Cancer patient survival in the elderly in Italy. ITACARE Working Group.
Italy, like most western populations, is sharply aging and changing its age structure with a striking increase in the oldest segment of the elderly. Since age is related to an exponential growth of cancer incidence rates and to a worsening of prognosis, the progressive aging of the population will constitute, in the future, an issue increasingly more important for public health. The present study is the first effort to present and analyze survival rates in italian elderly cancer patients in order to provide a starting point for the development of better clinical strategies addressed to the aged. The presented data come from a large data set consisting of survival data relating to 25,798 men and 20,479 women, aged 65-84 years at diagnosis, collected by Italian cancer registries participating in the ITACARE project. Relative survival rates of patients have been calculated by sex, quinquennial age classes and the considered entire age class for overall malignant neoplasms and the 10 most frequent cancer sites in the elderly. When all Italian data for all cancers in the 65-84 year age group were pooled, survival rates at 5 years from the diagnosis was 27% and 39% in men and women, respectively. As regards specific sites, survival rates below 50% were observed for lung, stomach and ovary cancer at 1 year from diagnosis. At 5 years from diagnosis, the rates were less than 50% for colon, prostate, cervix, multiple myeloma, non-Hodgkin's lymphoma and melanoma (only in men). The best survival at 5 years from diagnosis (above 50%) was in women for melanoma and corpus uteri and breast cancer. For all cancers, the prognosis for women was better in each considered age group even though a dramatic decrease in survival with age was observed in both sexes. In general, a similar decline in survival with increasing age characterized all considered specific sites. However, at closer observation, the patterns of a decrease revealed some differences. The ratio between the survival rates of 55-64 vs 65-84 year age class indicated that the sites with the greatest advantage of survival for younger patients (ratio > 1.5) were ovary, lung and melanoma (only in men), whereas the least advantage was observed for colon, corpus uteri, breast and prostate. By calendar periods, excluding non-Hodgkin's lymphoma for women, an increase in survival was observed for all considered sites, improving an encouraging successful trend in diagnostic and therapeutic progresses.


Occurrence of other malignancies in patients with gastrointestinal stromal tumors.
Almost one-third of gastrointestinal stromal tumors (GISTs) are discovered incidentally during investigative or therapeutic procedures for unrelated diseases. In this regard, GISTs may coexist with different types of cancer, either synchronously or metachronously. The frequency of this association and the spectrum of neoplasms involved have not been sufficiently analyzed. We conducted a review of the literature and our own records for cases with sporadic GISTs and other malignancies, with emphasis on solid tumors. Neurofibromatosis 1 and Carney triad-associated tumors were excluded. Based on these data, there were 518 cancers in 486 GIST patients among 4813 cases with informative data. The overall frequency of second tumors in different series varied from 4.5% to 33% (mean, 13%). A total of 29 patients had multiple malignancies. GISTs of gastric location were most commonly involved with other neoplasms, reflecting their overall high frequency (60%) of all GISTs. The major types of GIST-associated cancers were gastrointestinal carcinomas (n=228; 47%), lymphoma/leukemia, (n=36; 7%), and carcinomas of prostate (n=43; 9%), breast (n=34; 7%), kidney (n=27; 6%), lung (n=26; 5%), female genital tract (n=25; 5%), and carcinoid tumors (n=13; 3%). Other cancers included soft tissue and bone sarcomas (n=15; 3%), malignant melanoma (n=12; 2%), and seminoma (n=6; 1%). Occurrence of collision tumors and metastases of carcinoma or sarcoma into a GIST (the latter noted in 4 cases) can be challenging diagnostic problems. The potential nonrandom association and causal relationship between GIST and other neoplasms remain to be investigated.


The distribution of methylpentynol and of methylpentynol carbamate in tissues and body fluids of cats.
A method is described for the estimation of methylpentynol and methylpentynol carbamate in body fluids and tissues. After intravenous administration, the distribution of these drugs throughout the body was found to be similar to that of ethanol. They entered cells, and crossed the blood-brain barrier and the placenta. They were excreted or secreted into the saliva, milk, gastric secretion, aqueous and vitreous humour, amniotic liquor, bile and urine. Methylpentynol was found in the expired air. Calculation of the volume of distribution and measurement of concentration in the tissues showed that both drugs were only slowly metabolized or excreted, suggesting the possibility that blood concentrations might rise cumulatively over a period of days.


Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.
Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.


Primary and conversion percutaneous gastrojejunostomy under fluoroscopic guidance: 10 years of experience.
The objective of this study was to evaluate the safety and effectiveness of primary and conversion percutaneous radiologic gastrojejunostomy (PRGJ) under fluoroscopic guidance. Between January 1998 and July 2007, 29 patients (M/F=26:3) were enrolled. Indications for primary PRGJ (n=16) included recurrent aspiration pneumonia (n=8), prevention of gastroesophageal reflux in cases of disrupted gastrointestinal tract (n=6), or bypass of surgical anastomosis (n=1) or duodenal obstruction (n=1). Indications for conversion PRGJ (n=13) included recurrent aspiration pneumonia (n=11), malignant duodenal obstruction (n=1), or previous gastrostomy-related complication (n=1). All 29 procedures were successfully completed with 10.2-16.5-Fr feeding gastrojejunostomy tube tip located in the proximal jejunum. A single anchor was used in all patients with primary PRGJ. Clinical success was achieved in all study patients. There were no major complications. There was no evidence of gastroesophageal reflux or aspiration aggravation in any patient during the follow-up period. Four tubes were electively removed after healing of the esophageal rupture. The indwelling period was 10 to 429 days (mean, 110 days) after tube placement in the remaining 25 patients. Primary and conversion PRGJ under fluoroscopic guidance was a safe and effective procedure for enteral feeding as well as for preventing gastroesophageal reflux or aspiration pneumonia. In cases of primary gastrojejunostomy, use of single gastropexy was feasible and sufficient.


Design and methods of a social network isolation study for reducing respiratory infection transmission: The eX-FLU cluster randomized trial.
Social networks are increasingly recognized as important points of intervention, yet relatively few intervention studies of respiratory infection transmission have utilized a network design. Here we describe the design, methods, and social network structure of a randomized intervention for isolating respiratory infection cases in a university setting over a 10-week period. 590 students in six residence halls enrolled in the eX-FLU study during a chain-referral recruitment process from September 2012-January 2013. Of these, 262 joined as "seed" participants, who nominated their social contacts to join the study, of which 328 "nominees" enrolled. Participants were cluster-randomized by 117 residence halls. Participants were asked to respond to weekly surveys on health behaviors, social interactions, and influenza-like illness (ILI) symptoms. Participants were randomized to either a 3-Day dorm room isolation intervention or a control group (no isolation) upon illness onset. ILI cases reported on their isolation behavior during illness and provided throat and nasal swab specimens at onset, day-three, and day-six of illness. A subsample of individuals (N=103) participated in a sub-study using a novel smartphone application, iEpi, which collected sensor and contextually-dependent survey data on social interactions. Within the social network, participants were significantly positively assortative by intervention group, enrollment type, residence hall, iEpi participation, age, gender, race, and alcohol use (all P<0.002). We identified a feasible study design for testing the impact of isolation from social networks in a university setting. These data provide an unparalleled opportunity to address questions about isolation and infection transmission, as well as insights into social networks and behaviors among college-aged students. Several important lessons were learned over the course of this project, including feasible isolation durations, the need for extensive organizational efforts, as well as the need for specialized programmers and server space for managing survey and smartphone data.


Progress and Perspective of Electrocatalytic CO2 Reduction for Renewable Carbonaceous Fuels and Chemicals.
The worldwide unrestrained emission of carbon dioxide (CO2) has caused serious environmental pollution and climate change issues. For the sustainable development of human civilization, it is very desirable to convert CO2 to renewable fuels through clean and economical chemical processes. Recently, electrocatalytic CO2 conversion is regarded as a prospective pathway for the recycling of carbon resource and the generation of sustainable fuels. In this review, recent research advances in electrocatalytic CO2 reduction are summarized from both experimental and theoretical aspects. The referred electrocatalysts are divided into different classes, including metal-organic complexes, metals, metal alloys, inorganic metal compounds and carbon-based metal-free nanomaterials. Moreover, the selective formation processes of different reductive products, such as formic acid/formate (HCOOH/HCOO-), monoxide carbon (CO), formaldehyde (HCHO), methane (CH4), ethylene (C2H4), methanol (CH3OH), ethanol (CH3CH2OH), etc. are introduced in detail, respectively. Owing to the limited energy efficiency, unmanageable selectivity, low stability, and indeterminate mechanisms of electrocatalytic CO2 reduction, there are still many tough challenges need to be addressed. In view of this, the current research trends to overcome these obstacles in CO2 electroreduction field are summarized. We expect that this review will provide new insights into the further technique development and practical applications of CO2 electroreduction.


Interfacial Enhancement of Photovoltaic Performance in MAPbI3/CsPbI3 Superlattice.
Perovskite solar cells have continued to fascinate over the past decade due to fast increasing power conversion efficiency and very low fabrication cost but still suffered from poor stability. Interface engineering is evolved to be one of the most promising solutions to the instability problem. In this work, we perform a first-principles study on the MAPbI3/CsPbI3 interface system, aiming at clarifying the underlying mechanism of interfacial enhancement of solar cell performance. We devise the atomistic modeling of superlattices as increasing the number of included unit cells and carry out structural optimizations, revealing that the binding strength between the perovskite layers becomes stronger while the band gap decreases as the supercell size increases. Using enough large supercells of the interface system, we further estimate the formation energies of the interfacial vacancy defects and activation barriers for vacancy-mediated I atom migrations. Our calculations show the shallow transition states for most of the defects and the higher activation barriers for I atom migrations across the interface, providing an evidence of performance enhancement by the interface formation. By giving an insightful understanding of the MAPbI3/CsPbI3 heterojunction, this work definitely contributes to the design of interface systems for high-performance solar cells.


