radiation-their diversification in freshwater ecosystems has been replicated many times. To better understand the repeatability of that adaptive radiation, we examined the influence of geographic scale on levels of parallel evolution by quantifying phenotypic and genetic divergence between lake and stream stickleback pairs sampled at regional (Vancouver Island) and global (North America and Europe) scales. We measured phenotypes known to show lake-stream divergence and used reduced representation genome-wide sequencing to estimate genetic divergence. We assessed the scale dependence of parallel evolution by comparing effect sizes from multivariate models and also the direction and magnitude of lake-stream divergence vectors. At the phenotypic level, parallelism was greater at the regional than the global scale. At the genetic level, putative selected loci showed greater lake-stream parallelism at the regional than the global scale. Generally, the level of parallel evolution was low at both scales, except for some key univariate traits. Divergence vectors were often orthogonal, highlighting possible ecological and genetic constraints on parallel evolution at both scales. Overall, our results confirm that the repeatability of adaptive radiation decreases at increasing spatial scales. We suggest that greater environmental heterogeneity at larger scales imposes different selection regimes, thus generating lower repeatability of adaptive radiation at larger spatial scales.


Validity of the QuickDASH in patients with shoulder-related disorders undergoing surgery.
Validity study. To determine the validity of the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) in comparison to the full DASH in patients undergoing total shoulder arthroplasty (TSA) and rotator cuff repair (RCR). The QuickDASH is a shorter version of the DASH that may reduce respondent burden while retaining similar measurement properties. One hundred thirty-two patients undergoing TSA or RCR were assessed at baseline and at 3 and 6 months postoperatively. The patients completed the DASH, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form self-report section, and the Western Ontario Rotator Cuff index, and were tested to determine their shoulder range of motion and isometric strength. The differences between scores on the DASH and QuickDASH across the scale range were evaluated using the Bland-Altman technique. Item difficulty, correlations with other patient-reported outcome measures, and physical impairments were used to assess validity. Known group validity was assessed by examining differentiation of work status. Responsiveness was assessed through standardized response means. QuickDASH scores were slightly higher than DASH scores, with a mean difference of 1 to 1.3 points for the TSA group and 1 to 3 points for the RCR group tested preoperatively, and at 3 months and 6 months postoperatively, although limits of agreement were wide (ranging from -10 to 13 across all estimates). The QuickDASH items were distributed across the full DASH, when ranked by item difficulty, for both patient groups. The correlation between the QuickDASH and DASH was almost perfect (r>0.92). Correlations between the DASH/QuickDASH and other patient-reported outcome measures ranged from moderate to very large (American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form self-report section, r=0.47-0.85; Western Ontario Rotator Cuff index, r=0.83-0.91), whereas correlations to impairments were small to moderate. Correlation estimates varied by less than 0.07, depending on whether the DASH or QuickDASH was used, suggesting equivalent construct validity. Both the DASH and QuickDASH discriminated between working and nonworking patients, with similar group differences and statistical significance (P<.01). The QuickDASH and DASH showed similar responsiveness between presurgery and 6-month follow-up (standardized response mean, 1.1 following TSA and 0.8 following RCR). When substituting the QuickDASH for the full DASH, similar score estimates, discrimination of clinically relevant subgroups, and responsiveness can be expected across patients following TSA and RCR.


Properties of low order transverse modes in argon ion lasers.
A study has been conducted to determine the trade-offs among beam divergence, output power, and mirror alignment tolerances of high power argon ion lasers operating in various low order transverse modes. The radial intensity distribution and angular divergence of the actual laser modes from the active cavity have been measured and are compared with the theoretical passive cavity modes. The intensity distributions of higher order laser modes are found to differ markedly from those predicted by theory. The differences consist primarily of enhancement of the intensity of the off-axis peaks relative to that of the center peaks. These differences are caused by the relative high small-signal gain and the saturable gain characteristics of the medium. The beam divergence in free space of different transverse modes agrees very closely with that predicted for the passive cavity modes. The three lowest order transverse modes (i.e., TEM(00), TEM(01*), and TEM(10)) diverge at 1.1, 2.4, and 3.6 times the rate of a diffraction limited gaussian beam having the same diameter at the 1/e(2) intensity points. The mirror alignment tolerances associated with different transverse modes have been measured for both double concave and plano concave cavity configurations using a wide variety of spherical mirrors. For a given cavity configuration, as the order of the transverse mode increases, the alignment requirements become progressively less stringent. In accordance with theory, the alignment tolerances are found to be less severe for double concave cavities than for plano concave cavities. For a given cavity configuration, higher order transverse modes have a larger beam diameter and consequently couple to a larger volume of the laser medium. Therefore, a greater power output may be obtained in a given length by using a higher order transverse mode. Data on the relative power available in different transverse modes as a function of cavity configuration are given. A knowledge of the trade-offs among beam divergence, cavity stability, and power output for different transverse modes allows the optimum transverse mode and cavity configuration for a given laser application to be selected.


Androgen regulation of SMR2 gene expression in rat submandibular gland: evidence for a graded but not a binary response.
Expression of SMR2, a member of the gene family encoding salivary glutamine/glutamic acid-rich proteins, is regulated by androgens in rat submandibular gland acinar cells. To further characterize SMR2 regulation, we analyzed SMR2 expression during submandibular gland postnatal development and rat puberty at both a global and a single-cell level. Using in situ detection of mature and primary SMR2 transcripts, we show that SMR2 expression is heterogeneous among acinar cells. However, only one cell population with various amounts of mRNAs can be defined. The number of high-expressing cells increases in males during puberty and in females up to 6 weeks of age, suggesting that some factor in addition to acinar differentiation might be important for SMR2 expression in female rats. Involvement of the beta-adrenergic system in regulating SMR2 expression was tested in rats exposed daily to isoproterenol for 4 days. Under these conditions we found an increase in SMR2 expression in female rats, associated with an increase in SMR2 mRNA levels in most acinar cells. This suggests that a signaling cascade, elicited by beta-adrenergic stimuli, might act in concert with androgens to regulate SMR2 expression.


