Employee empowerment, innovative behavior and job productivity of public health nurses: a cross-sectional questionnaire survey.
Employee empowerment is an important organizational issue. Empowered employees with new ideas and innovative attributes may increase their ability to respond more effectively to face extensive changes in current public health care work environments. The objective of this study was to investigate the relationships between employee empowerment, innovative behaviors and job productivity of public health nurses (PHNs). This study conducted a cross-sectional research design. Purposive sampling was conducted from six health bureaus in northern Taiwan. 670 PHNs were approached and 576 valid questionnaires were collected, with a response rate of 85.9%. Structured questionnaires were used to collect data by post. Meaning and competence subscales of psychological empowerment, information and opportunity subscales of organizational empowerment, and innovative behaviors were the predictors of job productivity, only accounting for 16.4% of the variance. The competence subscale of psychological empowerment made the most contribution to job productivity (beta = 0.31). Meaning subscale of psychological empowerment has a negative impact on job productivity. Employee empowerment and innovative behavior of PHNs have little influence on job productivity. Employees with greater competence for delivering public health showed higher self-evaluated job productivity. The negative influences on job productivity possibly caused by conflict meaning on public health among PHNs in current public health policy. It should be an issue in further researches. Public health department should strengthen continuing education to foster competence of psychological sense of empowerment and innovative behavior to increase job productivity


Comparative gene genealogical analyses of strains of serotype AD identify recombination in populations of serotypes A and D in the human pathogenic yeast Cryptococcus neoformans.
Cryptococcus neoformans is a major pathogen of humans throughout the world. Using commercial monoclonal antibodies to capsular epitopes, strains of C. neoformans manifest five serotypes: A, B, C, D and AD. Previous studies demonstrated significant divergence among serotypes A, B, C and D, which are typically haploid. In contrast, most strains of serotype AD are diploid or aneuploid and result from recent hybridization between strains of serotypes A and D. Whether serotypes A, B, C and D represent strictly asexual lineages is not known. Using comparative genealogical analyses of two genes, the authors investigated whether recombination occurred among strains within serotypes A and D. For each of 14 serotype AD strains, a portion (642 bp) of the orotidine monophosphate pyrophosphorylase (URA5) gene was cloned and sequenced. Each of these 14 strains contained two different alleles and sequences for both alleles were obtained. The URA5 gene genealogy was compared to that derived from the laccase (LAC) gene, which was reported recently for the same 14 strains. For both genes, each of the 14 serotype AD strains contained two phylogenetically distinct alleles: one allele was highly similar to those from serotype A strains and the other to alleles from serotype D strains. However, within both the serotype A allelic group and the serotype D allelic group, there was significant incongruence between genealogies derived from URA5 and LAC. The results suggest recombination in natural populations of both serotypes A and D.


Teaching telehealth consultation skills.
Although teleconsultations have been used for many years in Australia, there has been a recent increase following new government incentives. There is a paucity of literature on enabling medical students to acquire the relevant skills. With a focus on equipping students for practice in rural and remote areas, our medical school has developed an innovative clinical skills lesson to prepare our students for their rural practice placements. This lesson was delivered to all students in their third year of training in small groups to enable interactive learning. The objectives of the lesson were to familiarise students with: the various methods of conducting teleconsultations currently in use; the legal and ethical considerations; the technical and procedural issues; and the barriers and benefits for patients and doctors. Students rotated through four different stations over 2 hours and the lesson was evaluated using a student survey. Medical students self-reported statistically significant improvements in understanding the issues and procedures, and in confidence in conducting a telehealth consultation. Analysis of the results and student comments demonstrated that students recognise the value of telemedicine learning, and benefit from formal teaching on all aspects of telemedicine, including technology, ethics and protocols. Interestingly, the students found the opportunity to discuss areas such as the ethics of, and barriers to, the use of teleconsultations to be the most challenging and helpful of all of the stations. There is a paucity of literature on enabling medical students to acquire the relevant [teleconsultation] skills.


Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis.
Mechanical signals from the tumor microenvironment modulate cell mechanics and influence cell metabolism to promote cancer aggressiveness. Cells withstand external forces by adjusting the stiffness of their cytoskeleton. Microtubules (MTs) act as compression-bearing elements. Yet how cancer cells regulate MT dynamic in response to the locally constrained environment has remained unclear. Using breast cancer as a model of a disease in which mechanical signaling promotes disease progression, we show that matrix stiffening rewires glutamine metabolism to promote MT glutamylation and force MT stabilization, thereby promoting cell invasion. Pharmacologic inhibition of glutamine metabolism decreased MT glutamylation and affected their mechanical stabilization. Similarly, decreased MT glutamylation by overexpressing tubulin mutants lacking glutamylation site(s) decreased MT stability, thereby hampering cancer aggressiveness in vitro and in vivo. Together, our results decipher part of the enigmatic tubulin code that coordinates the fine-tunable properties of MT and link cell metabolism to MT dynamics and cancer aggressiveness.


Variation in pre-treatment count lead time and its effect on baseline estimates of cage-level sea lice abundance.
Treatment efficacy studies typically use pre-treatment sea lice abundance as the baseline. However, the pre-treatment counting window often varies from the day of treatment to several days before treatment. We assessed the effect of lead time on baseline estimates, using historical data (2010-14) from a sea lice data management programme (Fish-iTrends). Data were aggregated at the cage level for three life stages: (i) chalimus, (ii) pre-adult and adult male and (iii) adult female. Sea lice counts were log-transformed, and mean counts by lead time relative to treatment day were computed and compared separately for each life stage, using linear mixed models. There were 1,658 observations (treatment events) from 56 sites in 5 Bay Management Areas. Our study showed that lead time had a significant effect on the estimated sea lice abundance, which was moderated by season. During the late summer and autumn periods, counting on the day of treatment gave significantly higher values than other days and would be a more appropriate baseline estimate, while during spring and early summer abundance estimates were comparable among counts within 5 days of treatment. A season-based lead time window may be most appropriate when estimating baseline sea lice levels.


Practice, efficacy and cost of staging suspected non-small cell lung cancer: a retrospective study in two Dutch hospitals.
A study was undertaken to investigate the clinical practice, yield, and costs of preoperative staging in patients with suspected NSCLC and to obtain baseline data for prospective studies on the cost effectiveness of (18)F-fluorodeoxyglucose positron emission tomography in the management of these patients. A retrospective study of the medical records of all patients with suspected NSCLC was performed during a 2 year interval (1993-4) in an academic and a large community hospital. Three hundred and ninety five patients with suspected NSCLC were identified; 58 were deemed to be medically inoperable and 337 patients proceeded to the staging process. Staging required a mean (SD) of 5.1 (1.5) diagnostic tests per patient (excluding thoracotomy) carried out over a median period of 20 days (IQR 10-31). Many of the tests (including both invasive and non-invasive) were done because previous imaging tests had suggested metastases, and in most cases the results of initial tests proved to be false positives. After clinical staging, 168 patients were considered to be resectable (stage I/II) and 144 patients underwent surgery with curative intent. At surgery 33 patients (23% of those who underwent surgery) were found to have irresectable lesions and 19 (13%) had a benign lesion. Surgery was also considered to be futile in 22 patients (15%) who developed metastases or local recurrence within 12 months following radical surgery. Hospital admission was responsible for most of the costs. In many patients staging involved considerable effort in terms of the number of diagnostic tests, the duration of the staging period and the cost, with limited success in preventing futile surgery. Failures relate to the quality of diagnostic preparation at every level of the TNM staging system.


Aboriginal birth cohort (ABC): a prospective cohort study of early life determinants of adiposity and associated risk factors among Aboriginal people in Canada.
Aboriginal people living in Canada have a high prevalence of obesity, type 2 diabetes, and cardiovascular disease (CVD). To better understand the pre and postnatal influences on the development of adiposity and related cardio-metabolic factors in adult Aboriginal people, we will recruit and follow prospectively Aboriginal pregnant mothers and their children - the Aboriginal Birth Cohort (ABC) study. We aim to recruit 300 Aboriginal pregnant mothers and their newborns from the Six Nations Reserve, and follow them prospectively to age 3 years. Key details of environment and health including maternal nutrition, glucose tolerance, physical activity, and weight gain will be collected. At birth, cord blood and placenta samples will be collected, as well as newborn anthropometric measurements. Mothers and offspring will be followed annually with serial measurements of diet and physical activity, growth trajectory, and adiposity. There is an urgent need to understand maternal and child factors that underlie the early development of adiposity and type 2 diabetes in Aboriginal people. The information generated from this cohort will assist the Six Nations community in developing interventions to prevent early adiposity in Aboriginal children.