Thermal wave interferometry: a potential application of the photoacoustic effect.
The Rosencwaig-Gersho equation for the photoacoustic signal is recast in a manner that emphasizes the crucial role thermal wave interference plays in the production of the photoacoustic signal. This formalism is then used to suggest a technique for extracting thermal information from the structure in the photoacoustic signal resulting from thermal wave interference. Experimental measurements illustrating this technique are presented.


A comparison of the Glasgow Coma Scale and the Reaction Level Scale (RLS85).
The Glasgow Coma Scale (GCS) and the Reaction Level Scale (RLS85) were compared for rating neurosurgical patients in regard to ranking order of deficit severity, interobserver variability, and coverage for relevant factors. Four physicians, four registered nurses, and four assistant nurses performed 72 pairwise ratings on 47 neurosurgical patients. The rank correlation between the GCS sum score and the RLS85 was -0.94, suggesting the same ranking order of severity and indicating that the underlying concepts of somnolence, delirium, and motor responses in coma are evaluated in the same way. By the sign test, the RLS85 was shown to have better interobserver agreement than the GCS sum score and the eye-motor-verbal (EMV) profile. The interobserver grading disagreements in both scales were distributed over the entire range of responsiveness, and for the GCS sum score they were slanted to combined segments 9 to 15. The RLS85 showed full coverage of relevant factors, while 43 (60%) of the 72 test occasions in the GCS sum score and the EMV profiles showed untestable features, most often because of patient intubation. The pseudoscore (that is, the choice of value given to untestable features) affects interobserver agreement as well as the estimated overall patient responsiveness in the GCS sum score. Assessment by the order of applying the scales showed a significant effect on the GCS eye-opening scale (p = 0.01) and the GCS sum score (p = 0.03), indicating a sensitivity to environmental stimuli unrelated to the patient's status. This study demonstrates that basically the same information as that found in the separate eye, motor, and verbal scales of the GCS can be combined directly into the RLS85, which has better interobserver agreement and better coverage than the GCS sum score.


Drug Library Screening for the Identification of Ionophores That Correct the Mistrafficking Disorder Associated with Oxalosis Kidney Disease.
Primary hyperoxaluria is the underlying cause of oxalosis and is a life-threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders. We miniaturized a cell-based high-content assay into 1536-well plate format and screened ~4200 pharmacologically relevant compounds including Food and Drug Administration, European Union, and Japanese-approved drugs. This assay employs CHO cells stably expressing AGT-170, a mutant that predominantly resides in the mitochondria, where we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. The miniaturized 1536-well assay yielded a Z' averaging 0.70 ± 0.07. Three drugs were identified as potential pharmacoperones from this pilot screen, demonstrating the applicability of this assay for large-scale high-throughput screening.


[Obesity, metabolic syndrome and diabetes: cardiovascular implications and therapy].
Obesity, metabolic syndrome and type-2 diabetes mellitus are three interrelated conditions that share a number of pathophysiological mechanisms and that are frequently observed to lead, in succession, to cardiovascular complications. The fact that their prevalence is increasing alarmingly should prompt all healthcare professionals urgently to implement measures to prevent these complications. The most effective, though also the least adopted, are those related to lifestyle modification. Drug treatment targeted at controlling risk factors (e.g., hypertension, dyslipidemia, and thrombophilia), metabolic abnormalities, and excess weight is also necessary.


Possible role of trace elements in epilepsy and febrile seizures: a meta-analysis.
Seizures are among the most common causes of apparent life-threatening events. There are discrepancies among the published reports on the correlation between epilepsy/febrile seizures and deficiency or overload of trace elements. The objective of this review and meta-analysis was to examine the present knowledge on the concentrations of the most investigated trace metals, including zinc, copper, selenium, and magnesium, in patients with epilepsy and febrile seizures. The PubMed and Scopus databases were searched to identify case-control studies that compared the concentration of zinc, copper, magnesium, and selenium in serum, hair, or cerebrospinal fluid between patients with epilepsy/febrile seizures and controls. A total of 60 articles were included in the present study (40 pertaining to epilepsy and 25 pertaining to febrile seizures). The serum concentration of zinc in nontreated patients with epilepsy was significantly higher than in controls (P = 0.034). There were significantly reduced serum concentrations of zinc (P = 0.018) and selenium (P = 0.012) in patients with febrile seizures compared with controls. The concentrations of copper, magnesium, and zinc were all significantly altered in patients with epilepsy who received antiepileptic drugs compared with untreated patients with epilepsy. Designing treatments to selectively restore zinc levels may be a strategy for treating patients with epilepsy. It is still unclear whether these ions are causal to, or a cofactor in, the development of epilepsy. Knowledge of the effects of various antiepileptic drugs on trace element homeostasis could potentially be used to effectively guide appropriate therapeutic strategies in the future.


The intermediate S1' pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling.
Human matrix metalloproteinase-26 (MMP-26/endometase/matrilysin-2) is a newly identified MMP and its structure has not been reported. The enzyme active site S1' pocket in MMPs is a well defined substrate P1' amino acid residue-binding site with variable depth. To explore MMP-26 active site structure-activity, a series of new potent mercaptosulfide MMP inhibitors (MMPIs) with Leu or homophenylalanine (Homophe) side chains at the P1' site were selected. The Homephe side chain is designed to probe deep S1' pocket MMPs. These inhibitors were tested against MMP-26 and several MMPs with known x-ray crystal structures to distinguish shallow, intermediate, and deep S1' pocket characteristics. MMP-26 has an inhibition profile most similar to those of MMPs with intermediate S1' pockets. Investigations with hydroxamate MMPIs, including those designed for deep pocket MMPs, also indicated the presence of an intermediate pocket. Protein sequence analysis and homology modeling further verified that MMP-26 has an intermediate S1' pocket formed by Leu-204, His-208, and Tyr-230. Moreover, residue 233 may influence the depth of an MMP S1' pocket. The residue at the equivalent position of MMP-26 residue 233 is hydrophilic in intermediate-pocket MMPs (e.g. MMP-2, -8, and -9) and hydrophobic in deep-pocket MMPs (e.g. MMP-3, -12, and -14). MMP-26 contains a His-233 that renders the S1' pocket to an intermediate size. This study suggests that MMPIs, protein sequence analyses, and molecular modeling are useful tools to understand structure-activity relationships and provides new insight for rational inhibitor design that may distinguish MMPs with deep versus intermediate S1' pockets.


Characterization of sodium-dependent glucose transport in sheep tracheal epithelium.
The nonmetabolizable glucose analogue methyl(alpha-D-[U-14C]gluco)pyranoside ([14C]AMG) was used to study sodium-dependent glucose transport in two preparations: 1) discs punched from strips of sheep tracheal epithelium, and 2) freshly enzyme-isolated sheep tracheal epithelial cells. In discs, cellular accumulation of [14C]AMG was saturable and exhibited a Michaelis-Menten constant (Km) for AMG of 0.63 +/- 0.15 mM. Uptake was linear over 30 min and was inhibited maximally by 100 microM phlorizin [inhibition constant (Ki) approximately 20 nM], by replacement of external sodium with choline or by addition of 10 mM D-glucose (Ki = 0.19 +/- 0.02 mM). Accumulative uptake was activated, in a concentration-dependent manner, by external sodium [affinity constant (Ka) approximately 23 mM] with a Hill coefficient of greater than one but was abolished on depolarizing with high external potassium. In the presence of sodium, D-galactose and AMG both inhibited uptake of [14C]AMG, whereas L-glucose, D-fructose, and D-mannose were ineffective. In isolated cells, [14C]AMG accumulated only in the presence of external sodium and uptake was inhibited by the addition of D-glucose (Ki approximately 0.2 mM), D-galactose, and AMG but not by L-glucose or D-xylose. We conclude that sheep tracheal epithelium exhibits sodium-dependent glucose uptake with a very high affinity for phlorizin, which indicates the presence of a novel isoform of the transporter.


Synthesis of photo-luminescent Zn(II) Schiff base complexes and its derivative containing Pd(II) moiety.
An efficient method was developed for the preparation of a series of zinc Schiff base complexes. Introduction of a pyridyl group as a bridging unit as well as incorporation of ethynyl and electron-donating groups into the salicylidene moiety of these complexes moderately enhances the photoluminescence intensity and quantum yield. Electron-rich palladium groups possibly influence the photophysical character through the bridging C[triple bond]C bond. The crystal structure of the pyridine adduct of a salen Zn complex is determined by X-ray diffraction analysis.