Individual administration of three tanniferous forage plants to lambs artificially infected with Haemonchus contortus and Cooperia curticei.
We investigated direct anthelmintic effects associated with the feeding of fresh tanniferous forages against established populations of Haemonchus contortus and Cooperia curticei in lambs. Twenty-four parasite naive lambs were inoculated with a single dose of infective larvae of these two parasites 27 days prior to the start of the feeding experiment. Lambs were individually fed with either chicory (Cichorium intybus), birdsfoot trefoil (Lotus corniculatus), sainfoin (Onobrychis viciifolia) or a ryegrass/lucerne mixture (control) for 17 days. Animals where then united to one flock and subjected to control feeding for another 11 days to test the sustainability of potentially lowered egg excretion generated by tanniferous forage feeding. When compared to the control, administration of all tanniferous forages was associated with significant reductions of total daily faecal egg output specific to H. contortus (chicory: 89%; birdsfoot trefoil: 63%; sainfoin: 63%; all tests P<0.05) and a tendency of reduced H. contortus worm burden (chicory: 15%; birdsfoot trefoil: 49% and sainfoin: 35% reduction). Irrespective of the condensed tannin (CT) containing fodder, no anthelmintic effects were found against C. curticei. Cessation of CT-feeding followed by non-CT control feeding did not result in a re-emergence of faecal egg counts based on faecal dry matter (FECDM) in any group, suggesting that egg output reductions are sustainable. The moderate to high concentrations of CTs in birdsfoot trefoil (15.2 g CTs kg(-1) dry matter (DM)) and sainfoin (26.1 g CTs kg(-1) DM) were compatible with the hypothesis that the antiparasitic effect of these forages is caused by their content of CTs. For chicory (3 g CTs kg(-1) DM), however, other secondary metabolites need to be considered. Overall, birdsfoot trefoil and in particular sainfoin seem promising candidates in contributing to an integrated control strategy against H. contortus not only by mitigating parasite related health disturbances of the host but also by a sustained reduction of pasture contamination.


Effects of fast- and slow-setting calcium silicate-based root-end filling materials on the outcome of endodontic microsurgery: a retrospective study up to 6 years.
The purpose of this retrospective study was to evaluate and compare the effects of fast- and slow-setting calcium silicate-based materials (CSMs) used for root-end filling on the outcome of endodontic microsurgery. We searched a clinical database for patients who had received endodontic microsurgery between 2001 and 2016. Included cases were divided into two groups according to the type of CSM used for root-end filling: slow-setting CSM (SCSM) and fast-setting CSM (FCSM). The cases in two groups were subjected to 1:1 nearest neighbor propensity score matching for the following variables: age, sex, tooth type, quality of canal filling, lesion type, and postoperative restoration. For each matched case, the outcome was determined as success or failure according to clinical and radiographic evaluations performed at least 1 year after surgery. Multivariate logistic regression analysis was performed to identify prognostic factors and estimate their effects. In total, 304 cases of endodontic microsurgery (179 SCSM and 125 FCSM) were identified, and 1:1 propensity score matching finally included 122 cases from each group. After matching, all covariates were associated with an absolute standardized difference of < 0.1. The overall success rates were 85.2% and 93.4% for the SCSM and FCSM groups, respectively (p = 0.062). Age, tooth type, lesion type, and CSM type were significantly associated with the outcome of endodontic microsurgery (p < 0.05). Within the limitations, the outcome of endodontic microsurgery using FCSMs was comparable with that of SCSMs. The findings suggest that the type of CSM used for root-end filling, particularly in terms of the initial setting time, could affect the outcome of endodontic microsurgery. FCSMs could be considered for use as root-end filling materials in endodontic microsurgery, particularly in complicated clinical situations which require rapid initial setting of the materials.


Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells.
Retinal ganglion cells (RGCs), the output neurons of the retina, have axons that project via the optic nerve to diverse targets in the brain. Typically, RGC axons do not branch before exiting the retina and thus do not provide it with synaptic feedback. Although a small subset of RGCs with intraretinal axon collaterals has been previously observed in human, monkey, cat, and turtle, their function remains unknown. A small, more recently identified population of RGCs expresses the photopigment melanopsin. These intrinsically photosensitive retinal ganglion cells (ipRGCs) transmit an irradiance-coding signal to visual nuclei in the brain, contributing both to image-forming vision and to several nonimage-forming functions, including circadian photoentrainment and the pupillary light reflex. In this study, using melanopsin immunolabeling in monkey and a genetic method to sparsely label the melanopsin cells in mouse, we show that a subgroup of ipRGCs have axons that branch en route to the optic disc, forming intraretinal axon collaterals that terminate in the inner plexiform layer of the retina. The previously described collateral-bearing population identified by intracellular dye injection is anatomically indistinguishable from the collateral-bearing melanopsin cells identified here, suggesting they are a subset of the melanopsin-expressing RGC type and may therefore share its functional properties. Identification of an anatomically distinct subpopulation in mouse, monkey, and human suggests this pathway may be conserved in these and other species (turtle and cat) with intraretinal axon collaterals. We speculate that ipRGC axon collaterals constitute a likely synaptic pathway for feedback of an irradiance signal to modulate retinal light responses.