RabD, a Dictyostelium Rab14-related GTPase, regulates phagocytosis and homotypic phagosome and lysosome fusion.
RabD, a Dictyostelium Rab14-related GTPase, localizes in the endo-lysosomal pathway and contractile vacuole system of membranes. Cell lines expressing dominant-negative RabD were defective in endocytosis, endosomal membrane flow and homotypic lysosome fusion. In support of a role for RabD in fusion, cells overexpressing constitutively active RabD(Q67L) accumulated enlarged hydrolase-rich acidic vesicles ringed with GFP-RabD, consistent with RabD directly regulating lysosome fusion. To determine whether RabD also regulated phagocytosis and/or homotypic phagosome fusion (a process stimulated by many intracellular pathogens), cells overexpressing dominant-active (RabD(Q67L)) or dominant-negative (Rab(N121I)) RabD were analyzed microscopically and biochemically. The rate of phagocytosis was increased two-fold in RabD(Q67L)-expressing cells and reduced by 50% in RabD(N121I)-expressing cells compared with control cells. To examine the role of RabD in the formation of multiparticle phagosomes, we performed a series of pulse-chase experiments using fluorescently labeled bacteria and fluorescent latex beads. The rate of fusion of newly formed phagosomes was five times higher in the RabD(Q67L)-expressing cells and reduced by over 50% in RabD(N121I)-expressing cells as compared with control cells. GFP-RabD(Q67L) was found to ring multiparticle spacious phagosomes, which supports a direct role for this protein in regulating fusion. Inhibition of PI 3-kinase activity, which is known to regulate phagosome fusion in the wild-type cells, reduced the rate of phagosome fusion in RabD(Q67L+) cells, indicating that RabD acted upstream of or parallel with PI 3-kinase. We hypothesize that RabD and, possibly, Rab14, a related GTPase that associates with phagosomes in mammalian cells, are important regulators of homotypic phagosome and endo-lysosome fusion.


Impaired perception of sincerity after severe traumatic brain injury.
People with a severe traumatic brain injury (TBI) often experience problems understanding non-literal utterances such as sarcasm and lies in dyadic exchanges. This study aimed to investigate whether these problems extend to settings where speakers vary in their degree of sincerity and whether such problems are associated with deficits in social cognitive abilities (emotion perception, theory of mind, and self-reported empathy) or cognitive abilities (abstract reasoning, working memory, processing speed, attentional switching). Thirty-one adults with severe TBI (24 males) and 25 demographically matched controls (20 males) participated. They watched video vignettes depicting four actors volunteering for additional duties. Each speaker made a limited verbal response which literally suggested a willingness to be involved, but the sincerity with which the response was made was tempered by the actor's emotional demeanour. Participants rated each speaker in the vignettes for degree of sincerity (0-100%). Standardized measures of cognitive and social cognitive function were also taken. Control participants had excellent agreement (α = .90) in their rankings of actors according to sincerity. TBI participants were less consistent (α = .65). Overall, they were sensitive to decreasing sincerity but generally less accurate than control participants. They were poorer at differentiating between levels of sincerity and rated insincere expressions as more sincere, although they rated sincere expressions similarly. Poorer working memory and poorer social cognition were associated with poorer sincerity/sarcasm detection in the participants with TBI, but only social cognition was uniquely associated. Some adults with TBI have difficulty assessing the level of sincerity of speakers. Moreover, poorer social cognition abilities are associated with this difficulty.


Suppressing generation of iodine impurity via an amidine additive in perovskite solar cells.
In perovskite solar cells, I- tends to oxidize to I2 due to its low redox potential. The generated I2 has been proved to be detrimental to device performance. Herein, for the first time, an amidine DBU is introduced as an additive into the precursor of the perovskite layer. The reductive DBU can suppress the formation of iodine impurity, resulting in a highly pure perovskite polycrystalline film. The efficiency and stability of the perovskite solar cells are thus improved.