Genotype-Dependent Interaction of Lentil Lines with Ascochyta lentis.
Ascochyta blight of lentil is a prevalent disease in many lentil producing regions and can cause major yield and grain quality losses. The most environmentally acceptable and economically profitable method of control is to develop varieties with high levels of durable resistance. Genetic studies to date suggest that ascochyta blight resistance genes (R-gene) in lentil lines CDC Robin, ILL 7537, 964a-46, and ILL 1704 are non-allelic. To understand how different R-genes manifest resistance in these genotypes and an accession of Lens ervoides, L-01-827A, with high level of resistance to ascochyta blight, cellular and molecular defense responses were compared after inoculation with the causal pathogen Ascochyta lentis. Pathogenicity testing of the resistant lines to A. lentis inoculation revealed significantly lower disease severity on CDC Robin and ILL 7537 compared to ILL 1704 and 964a-46, and no symptoms of disease were observed on L-01-827A. Histological examinations indicated that cell death triggered by the pathogen might be disrupted as a mechanism of resistance in CDC Robin. In contrast, limiting colonization of epidermal cells by A. lentis is a suggested mechanism of resistance in 964a-46. A time-series comparison of the expressions of hallmark genes in salicylic acid (SA) and jasmonic acid (JA) signal transduction pathways between CDC Robin and 964a-46 was conducted. These partially resistant genotypes differed in the timing and the magnitude of SA and JA signaling pathway activation. The SA signaling pathway was only triggered in 964a-46, whereas the JA pathway was triggered in both partially resistant genotypes CDC Robin and 964a-46. The expression of JA-associated genes was lower in 964a-46 than CDC Robin. These observations corroborate the existence of diverse ascochyta blight resistance mechanisms in lentil genotypes carrying different R-genes.


Subjective confidence in one's answers: the consensuality principle.
In answering general-information questions, a within-person confidence-accuracy (C-A) correlation is typically observed, suggesting that people can monitor the correctness of their knowledge. However, because the correct answer is generally the consensual answer--the one endorsed by most participants--confidence judgment may actually monitor the consensuality of the answer rather than its correctness. Indeed, the C-A correlation was positive for items with a consensually correct answer but negative for items with a consensually wrong answer. Results suggest that the consensuality-confidence correlation may be mediated by 2 internal mnemonic cues that are correlated with consensuality: Consensual answers are reached faster and are selected more consistently by the same person on different occasions than nonconsensual answers. The results argue against a direct-access view of confidence judgments and suggest that such judgments will be accurate only as long as people's responses are by and large correct across the sampled items, thus stressing the criticality of a representative design.


Life Cycle Assessment of urban wastewater reuse with ozonation as tertiary treatment: a focus on toxicity-related impacts.
Life Cycle Assessment has been used to compare different scenarios involving wastewater reuse, with special focus on toxicity-related impact categories. The study is based on bench-scale experiments applying ozone and ozone in combination with hydrogen peroxide to a wastewater effluent from a Spanish sewage treatment plant. Two alternative characterisation models have been used to account for toxicity of chemical substances, namely USES-LCA and EDIP97. Four alternative scenarios have been assessed: wastewater discharge plus desalination supply, wastewater reuse without tertiary treatment, wastewater reuse after applying a tertiary treatment consisting on ozonation, and wastewater reuse after applying ozonation in combination with hydrogen peroxide. The results highlight the importance of including wastewater pollutants in LCA of wastewater systems assessing toxicity, since the contribution of wastewater pollutants to the overall toxicity scores in this case study can be above 90%. Key pollutants here are not only heavy metals and other priority pollutants, but also non-regulated pollutants such as pharmaceuticals and personal care products. Wastewater reuse after applying any of the tertiary treatments considered appears as the best choice from an ecotoxicity perspective. As for human toxicity, differences between scenarios are smaller, and taking into account the experimental and modelling uncertainty, the benefits of tertiary treatment are not so clear. From a global warming potential perspective, tertiary treatments involve a potential 85% reduction of greenhouse gas emissions when compared with desalination.


Contractile properties, structure and fiber phenotype of intact and regenerating slow-twitch muscles of mice treated with cyclosporin A.
We have studied the contractile properties, structure, fiber-type composition, and myosin heavy chain (MyHC) expression pattern of regenerating and intact soleus muscles of adult CBA/J mice treated with cyclosporin A (CsA) or vehicle solutions (Cremophor, saline). A comparison of muscles after 4-7 weeks drug application with those receiving vehicle showed that the isometric contractile force of intact drug-treated muscles was reduced (tetanus, -21%; twitch, -34%) despite normal mass and muscle cross-sectional area. The frequency of fast-twitch fibers was increased, whereas no innervation deficits, histopathological alterations, or changes in fiber numbers were observed. Regeneration after cryolesion of the contralateral soleus proceeded more slowly in CsA-treated than in vehicle-treated animals. Despite this, when muscle properties reached mature levels (4-7 weeks), muscle mass recovery was better in CsA-treated animals (30% higher weight, 50% more fiber profiles in cross-sections). The force production per unit cross-sectional area was deficient, but not the maximum tension. Twitch time-to-peak and half-relaxation time were shorter than controls correlating with a predominance of fast-twitch fibers (98% Type II fibers versus 16%-18% in control muscles) and fast MyHC isoforms. Partial reversal of this fast phenotype and an increase in muscle force were observed when the animals were left to recover without treatment for 5-8 weeks after CsA application over 7 weeks. The high numbers of fiber profiles in CsA-treated regenerated muscles and increased mass remained unchanged after withdrawal. Thus, CsA treatment has a hyperplastic effect on regenerating muscles, and drug-induced phenotype alterations are much more prominent in regenerated muscles.


Stereoselective pharmacokinetics of oxybutynin and N-desethyloxybutynin in vitro and in vivo.
In vitro studies and the multiple applications of an oxybutynin (OXY) transdermal delivery system to Japanese healthy volunteers were conducted to characterize the stereoselectivity in the pharmacokinetics of OXY and its metabolite, N-desethyloxybutynin (DEOB). In human liver microsomes, (R)-OXY and (R)-DEOB were eliminated slightly slower than the corresponding (S)-enantiomers. The production of DEOB from OXY for the (R)-enantiomer was also slower than that for the (S)-enantiomer. In human P450-expressing liver microsomes, OXY was metabolized mainly by CYP3A4 among five cytochrome P450s (CYPs) tested (CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) and the kinetics were slightly different for the enantiomer. The unbound fraction of (R)-OXY in plasma was almost two times higher than that of (S)-OXY, whereas (R)-DEOB was bound to plasma protein more than (S)-DEOB. No differences were observed in the blood-plasma concentration ratios for the enantiomers. After multiple applications of the transdermal delivery system, the plasma concentrations of (R)-OXY were lower than those of (S)-OXY. These data indicate that for the stereoselectivity of OXY, the unbound fraction of each OXY enantiomer was a major factor and the metabolism in liver had a minimal effect.


Machine Learning Prediction of Resistance to Subinhibitory Antimicrobial Concentrations from Escherichia coli Genomes.
Escherichia coli is an important cause of bacterial infections worldwide, with multidrug-resistant strains incurring substantial costs on human lives. Besides therapeutic concentrations of antimicrobials in health care settings, the presence of subinhibitory antimicrobial residues in the environment and in clinics selects for antimicrobial resistance (AMR), but the underlying genetic repertoire is less well understood. Here, we used machine learning to predict the population doubling time and cell growth yield of 1,407 genetically diverse E. coli strains expanding under exposure to three subinhibitory concentrations of six classes of antimicrobials from single-nucleotide genetic variants, accessory gene variation, and the presence of known AMR genes. We predicted cell growth yields in the held-out test data with an average correlation (Spearman's ρ) of 0.63 (0.36 to 0.81 across concentrations) and cell doubling times with an average correlation of 0.59 (0.32 to 0.92 across concentrations), with moderate increases in sample size unlikely to improve predictions further. This finding points to the remaining missing heritability of growth under antimicrobial exposure being explained by effects that are too rare or weak to be captured unless sample size is dramatically increased, or by effects other than those conferred by the presence of individual single-nucleotide polymorphisms (SNPs) and genes. Predictions based on whole-genome information were generally superior to those based only on known AMR genes and were accurate for AMR resistance at therapeutic concentrations. We pinpointed genes and SNPs determining the predicted growth and thereby recapitulated many known AMR determinants. Finally, we estimated the effect sizes of resistance genes across the entire collection of strains, disclosing the growth effects for known resistance genes in each individual strain. Our results underscore the potential of predictive modeling of growth patterns from genomic data under subinhibitory concentrations of antimicrobials, although the remaining missing heritability poses a challenge for achieving the accuracy and precision required for clinical use. IMPORTANCE Predicting bacterial growth from genome sequences is important for a rapid characterization of strains in clinical diagnostics and to disclose candidate novel targets for anti-infective drugs. Previous studies have dissected the relationship between bacterial growth and genotype in mutant libraries for laboratory strains, yet no study so far has examined the predictive power of genome sequence in natural strains. In this study, we used a high-throughput phenotypic assay to measure the growth of a systematic collection of natural Escherichia coli strains and then employed machine learning models to predict bacterial growth from genomic data under nontherapeutic subinhibitory concentrations of antimicrobials that are common in nonclinical settings. We found a moderate to strong correlation between predicted and actual values for the different collected data sets. Moreover, we observed that the known resistance genes are still effective at sublethal concentrations, pointing to clinical implications of these concentrations.


Conductance routes for protons across membrane barriers.
Simple phospholipid bilayers show a high level of permeability to protons; in spite of this fact, large proton gradients existing across such bilayers may decay very slowly. In sealed systems, the free movement of protons across a membrane barrier is severely restricted by the coincident development of a proton diffusion potential. Using the fluorescent weak acid N-[5-(dimethylamino)naphth-1-ylsulfonyl]glycine strongly buffered systems movement of the small number of protons giving rise to this electrical potential is insufficient to perturb the proton concentration gradient; significant flux of protons (and hence significant collapse of the concentration gradient) can only occur if protons traverse the membrane as part of an electroneutral complex or if there is a balancing flow of appropriate counterions. In both instances, proton flux is obligatorily coupled to the translocation of species other than protons. In weakly buffered systems, the small initial uncoupled electrogenic flux of protons may significantly alter the concentration gradient. This initial rapid gradient collapse caused by uncoupled electrogenic proton movements is then superimposed upon the residual collapse attributable to tightly coupled proton flux. The initial uncoupled electrogenic proton flux shows a temperature dependence very similar to that demonstrated for water permeation across simple lipid bilayers; upon cooling, there is a sharp decrease in flux at the temperature coinciding with the main gel-liquid-crystalline phase transition of the lipid. The coupled proton flux shows a markedly different temperature dependence with no dramatic change in rate at the phase transition temperature and strong similarity to the behavior previously seen with solutes known to be permeating as electrically neutral compounds.(ABSTRACT TRUNCATED AT 250 WORDS)


Age-Associated Differences in Infection of Human Skin in the SCID Mouse Model of Varicella-Zoster Virus Pathogenesis.
Varicella-zoster virus (VZV) is the skin-tropic human alphaherpesvirus responsible for both varicella-zoster and herpes zoster. Varicella-zoster and herpes zoster skin lesions have similar morphologies, but herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. We hypothesized that skin aging could also influence the outcome of the anterograde axonal transport of VZV to skin. We utilized human skin xenografts maintained in immunodeficient (SCID) mice to study VZV-induced skin pathology in vivo in fetal and adult skin xenografts. Here we found that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations. In addition to measures of VZV infection, we examined the expression of type I interferon (IFN) pathway components in adult skin and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo Our results demonstrated that VZV infection of adult skin triggers intrinsic IFN-mediated responses such as we have described in VZV-infected fetal skin xenografts, including MxA as well as promyelocytic leukemia protein (PML), in skin cells surrounding lesions. Further, we observed that VZV elicited altered cell signaling and proliferative and inflammatory responses that are involved in wound healing, driven by follicular stem cells. These cellular changes are consistent with VZV-induced activation of STAT3 and suggest that VZV exploits the wound healing process to ensure efficient delivery of the virus to keratinocytes. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivoIMPORTANCE Varicella-zoster virus (VZV) is the agent responsible for both varicella-zoster and herpes zoster. Herpes zoster occurs disproportionally in older individuals and is often associated with a more extensive local rash and severe zoster-related neuralgia. To examine the effect of skin aging on VZV skin lesions, we utilized fetal and adult human skin xenografts maintained in immunodeficient (SCID) mice. We measured VZV-induced skin pathology, examined the expression of type I interferon (IFN) pathway components in adult skin, and investigated elements of the cutaneous proliferative and inflammatory response to VZV infection in vivo Our results demonstrate that characteristics of aging skin are preserved in xenografts; that VZV replication is enhanced in skin from older compared to younger adults, correlating with clinical observations; and that VZV infection elicits altered cell signaling and inflammatory responses. Adult skin xenografts offer an approach to further investigate VZV-induced skin pathologies in vivo.


Incidental simultaneous finding of intravascular histiocytosis and reactive angioendotheliomatosis: a case report.
Reactive angioendotheliomatosis (RAE) is a rare cutaneous vascular disorder characterized by intravascular hyperplasia of endothelial cells, sometimes with a vascular proliferation. Intravascular histiocytosis (IH) is a similar vascular disorder characterized by the presence of dilated vessels containing aggregates of mononuclear histiocytes (macrophages) within their lumina. Although their pathogenesis remains uncertain, there has been speculation about the possible relationship between IH and RAE. We report a case of coexistence of RAE and IH in a patient who underwent a wide reexcision of a metastatic malignant melanoma. The excision specimen did not show any residual melanoma but exhibited an intravascular collection of CD-68-positive histiocytes admixed with CD-31-positive endothelial cells and fibrin surrounded by D2-40-positive vascular wall. The presence of intravascular cells initially raised concern of intravascular invasion by melanoma. As there was no clinical lesion and immunohistochemical stains for melanocytic makers were negative, we interpret this as an incidental finding. Knowledge of this benign vascular disorder is important because the histologic changes may be mistaken for intravascular invasion of a malignant neoplasm.


Electrode independence in intraneural cochlear nerve stimulation.
We have previously reported feline electrophysiological and anatomical studies focused on the development of an intraneural auditory neuroprosthesis. Because only the tips of the electrodes implanted in the cochlear nerve are the stimulating elements that abut the nerve axons, we hypothesize that intraneural stimulation will be highly focal in nature. In this article, we report the electrophysiological characterization of the selective activation of subpopulations of cochlear nerve fibers via electrodes implanted in feline cochlear nerve. We have used a forward-masking paradigm to estimate the extent of stimulation overlap produced by pairs of electrodes implanted into the cochlear nerve. The technique uses sequential stimulation via masking and probe electrodes and monitoring of the electrically evoked auditory brain stem response as an index of cochlear nerve fiber recruitment. We investigated overlap in all possible electrode pair combinations. Many electrode pairs manifest virtually no overlap in the subpopulations of fibers excited by perithreshold stimuli, whereas most had considerable overlap at higher stimulation levels. However, we also noted that our measured overlap was similar across electrodes possibly because of lack of specificity of the whole nerve electrically evoked auditory brain stem response as an assay for this parameter. These findings indicate that direct cochlear nerve stimulation via intraneural electrodes provides selective excitation of small subpopulations of cochlear nerve fibers, and suggest that cochlear nerve stimulation may selectively evoke narrow-band frequency percepts.


The thermoregulation of halothane versus isoflurane in humans receiving ophthalmological surgery.
Although suppression of thermoregulatory mechanisms during anaesthesia is generally assumed, the extent to which thermoregulation may be inactive is unknown. Twenty unpremedicated, ASA physical status class I patients (17 men and 3 women) scheduled for retinal detachment surgery were studied to evaluate the different changes of core and two skin-surface temperatures during halothane or isoflurane anaesthesia. Anaesthesia was induced by mask inhalation of halothane or isoflurane in nitrous oxide 70% and oxygen and was maintained by mechanical ventilation during surgery with halothane or isoflurane in nitrous oxide 50% and oxygen only. Core temperature (rectus) and skin-surface temperatures (forearm and fingertip) were measured during surgery using three separate thermometers (Y.S.I.: Yellow springs instrument Co., Inc. G541-211-Y01-33A0). Operating room temperatures were recorded in every case. Significant vasoconstriction was prospectively defined by a skin-surface temperature gradient between two sampling sites > or = 4 degrees C. The result indicated that there was no significant difference between core temperatures and skin-surface temperature gradients during halothane anaesthesia and isoflurane anaesthesia. However, three of the ten patients had their skin-surface temperature gradients > or = 4 degrees C in the halothane group. None of the ten patients had their skin-surface temperature gradients > or = 4 degrees C in the isoflurane group.


[The role of peptides in aging control: results and prospects of research].
The paper summarizes results of long-term research designed to elucidate mechanisms of aging and evaluate efficacy of peptide bioregulators for the prevention of age-specific pathology. Peptides obtained by up-to-date methods in Russia, U.S.A., U.K., Germany, Italy, Spain, and France are reviewed. A molecular model is proposed to describe complementary interactions of short-chain peptides with gene promoters underlying initiation of protein synthesis. Prospects for the use of peptide bioregulators to prevent premature aging of the employable population in Russia are discussed.


Effect of DTPA on the nephrotoxicity induced by uranium in the rat.
The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 microg kg(-1)) to toxic (639 microg kg(-1)) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 micromol kg(-1)) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results.


Beating a path to nursing's door: scientific support for holistic practice.
Nursing has a long history of a holistic focus on patient care. The current emphasis on the need for holism indicates that the "world" is more aware of the value of nursing. To enhance this possibility, nurses need to use empirical evidence to support holistic practice.


Can coffee prevent caries?
To determine the anti-carious effect of coffee in humans. Coffee represents one of the most consumed products by the population. A random sample of 1000 individuals, of both sexes, who consumed only coffee as a beverage and who visited the Out-Patient Department of KLE Society's Institute of Dental Sciences, with a dental complaint and no history of any major illness, were considered as subjects. The patients' histories with regard to the coffee intake, such as, period of consumption, frequency of consumption, whether taken with milk or wihout milk, with sugar or without sugar, and the brand make, was noted. History of the type of diet, consumption of sweets, periodicity of brushing, and whether they had undergone fluoride applications were also noted. A thousand patients who consumed beverages other than coffee were taken as the control. The results showed that coffee most consumed was roasted coffee, and the frequency on an average was about three cups per day, for an average period of 35 years. The Decayed/Missing/Filled Surface (DMFS) scores varied from 2.9, in subjects who drank black coffee, to 5.5 in subjects who consumed coffee together with sweeteners and creaming agents. The DMFS score was 3.4 in subjects who consumed coffee together with milk but no sugar. The DMFS score of the control subjects was 4, indicating that coffee if consumed alone had anticaries action, but in the presence of additives the antibacterial and anticaries action was totally minimized. Thus coffee can help in prevention of dental caries if consumed without additives.


Ultrastructure and histogenesis of the renal tumors of childhood: an overview.
This review discusses the ultrastructural and immunohistochemical features of the common childhood renal tumors, with an emphasis on their diagnostic usefulness. Speculations regarding their histogenesis also are presented, with the hope that these may serve to diminish some of the confusion surrounding the classification of these morphologically diverse lesions.


Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation.
Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.