Radionuclides transfer into halophytes growing in tidal salt marshes from the Southwest of Spain.
Estuaries are sinks of materials and substances which are released directly into them or transported from rivers that drain the basin. It is usual to find high organic matter loads and fine particles in the sediments. We analyzed radionuclide concentrations ((210)Po, (230)Th, (232)Th, (234)U, (238)U, (226)Ra, (228)Th, (228)Ra, (40)K) in sediments and three different organs (roots, stems and leaves) of three species of halophytes plants (Spartina maritima, Spartina densiflora and Sarcocornia perennis). The study was carried out in two tidal salt marshes, one polluted by U-series radionuclides and another nearby that was unpolluted and was used as a control (or reference) area. The Tinto River salt marsh shows high levels of U-series radionuclides coming from mining and industrial discharges. On the contrary, the unperturbed Piedras River salt marsh is located about 25 km from the Tinto marsh, and shows little presence of contaminants and radionuclides. The results of this work have shown that natural radionuclide concentrations (specially the U-isotopes) in the Tinto salt marsh sediments are one order of magnitude higher than those in the Piedras marsh. These radionuclide enhancements are reflected in the different organs of the plants, which have similar concentration increases as the sediments where they have grown. Finally, the transfer factor (TF) of the most polluted radionuclides (U-isotopes and (210)Po) in the Tinto area are one order of magnitude higher than in the Piedras area, indicating that the fraction of each radionuclide in the sediment originating from the pollution is more available for the plants than the indigenous fraction. This means that the plants of the salt marshes are unhelpful as bioindicators or for the phytoremediation of radionuclides.


Generalized scintillation detection and ranging results obtained by use of a modified inversion technique.
The measurement of the strength of atmospheric optical turbulence by use of a modified generalized SCIDAR (scintillation detection and ranging) inversion technique is outlined and demonstrated. This new method for normalizing and inverting scintillation covariances incorporates the geometry specific to generalized SCIDAR. Examples of profiles from two astronomical observation sites are presented.


Co-expression network analysis of lncRNAs and mRNAs in OPTN-silenced cells.
The aim of the present study was to reveal the role of long noncoding RNAs (lncRNAs) in the regulation of the pathogenesis of optineurin (OPTN)-silenced cells. The microarray data set GSE12452 was re-annotated using the non-coding RNA function annotation server to identify differentially expressed lncRNAs. Weighted correlation network analysis was used to construct an lncRNA-lncRNA co-expression network and identify co-expression modules. Three OPTN small interfering RNAs (siRNAs) were transiently transfected into HeLa cells. Reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect OPTN expression and select the most effective OPTN siRNA to construct stably transfected cells. RT-qPCR was used to quantify the identified lncRNAs in the OPTN-silenced cells. The potential functions of these modules were explored by the functional enrichment of the corresponding co-expressed genes. A total of 3,495 lncRNAs were re-annotated. Of these, matrix metalloprotease 12 and RP11-169D4.1 were upregulated, and RP1-212P9.2 was downregulated. The results of the RT-qPCR analysis of RP1-212P9.2 and RP11‑169D4.1 were consistent with the re-annotated data in the OPTN‑silenced cells. Gene Ontology analyses indicated that the biological functions of the mRNAs co-expressed with these lncRNAs were associated with gene product regulation, and neuronal migration, polarity and differentiation. In addition, Kyoto Encyclopedia of Genes and Genomes analysis indicated that the two validated lncRNAs were associated with the transforming growth factor-β signaling pathway and the apoptosis pathway, respectively. In conclusion, the abnormal lncRNAs identified in OPTN-silenced cells indicate that lncRNAs may contribute to the molecular pathogenesis of OPTN-associated diseases.


Tearing of free-standing graphene.
We examine the fracture mechanics of tearing graphene. We present a molecular dynamics simulation of the propagation of cracks in clamped, free-standing graphene as a function of the out-of-plane force. The geometry is motivated by experimental configurations that expose graphene sheets to out-of-plane forces, such as back-gate voltage. We establish the geometry and basic energetics of failure and obtain approximate analytical expressions for critical crack lengths and forces. We also propose a method to obtain graphene's toughness. We observe that the cracks' path and the edge structure produced are dependent on the initial crack length. This work may help avoid the tearing of graphene sheets and aid the production of samples with specific edge structures.