Long term EEG analytical and neurological follow-up study in completed stroke patients after extra-intracranial vascular anastomosis.
In 33 chronic stroke patients, who had internal carotid or middle cerebral artery occlusion that resulted in neurological deficit persisting for an average of more than 10 weeks, it was possible to perform a postoperative follow-up study for a period of six to eight years after extra-intracranial vascular anastomosis. Serial neurological examinations with grading of motor deficit and EEG analyses were performed to assess the clinical course of the cerebral lesion. These long term examinations showed a postoperative continuing improvement of electrical brain activity in nearly two thirds of the patients, nine patients showed no significant changes and three worsened. The EEG analytical findings correlated well to the neurological findings. An increase of electrical brain activity was bilateral with accentuation over the affected hemisphere, a phenomenon known from follow-up nrCBF measurements after anastomosis. During the follow-up one patient died five years, one six years following stroke under signs of cardiovascular disease, and one after six years suffering from a recurrent stroke opposite to the side of anastomosis. In conclusion the findings indicate that EEG analysis is of value for assessment of long term follow-up of cerebral ischaemic lesions, chronic ischaemic alterations of the brain can be improved by anastomosis, and especially in comparison to a non-operated group of stroke patients, the course of the operated one seemed to be more advantageous, as the five-year survival rate of the Framingham study for stroke victims is 69%.


Changes in Escherichia coli rRNA promoter activity correlate with changes in initiating nucleoside triphosphate and guanosine 5' diphosphate 3'-diphosphate concentrations after induction of feedback control of ribosome synthesis.
rRNA synthesis is the rate-limiting step in ribosome synthesis in Escherichia coli. Its regulation has been described in terms of a negative-feedback control loop in which rRNA promoter activity responds to the amount of translation. The feedback nature of this control system was demonstrated previously by artificially changing ribosome synthesis rates and observing responses of rRNA promoters. However, it has not been demonstrated previously that the initiating nucleoside triphosphate (iNTP) and guanosine 5'-diphosphate 3'-diphosphate (ppGpp), the molecular effectors responsible for controlling rRNA promoters in response to changes in the nutritional environment, are responsible for altering rRNA promoter activities under these feedback conditions. Here, we show that most feedback situations result in changes in the concentrations of both the iNTP and ppGpp and that the directions of these changes are consistent with a role for these two small-molecule regulators in feedback control of rRNA synthesis. In contrast, we observed no change in the level of DNA supercoiling under the feedback conditions examined.


Immunohistochemical evidence of abnormal expression of the antioncogene-encoded p53 phosphoprotein in Hodgkin's disease and CD30+ anaplastic lymphomas.
The gene encoding p53 phosphoprotein, originally believed to be an oncogene, recently has been proposed as a candidate antioncogene (tumor-suppressor gene). Abnormalities of the p53 gene expression have been demonstrated in different human malignancies including carcinomas and sarcomas, but little information concerning p53 immunoreactivity in human lymphomas is so far available. In this study immunohistochemical staining for p53-protein was performed on frozen- and paraffin-embedded samples from patients with Hodgkin's (HD) and non-Hodgkin's lymphomas (NHL). No p53 immunoreactivity could be demonstrated in any cell type in nonneoplastic lymphoid samples, including germinal center cells in reactive lymph nodes and cortical thymocytes. On the other hand, a significant proportion of p53+ neoplastic cells was observed in 23 of 31 cases of HD and 17 of 68 cases of NHL. All positive lymphoma cases were diagnosed as high-grade or CD30+ anaplastic NHL. The demonstration of abnormal expression of p53 protein in these diseases can contribute to addressing unresolved issues regarding the origin and pathogenesis of HD and CD30+ anaplastic lymphomas.


Serum zinc and copper during long-term total parenteral nutrition.
Changes in serum zinc and copper levels were studied in 17 patients who received 18 courses of total parenteral nutrition for 28 to 89 days. Mean serum zinc levels decreased significantly after 4 weeks of therapy in the group without zinc supplementation when compared with pretreatment levels (p less than 0.05) and in a second group who received about 1.5 mg of zinc per day (p less than 0.05). Serum copper levels fell consistently and significantly in patients of both groups. However, no obvious clinical signs or symptoms of zinc or copper deficiencies were observed. Blood transfusions were not able to significantly change the serum levels of zinc or copper. Although serum alkaline phosphatase has been suggested as a functional indicator of zinc deficiency, the concomitant hepatic or skeletal dysfunction of the patients made its interpretation difficult. These findings indicate that a decrease in serum zinc and copper is common during TPN using solutions unsupplemented with these trace elements. Supplementation of TPN solutions with zinc, copper, and other trace elements is recommended.


Bonding brackets on white spot lesions pretreated by means of two methods.
The aim of this study was to evaluate the shear bond strength (SBS) of brackets bonded to demineralized enamel pretreated with low viscosity Icon Infiltrant resin (DMG) and glass ionomer cement (Clinpro XT Varnish, 3M Unitek) with and without aging. A total of 75 bovine enamel specimens were allocated into five groups (n = 15). Group 1 was the control group in which the enamel surface was not demineralized. In the other four groups, the surfaces were submitted to cariogenic challenge and white spot lesions were treated. Groups 2 and 3 were treated with Icon Infiltrant resin; Groups 4 and 5, with Clinpro XT Varnish. After treatment, Groups 3 and 5 were artificially aged. Brackets were bonded with Transbond XT adhesive system and SBS was evaluated by means of a universal testing machine. Statistical analysis was performed by one-way analysis of variance followed by Tukey post-hoc test. All groups tested presented shear bond strengths similar to or higher than the control group. Specimens of Group 4 had significantly higher shear bond strength values (p < 0.05) than the others. Pretreatment of white spot lesions, with or without aging, did not decrease the SBS of brackets.


Overview of tigecycline efficacy and safety in the treatment of complicated skin and skin structure infections - a European perspective.
In a randomized, double-blind, multicenter, multinational, controlled trial, 546 patients with complicated skin and skin structure infections received tigecycline 100 mg/day (a 100-mg initial dose and then 50 mg intravenously twice daily) or the combination of vancomycin 2 g/day (1 g intravenously twice daily) and aztreonam 4 g/day (2 g intravenously twice daily) for up to 14 days. Three hundred eighty-five (385) were from Europe. The primary endpoint was the clinical response in the clinical modified intent-to-treat (c-mITT) and clinically evaluable populations at the test-of-cure visit 12 to 92 days after the last dose. The microbiologic response at the test-of-cure visit was also assessed. Safety was assessed by physical examination, laboratory results and adverse event reporting. Of the patients enrolled in Europe, 376 patients were included in the c-mITT population (tigecycline group, n = 189; vancomycin/aztreonam group, n = 187), and 326 were clinically evaluable (tigecycline group, n = 167; vancomycin/aztreonam group, n = 159). The clinical responses in the tigecycline and the vancomycin/aztreonam groups in the clinically evaluable population were 89.8% versus 95.0%. Microbiologic eradication (documented or presumed) occurred in 84.8% of the European patients receiving tigecycline and 93.2% of the European patients receiving vancomycin/aztreonam. The number of European patients reporting adverse events was similar in the two groups, with increased nausea and vomiting rates in the tigecycline group and an increased incidence of rash and increases in alanine aminotransferase and aspartate aminotransferase levels in the vancomycin/aztreonam group. Current data support findings from the overall results in the Phase 3 study and suggest that tigecycline is safe and effective for the treatment of complicated skin and skin structure infections.


A decade on: has the use of integrated care pathways made a difference in Lanarkshire?
This article aimed to: (1) review the work carried out in Lanarkshire between 1996 and 1999 on a Scottish Executive funded project and (2) to discuss the situation from 1999 to 2006. (1) This 3-year project led to the successful development and implementation of over 100 integrated care pathways in an urban teaching hospital (Glasgow) and a district general hospital (Lanarkshire) and was the first in-depth study of integrated care pathways to be undertaken in Scotland. The main report on the project was produced in 1999 (Clinical Audit and Quality using Integrated Pathways of Care) and reported increased adherence to British Thoracic Society and Scottish Intercollegiate Guidelines Network guidelines and multiple best practice statements, and improved standards of documentation. The general findings were that process indicators were improved by integrated care pathway use and there was some suggestion of improved length of stay with no apparent effect on outcome. Evidence was found that integrated care pathways have made a difference for both patients and staff. (2) This provides an update of integrated care pathway development in a changing environment within NHS Lanarkshire and examines some of the key factors for success.


Three new isolates of porcine respiratory coronavirus with various pathogenicities and spike (S) gene deletions.
Three new isolates of porcine respiratory coronavirus (PRCV) were isolated and partially characterized. These PRCV isolates showed a selective tropism for respiratory tissue and were antigenically related to transmissible gastroenteritis virus. PCR amplification of the 5' half of the spike (S) genes of the three PRCV isolates indicated that a large deletion, characteristic of PRCV, was present. By using cDNA probes specific for the transmissible gastroenteritis virus S gene, the PCR products were shown to be specific in a Southern blot. The three new PRCV isolates were shown to vary in S gene deletion size. In a separate study, these isolates have also been shown to vary in pathogenicity. These new PRCV isolates should serve as important tools in gaining a better understanding of the pathogenesis of coronavirus infections.


Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses.
Diets rich in vegetables and fruits are associated with reduced risk of several major diseases, including neurodegenerative disorders. Although some beneficial phytochemicals might function solely as antioxidants, it is becoming clear that many of the beneficial chemicals in vegetables and fruits evolved as toxins (to dissuade insects and other predators) that, at subtoxic doses, activate adaptive cellular stress-response pathways in a variety of cells including neurons. Examples of such 'preconditioning' or 'neurohormesis' pathways include those involving cell-survival signaling kinases, the transcription factors NRF2 and CREB, and histone deacetylases of the sirtuin family. In these ways, neurohormetic phytochemicals such as resveratrol, sulforaphanes and curcumin might protect neurons against injury and disease by stimulating the production of antioxidant enzymes, neurotrophic factors, protein chaperones and other proteins that help cells to withstand stress. Thus, as we discuss in this review, highly conserved longevity and survival pathways in neurons are the targets of many phytochemicals.


Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme.
The Electron transport chain (ETC) is responsible for oxidative phosphorylation-mediated mitochondrial respiration. Here we wanted to address the mahanine-induced targeted pathways in glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated mahanine, as a novel mitochondrial complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of mahanine. During G0/G1 arrest, other hallmark proteins like, cyclin D1/cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of mahanine was also established in in vivo mice model. Mahanine-induced complex-III inhibition triggered enhanced ROS in hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that mahanine-treated G0/G1 arrested cells were less potent to form xenograft tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage. Taken together, our results established that complex-III of ETC is one of the possible potential targets of mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes.


Long-term impact of HIV diagnosis on mood and substance use--St Stephen's cohort study.
Twenty HIV positive and 68 HIV negative subjects were assessed by the Hospital Anxiety and Depression Scale and by the Alcohol and Drugs Frequency Schedule immediately prior to notification of their HIV serostatus and 6 months after serodiagnosis. The 2 groups did not differ significantly in levels of anxiety or depression at baseline or follow-up. There were borderline levels of pathological anxiety prior to notification of HIV serostatus in both groups. The drop to normal levels of anxiety which had occurred by follow-up was significant in the HIV positive group. About a third of subjects in both groups were regularly making use of alcohol and/or drugs, both at baseline and follow-up. Mean levels of weekly alcohol intake for both groups ranged from about 20 to 30 units per week. The drugs most commonly used (in any frequency) were nitrates ('poppers') and cannabis.


Immunohistochemical study of galectin-3 in mature and immature bull testis and epididymis.
Galectin-3, a member of the beta-galactoside-binding protein family, has been implicated in mammalian sperm maturation. We examined galectin-3 expression in the testis and epididymis of sexually mature and immature bulls. Western blot analysis showed varying levels of galectin-3 in the bull testis and epididymis, and galectin-3 immunoreactivity was higher in the mature testis and epididymis than in immature organs. Galectin-3 was primarily localized in interstitial cells of the immature bull testis and in the peritubular myoid and interstitial cells of the mature testis. In the immature epididymis head, galectin-3 was primarily in the principal and basal cells of the epithelium. In the mature epididymis head, moderate levels of galectin-3 were detected in the sperm, while low levels were found in the stereocilia, epithelium and connective tissue. In the immature epididymis body, moderate protein levels were detected in the principal cells, while lower levels were found in the basal cells. The mature epididymis body showed moderate levels of galectin-3 immunostaining in the stereocilia and epithelium, but low levels in the connective tissue. In the immature epididymis tail, only low levels of galectin-3 staining were found in the epithelium, whereas the mature epididymis tail showed high levels of galectin-3 in the principal cells, moderate levels in the basal cells and low levels in connective tissue. These findings suggest that galectin-3 expression plays a role in the maturation and activation of sperm in bulls.


Reproductive genetics: Canadian and European perspectives.
Unlike medically assisted conception, the issue of the impact on women of reproductive genetic testing has been characterized by the emergence of a more 'relativist' position. This relativist position is grounded in the understanding of the universality of problems arising from human genetics. An analysis of the major reports emanating from different European countries will demonstrate that the discussion regarding the impact of medically assisted conception and reproductive genetic testing on women is often incidental and secondary. There are similarities and differences in the issues raised in the evaluation of both these technologies. Similarities, in their experimental character, the concomitant social pressure, the myth of the perfect child and the increased medicalization. Differences, in the inherent responsibility or guilt accompanying genetic testing, the timing of choices, the possibility of sex selection, the use and control of genetic information, the sense of intergenerational responsibility and the current qualification of such genetic testing as medical and diagnostic as opposed to a technology of 'convenience' as was often the case with the treatment of infertility. In contrast to the European reports, the work of the Canadian Royal Commission on New Reproductive Technologies has as its primary focus the impact of both these technologies on women, children and society.


How Tennessee finances Medicaid.
Tennessee is fortunate to have a comprehensive Medicaid program involving some 22 optional services, all financed through a combination of state revenues. These range from general state revenues to provider-donated funds, provider-specific taxes, and recently, a privilege tax. The state pays approximately $920 million to participate in Medicaid; the state's share generates $1.9 billion in federal dollars. The current system for financing the state's Medicaid program is unsustainable. Because Tennessee is relatively poor, legislators cannot afford to continue to increase its share of Medicaid expenditures at a rate 10 times greater than the general revenue increase from the entire state. To continue a comprehensive Medicaid program, Tennessee must move forward with alternative strategies to control Medicaid expenditures and manage resources.


New olenelloid trilobites from the Northwest Territories, Canada.
The Olenelloidea are a superfamily of early Cambrian trilobites, which have been the subject of several phylogenetic analyses and also used to address macroevolutionary questions regarding the nature and timing of the Cambrian radiation. The Sekwi Formation of the Mackenzie Mountains, Northwest Territories, Canada, has yielded numerous species from this clade, and here we present new information that expands on the diversity known from this biogeographically and biostratigraphically important region. In particular, we describe seven new species, (Olenellus baileyi, Mesonacis wileyi, Elliptocephala jaredi, Holmiella taurus, H. domackae, Mummaspis delgadoae, and Bristolia colberti). Also recovered are specimens of Elliptocephala logani, specimens that shared affinities with Olenellus clarki, O. getzi, O. fowleri, and Frizolenellus hanseni, and one partial specimen, which appears to be a new species of Bolbolenellus.


Is GPR119 agonism an appropriate treatment modality for the safe amelioration of metabolic diseases?
GPR119 is a recently deorphanised G-protein coupled receptor which has been suggested to be important in mediating systemic metabolic homeostasis. Research to date has primarily focused on the ability of GPR119 to promote euglycaemia and thus as a therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Indeed, previous studies have shown that GPR119 promotes glucose-stimulated insulin secretion, pancreatic β-cell function and glucagon-like peptide-1 release, all of which provide valid mechanisms through which GPR119 may improve systemic glucose homeostasis. In the current review, the authors provide a brief overview of the known functions of GPR119 and then discuss the novel potential for GPR119 to regulate metabolic function in skeletal and cardiac muscle and how this may translate to improvements or impairments in systemic health. GPR119 is largely purported as being anti-diabetic and has been rapidly progressed to clinical trials, mainly as anti-diabetic agents. However, emerging data suggest that this class of agonists may have a detrimental effect at the level of the muscle. This may potentiate the development and progression of metabolic diseases such as T2DM. Therefore, further research is required before GPR119 receptor agonists can be prescribed with confidence as an anti-diabetic agent.


Measurement of force applied by infant tongue to the nipple during sucking and investigation of the mechanism of tongue movement.
In order to clarify the dynamic mechanisms involved in sucking by infants, we developed an artificial nipple with built-in force sensors and have measured the contact force between the tongue and the artificial nipple in infants including healthy, premature and low birth weight. In this study, we measured the force applied by the tongue on the artificial nipple in 10 healthy infants and in 10 infants who were also tube-fed and investigated the differences in dynamic actions between the two groups to extract factors involved in satisfactory sucking. The results showed that differences in the maximum force applied and in the time to reach the maximum force were found between infants with and without established oral feeding. For an infant to suck satisfactorily, 1) the time for the force to propagate from the tongue tip to the tongue root needs to constitute at least 8 % of the sucking period and 2) the force applied at the tongue tip needs to be at least 50% of the force at the tongue root.


Contrast-induced acute kidney injury: how should at-risk patients be identified and managed?
Contrast-induced acute kidney injury (CIAKI) refers to a sudden deterioration in renal function associated with the use of iodinated contrast media. CIAKI can lead to increased morbidity and mortality. Risk of CIAKI is low in the general population but increased in patients with risk factors, which include chronic kidney disease (particularly secondary to diabetes mellitus) and advanced age. Screening for risk factors and implementation of prevention practices in at-risk patients is recommended. Patients at risk of CIAKI because of chronic kidney disease can be identified by serum creatinine measurement, although, preferably, this should be applied to estimate glomerular filtration rate; screening questionnaires or risk scoring can also identify at-risk patients. Current best practice calls for intravenous periprocedural volume expansion in at-risk patients, but this is not practical in all clinical settings. No pharmacological approach has been demonstrated to offer consistent protection. Volume/dose of contrast agent should be the lowest needed to achieve a diagnostic result. The use of iso-osmolar contrast media is recommended for high-risk patients, because recent controlled clinical trials in coronary procedure settings have shown a lower nephrotoxicity of iodixanol, as compared with several low-osmolar contrast agents. However, additional studies involving a larger selection of iso- and low-osmolar contrast media are needed, particularly with intravenous use for computed tomography scans, if their use in this patient population is to be optimized.


Characteristics of thermospheric infrasound predicted using ray tracing and weakly non-linear waveform analyses.
Infrasonic signals refracted by thermal gradients in the rarefied upper atmosphere are modeled using a combination of ray tracing and weak shock theory to develop an understanding of thermospheric infrasound signals produced by energetic, transient sources. Canonical arrival structures in the form of u-wave signatures are identified for returns refracted at lower altitudes within the thermosphere, and possible multi-pathing produced by effective sound speed inflections are investigated to elucidate more complex arrival structures, which are found to be spatially localized. Variability in the source characteristics is investigated and it is found that whereas some waveform phase information is lost due to finite amplitude effects, arrival characteristics are strongly dependent on the peak overpressure near the source. Variability in the propagation path is considered using archived atmospheric specifications and implies that despite uncertainties related to the dynamic and sparsely sampled nature of the atmosphere, thermospheric signatures might be useful in estimating the yield for explosive sources. Last, thermospheric arrivals from a failed rocket launch, as well as those from several large chemical explosions, are analyzed and it is found that qualitative trends match those predicted, and analyses here provide additional insight into such signatures.


Transition-metal ions in zeolites: coordination and activation of oxygen.
Zeolites containing transition-metal ions (TMIs) often show promising activity as heterogeneous catalysts in pollution abatement and selective oxidation reactions. In this paper, two aspects of research on the TMIs Cu, Co, and Fe in zeolites are discussed: (i) coordination to the lattice and (ii) activated oxygen species. At low loading, TMIs preferably occupy exchange sites in six-membered oxygen rings (6MR), where the TMIs preferentially coordinate with the O atoms of Al tetrahedra. High TMI loadings result in a variety of TMI species formed at the zeolite surface. Removal of the extralattice O atoms during high-temperature pretreatments can result in autoreduction. Oxidation of reduced TMI sites often results in the formation of highly reactive oxygen species. In Cu-ZSM-5, calcination with O(2) results in the formation of a species, which was found to be a crucial intermediate in both the direct decomposition of NO and N(2)O and the selective oxidation of methane into methanol. An activated oxygen species, called alpha-O, is formed in Fe-ZSM5 and reported to be the active site in the partial oxidation of methane and benzene into methanol and phenol, respectively. However, this reactive alpha-O can only be formed with N(2)O, not with O(2). O(2)-activated Co intermediates in faujasite (FAU) zeolites can selectively oxidize alpha-pinene and epoxidize styrene. In Co-FAU, Co(III) superoxo and peroxo complexes are suggested to be the active cores, whereas in Cu and Fe-ZSM-5, various monomeric and dimeric sites have been proposed, but no consensus has been obtained. Very recently, the active site in Cu-ZSM-5 was identified as a bent [Cu-O-Cu](2+) core (Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 18908-18913). Overall, O(2) activation depends on the interplay of structural factors such as the type of zeolite and sizes of the channels and cages and chemical factors such as the Si/Al ratio and the nature, charge, and distribution of the charge-balancing cations. The presence of several different TMI sites hinders the direct study of the spectroscopic features of the active site. Spectroscopic techniques capable of selectively probing these sites, even if they only constitute a minor fraction of the total amount of TMI sites, are thus required. Fundamental knowledge of the geometric and electronic structures of the reactive active site can help in the design of novel selective oxidation catalysts.


Cooperative double deprotonation of bis(2-picolyl)amine leading to unexpected bimetallic mixed valence (M(-I), M(I)) rhodium and iridium complexes.
Cooperative reductive double deprotonation of the complex [Rh(I)(bpa)(cod)](+) ([4](+), bpa = PyCH(2)NHCH(2)Py) with one molar equivalent of base produces the bimetallic species [(cod)Rh(bpa-2H)Rh(cod)] (7), which displays a large Rh(-I),Rh(I) contribution to its electronic structure. The doubly deprotonated ligand in 7 hosts the two "Rh(cod)" fragments in two distinct compartments: a "square planar compartment" consisting of one of the Py donors and the central nitrogen donor and a "tetrahedral π-imine compartment" consisting of the other pyridine and an "imine C═N" donor. The formation of an "imine donor" in this process is the result of substantial electron transfer from the {bpa-2H}(2-) ligand to one of the rhodium centers to form the neutral imine ligand bpi (bpi = PyCH(2)N═CHPy). Hence, deprotonation of [Rh(I)(bpa)(cod)](+) represents a reductive process, effectively leading to a reduction of the metal oxidation state from Rh(I) to Rh(-I). The dinuclear iridium counterpart, complex 8, can also be prepared, but it is unstable in the presence of 1 mol equiv of the free bpa ligand, leading to quantitative formation of the neutral amido mononuclear compound [Ir(I)(bpa-H)(cod)] (2). All attempts to prepare the rhodium analog of 2 failed and led to the spontaneous formation of 7. The thermodynamic differences are readily explained by a lower stability of the M(-I) oxidation state for iridium as compared to rhodium. The observed reductive double deprotonation leads to the formation of unusual structures and unexpected reactivity, which underlines the general importance of "redox noninnocent ligands" and their substantial effect on the electronic structure of transition metals.


Changes in herbivore control in arable fields by detrital subsidies depend on predator species and vary in space.
Prey from the decomposer subsystem may help sustain predator populations in arable fields. Adding organic residues to agricultural systems may therefore enhance pest control. We investigated whether resource addition (maize mulch) strengthens aboveground trophic cascades in winter wheat fields. Evaluating the flux of the maize-borne carbon into the food web after 9 months via stable isotope analysis allowed differentiating between prey in predator diets originating from the above- and belowground subsystems. Furthermore, we recorded aphid populations in predator-reduced and control plots of no-mulch and mulch addition treatments. All analyzed soil dwelling species incorporated maize-borne carbon. In contrast, only 2 out of 13 aboveground predator species incorporated maize carbon, suggesting that these 2 predators forage on prey from the above- and belowground systems. Supporting this conclusion, densities of these two predator species were increased in the mulch addition fields. Nitrogen isotope signatures suggested that these generalist predators in part fed on Collembola thereby benefiting indirectly from detrital resources. Increased density of these two predator species was associated by increased aphid control but the identity of predators responsible for aphid control varied in space. One of the three wheat fields studied even lacked aphid control despite of mulch-mediated increased density of generalist predators. The results suggest that detrital subsidies quickly enter belowground food webs but only a few aboveground predator species include prey out of the decomposer system into their diet. Variation in the identity of predator species benefiting from detrital resources between sites suggest that, depending on locality, different predator species are subsidised by prey out of the decomposer system and that these predators contribute to aphid control. Therefore, by engineering the decomposer subsystem via detrital subsidies, biological control by generalist predators may be strengthened.


A prospective study of high-density lipoprotein cholesterol, cholesteryl ester transfer protein gene variants, and healthy aging in very old Japanese-american men.
High-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) gene deficiency mutations that increase HDL-C levels have been associated with exceptional longevity. However, a recent clinical trial of a promising CETP inhibitor that markedly increases HDL-C was terminated due to increased mortality. In light of this controversy, we examined the relationship among HDL-C, CETP mutations, and longevity phenotypes in the long-lived Japanese-American men of the Honolulu Heart Program (HHP). Japanese-American men (n = 3562) were followed for up to 8 years, from average age 78 to average age 84 (maximum age 99), or until death. Total mortality, cause-specific mortality, and healthy survival were evaluated for associations with HDL-C level and CETP genetic variants common in the Japanese population (CD442G and Int 14A). HDL-C was negatively associated with cardiovascular disease (CVD) mortality (p =.002) but not related to non-CVD (p =.147) or total (p =.547) mortality after adjustment for common risk factors. There was a trend for lower mortality for the men with the Int 14A variant. These men also had higher HDL-C levels (p =.047) and were significantly more likely to be healthy survivors (absence of six major age-related diseases and high physical/cognitive function) beyond the age of 90 years (p =.005). Low HDL-C level is a risk factor for CVD mortality in elderly Japanese-American men. High HDL-C and the Int 14A variant of the CETP gene may increase odds for healthy aging.


Iatrogenic spinal epidural abscesses: early diagnosis essential for good outcome.
Spinal epidural abscess usually arises by hematogenous, lymphatic or venous spread. The frequent use of invasive procedures at the spinal cord such as epidural injections to produce analgesia has led to an increased incidence of iatrogenic abscesses. We describe 8 patients who developed iatrogenic spinal epidural abscesses after paravertebral or intragluteal punctures respectively intravenous catheters to produce analgesia. Deep paravertebral or intragluteal injections were the cause of abscess formation in five, a contaminated intravenous line in two and a peridural catheter in one case. Pain of the affected vertebral column and malaise were the leading symptoms and Staphylococcus aureus was isolated in all cases. Diagnosis was made by means of magnetic resonance (n = 7) or Computed tomography (n = 1). Outcome was excellent with early therapy consisting of laminectomy and/or antibiotic treatment in the six patients treated within two days of appearance of symptoms. Invasive procedures at the spinal cord can lead to iatrogenic spinal epidural abscesses. Physicians dealing with deep punctures and catheter procedures should be aware of early symptoms and signs of an epidural abscess, since early diagnosis and specific therapy are the most important factors for a good outcome.


Pharmacological studies with the alpha 2-adrenoceptor antagonist midaglizole. Part II: Central and peripheral nervous systems.
Pharmacological properties of midaglizole (DG-5128, CAS 66529-17-7) on central and peripheral nervous systems were investigated in comparison with those of tolbutamide. 1. Central nervous system: Midaglizole showed little or no effects on general behavior (mouse), spontaneous motor activity (mouse), hexobarbital anesthesia (mouse), conditioned avoidance response (rat) and body temperature (rabbit) at an oral dose of 100 mg/kg. It also produced little or no changes in electroencephalogram (cat) and spinal reflex (cat) after intravenous dosing of 10 mg/kg. The drug lacked anticonvulsant and analgesic activities (mouse). Midaglizole produced clonic convulsion, mydriasis, lacrimation, increase in pinna reflex, decrease in spontaneous motor activity, increase in pain threshold (mouse) and rise in body temperature (rabbit) at oral dose of 300 mg/kg. Tolbutamide showed similar effects except that it potentiated hexobarbital anesthesia, slightly decreased convulsion and tended to decrease body temperature. 2. Autonomic nervous system: Midaglizole potentiated the pressor response to norepinephrine and inhibited the depressor response to acetylcholine at an intravenous dose of 10 mg/kg (anesthetized dogs). Similar results were observed after dosing of tolbutamide. Midaglizole potentiated the contractile response of nictitating membrane to pre- and post-ganglionic cervical sympathetic nerve stimulation after intravenous dosing of 1 mg/kg (cat). Tolbutamide lacked the activity on the contraction elicited by both stimulations. Midaglizole and tolbutamide had little or no effect on pupil size (rabbit). 3. Skeletal muscle contraction (neuromuscular junction): Midaglizole (3-10 mg/kg i.v.) slightly potentiated the tibialis anterior muscle contraction induced by peroneal nerve stimulation, but did not potentiate the contraction by direct (muscle) stimulation (rabbit). On the other hand, tolbutamide increased the contraction induced by both nerve and muscle stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)


Minihelix-loop RNAs: minimal structures for aminoacylation catalysts.
We report here an in vitro selected ribozyme, KL17, which is active in charging amino acids on its own 5'-OH group. The ribozyme consists of two catalytic domains, one of which (consisting of P5/P6/L6) recognizes amino acid substrates based on the steric environment of the side chain, whereas the other recognizes an aminoacylated oligonucleotide. The secondary structure of this ambidextrous ribozyme arranges into a pseudoknot, where L6 docks onto the 3'-terminal single-stranded region. The formation of this pseudoknot structure brings the P6 region, in which the essential catalytic core is most likely embedded, into the proximity of the 5'-OH group. Our studies show that the P6-L6 domain can be separated from the main body of KL17 and the derived P6-L6 minihelix-loop RNA can act as a trans-aminoacylation catalyst. In this report, we also compare this ribozyme with an analogous aminoacylation system previously characterized in our laboratory and illuminate the similarities and differences between these catalytic systems.


Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials.
5α-Reductase inhibitors (5ARIs) are widely used for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA). To review all the available data on the effect of 5ARIs on sexual function and assess whether 5ARIs increase the risk of sexual dysfunction. A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases. The search was limited to articles published in English and up to October 2015. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Data were analyzed using Stata 12.0. A fixed- or a random-effects model was used to calculate the overall combined risk estimates. Publication bias was assessed using Begg and Egger tests. Sexual dysfunction, erectile dysfunction, and decreased libido. After screening 493 articles, 17 randomized controlled trials with 17,494 patients were included. Nine studies evaluated the efficacy of 5ARIs in men with BPH. The other eight reported using 5ARIs in the treatment of men with AGA. The mean age of participants was 60.10 years across all studies. We included 10 trials (6,779 patients) on the efficacy and safety of finasteride, 4 trials (6,222 patients) on the safety and tolerability of dutasteride, and 3 trials (4,493 patients) using finasteride and dutasteride for AGA. The pooled relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in men with BPH and 1.21 (95% CI = 0.85-1.72) in men with AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in men with BPH and 0.66 (95% CI = 0.20-2.25) in men with AGA; and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in men with BPH and 1.16 (95% CI = 0.50-2.72) in men with AGA. Estimates of the total effects were generally consistent with the sensitivity analysis. No evidence of publication bias was observed. Evidence from the randomized controlled trials suggested that 5ARIs were associated with increased adverse effects on sexual function in men with BPH compared with placebo. However, the association was not statistically significant in men with AGA. Well-designed randomized controlled trials are indicated to study further the mechanism and effects of 5ARIs on sexual function.


Calling the Shots: How Family Courts Address the Firearms Ban in Protection Orders.
Access to firearms increases the risk of a batterer killing his partner. Moreover, firearms may be more common in homes where intimate partner abuse has occurred. The Violence Against Women Act of 1994 banned possession of firearms by individuals subject to civil protection orders. Yet little research has focused on how this ban is communicated to survivors and batterers. Drawing on systematic observations of protection order hearings, the current study explores factors related to judicial discussion of the ban in court. Implications for improving protection orders and for increasing battered women's safety are discussed.


Effects of Drought Stress on the Morphological Structure and Flower Organ Physiological Characteristics of Camellia oleifera Flower Buds.
Investigations on the impact of drought stress on the reproductive growth of C. oleifera have been relatively limited compared to the extensive research conducted on its nutritional growth. To study the effects of drought stress on the growth and development of C. oleifera flower buds, we investigated the effects of drought stress on the bud anatomical structure, relative water content, relative electrical conductivity, antioxidant enzyme activity, osmoregulation substance content, and hormone contents of C. oleifera using 4-year-old potted plants ('Huaxin' cultivar) as experimental materials. We observed C. oleifera flower bud shrinkage, faded pollen colour, shortened style length, decreased relative water content, increased relative electrical conductivity, and decreased pollen germination rate under drought stress. As the stress treatment duration increased, the malondialdehyde (MDA), soluble sugar (SS), soluble protein (SP), and proline (Pro) contents, as well as peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) activities increased. Moreover, the levels of the plant hormones indole acetic acid (IAA) and cytokinin (CTK) increased, whereas those of salicylic acid (SA) and jasmonic acid (JA) decreased, and those of abscisic acid (ABA) and gibberellin a3 (GA3) first increased and then decreased. Compared to the control group, the drought treatment group exhibited stronger antioxidant capacity, water regulation ability, and drought stress protection. These results indicate that C. oleifera is adaptable to drought-prone environments. The results of this study provide a theoretical basis for the evaluation of drought resistance in C. oleifera, as well as the development of water management strategies for cultivation.


The regionalization of radical cystectomy to specific medical centers.
Regionalization of high risk surgical procedures to larger teaching hospitals has been suggested as a means to improve the quality of care. We established a novel framework for characterizing regionalization, implemented it to determine the extent to which regionalization of radical cystectomy has occurred and delineated whether specific patient characteristics are associated with this phenomenon. We used the Nationwide Inpatient Sample to identify 22,088 patients who underwent radical cystectomy for bladder cancer from 1988 to 2000. Regionalization was assessed using 5 structural hospital measures, including teaching status, urban location, discharge volume, cystectomy volume and bed capacity. Adjusted models were developed to identify the significance of temporal trends and assess the association of demographic factors with structural qualities. Compared with 1988 to 1990 subjects were more likely to undergo cystectomy at teaching hospitals (OR 1.8), high cystectomy volume hospitals (OR 1.2), high discharge volume hospitals (OR 1.7) and large bed capacity medical centers (OR 1.4) in 1998 to 2000. The concentration of cystectomy to urban medical centers during the study years was 90% to 92%. The proportion of subjects undergoing partial cystectomy decreased from 23.9% to 16.6% as regionalization occurred. Older subjects were less likely to be treated at these regionalized centers. Without broad legislation from health care payers radical cystectomy has increasingly regionalized to specific medical centers. Despite this regionalization disparities in its use exist among specific, vulnerable patients. Addressing this may facilitate further concentration of this procedure.


NASICON-structured Na3Fe2PO4(SO4)2: a potential cathode material for rechargeable sodium-ion batteries.
The cost-effective and abundant availability of sodium offers an opportunity for rechargeable Na-ion batteries as an ideal replacement for rechargeable Li-ion batteries. However, the larger size and strong Na+-Na+ interaction create multidimensional phase instability and transformation problems, especially in layer-structured NaxMO2 (Mn, Co, Fe, and Ni) that inhibit the direct transformation of rechargeable Li-ion battery technology to Na-ion batteries. However, framework structures offer superior structural stability due to the interconnection of polyanions or polyhedra forming cationic octahedra. Sodium superionic conductor (NASICON)-type structures are well known for their superior Na+ ion transport and are identified as intercalative hosts as electrodes for rechargeable Na-ion batteries. Here, we report the synthesis of Na3Fe2PO4(SO4)2 in a NASICON framework structure and its investigation as a cathode in a Na/Na3Fe2PO4(SO4)2 cell working on the Fe3+/Fe2+ redox couple. The cell provides a single-phase reaction having a capacity approaching 70 mA h g-1 at 0.1 C after 50 cycles in the voltage range of 2 to 4.2 V, with a columbic efficiency approaching 100%. The large availability of Na and Fe with the stable redox and charge/discharge performance of NASICON-type Na3Fe2PO4(SO4)2 make it a possible cathode candidate for next-generation rechargeable sodium-ion batteries.


Mapping PARP-1 auto-ADP-ribosylation sites by liquid chromatography-tandem mass spectrometry.
We demonstrate a novel method for the identification of poly(ADP-ribose) polymerase-1 (PARP-1) autopoly(ADP-ribosyl)ation sites that is suited to collision induced dissociation (CID) tandem mass spectrometry. By employing phosphodiesterase to remove the majority of the poly(ADP-ribose) (pADPr) modification, we reduce the complexity of tandem mass spectrometric analysis of pADPr-modified tryptic peptides. The simplified ribose-5'-phosphate form of the peptides produce tandem mass spectra by CID that are readily interpreted and enable effective localization of the exact sites of PARP-1-catalyzed poly(ADP-ribosyl)ation. In conjunction with a phosphopeptide-like enrichment strategy that captures the ribose-5'-phosphate peptides, we identified eight novel sites of PARP-1 automodification, confirmed the localization of two sites previously reported, and provided evidence for two additional targeted peptides with ambiguous modification site assignments. Given the simplicity of the approach, the method is readily applicable to analysis of complex samples.


Low temperature pressure broadening of NH3 by D2.
We report experimentally measured cross sections for pressure broadening of ammonia inversion transitions by J=0, ortho-D2 at temperatures of 18-40 K. These measurements were made in a quasiequilibrium cell using the collisional cooling technique. Cross sections for broadening of the metastable (J,K)=(1, 1), (2, 2) and (3, 3) inversion transitions ranged from 67.5 A2 for (1, 1) at 20.0 K to 100.1 A2 for (3, 3) at 25.0 K. The J=0, ortho-D2 cross sections were found to be consistently larger than previously measured cross sections for low temperature broadening of NH3 by both He and H2.