Elevation of plasma high-density lipoproteins inhibits development of experimental abdominal aortic aneurysms.
Patients with abdominal aortic aneurysms have lower concentrations of high-density lipoproteins (HDLs), leading us to investigate whether increasing plasma HDLs could influence aneurysm formation. Using the angiotensin II-induced hypercholesterolemic and the CaCl(2)-induced normocholesterolemic mouse model of AAA, we investigated the hypothesis that elevation of HDLs inhibits AAA. HDLs elevated before or at the time of AAA induction reduced AAA formation in both models but had no effect on early ruptures. Analysis of protein lysates from specific aortic segments demonstrated site-specific effects of HDLs on early signal transduction and cellular attrition. We found that HDLs reduced extracellular signal related kinases 1/2 activation in the suprarenal segment, while having no effect on p38 mitogen-associated protein kinase activation in any aortic segment and inhibiting c-Jun N-terminal kinase activation in all aortic segments. In addition, HDL elevation inhibited angiotensin II-induced apoptosis while inducing autophagy in the suprarenal segment of the aorta. Using Illumina gene array profiling we investigated the ability of HDL to modulate basal suprarenal aortic gene expression. Increasing plasma HDLs inhibit experimental AAA formation, independent of hypercholesterolemia via reduced extracellular signal related kinases 1/2 activation and alteration of the balance of cellular attrition. HDLs modulate genes involved in matrix remodelling, cell migration, and proliferation.


15-Lipoxygenase is a component of the mammalian sperm cytoplasmic droplet.
Lipoxygenases (LOXs) are a family of enzymes capable of peroxidizing phospholipids. A member of the LOX family of enzymes, 15-LOX, participates in the degradation of mitochondria and other organelles within differentiating red blood cells, the reticulocytes. The present study provides biochemical and immunocytochemical evidence for the presence of 15-LOX in the sperm cytoplasmic droplet (CD). Testicular, epididymal and ejaculated spermatozoa were evaluated for the presence of 15-LOX using an affinity-purified immune serum raised against a synthetic peptide corresponding to the C-terminal sequence of rabbit reticulocyte 15-LOX. Western blotting revealed an appropriate single band of approximately 81 kDa in boar spermatozoa but not in boar seminal plasma. When ejaculated boar spermatozoa were subjected to separation on a 45/90% Percoll gradient, 15-LOX co-migrated with the immotile sperm and cellular debris/CD fractions, but not with the motile sperm fraction containing morphologically normal spermatozoa without CDs. Varied levels of 15-LOX were expressed in ejaculated sperm samples from boars with varied semen quality. By immunofluorescence, prominent 15-LOX immunoreactivity was found within the residual body in the testis and within the CDs from caput, corpus and cauda epididymal and ejaculated spermatozoa. Components of the ubiquitin-dependent proteolytic pathway, which is thought to facilitate both spermiogenesis and reticulocyte organelle degradation, were also detected in the sperm CD. These included ubiquitin, the ubiquitin-conjugating enzyme E2, the ubiquitin C-terminal hydrolase PGP 9.5, and various 20S proteasomal core subunits of the alpha- and beta-type. The 15-LOX and various components of the ubiquitin-proteasome pathway were also detected in sperm CDs of other mammalian species, including the human, mouse, stallion and wild babirusa boar. We conclude that 15-LOX is prominently present in the mammalian sperm CD and thus may contribute to spermiogenesis, CD function or CD removal.


Disclosing the bioactive metabolites involved in the in vitro anthelmintic effects of salt-tolerant plants through a combined approach using PVPP and HPLC-ESI-MSn.
Strategies to reduce dependence on synthetic drugs for the treatment of gastrointestinal nematodes (GIN) infections in ruminants include the search for novel anthelmintic scaffolds on plants, yet salt-tolerant plants remain overlooked. This study aims to evaluate the in vitro anthelmintic properties of selected salt-tolerant plants against GIN, and identify the potential bioactive secondary metabolites involved. For that purpose, 80% acetone/water extracts were prepared from dried biomass of aerial organs of nine salt-tolerant plant species and tested against Haemonchus contortus and Trichostrongylus colubriformis by the Larval Exsheathment Inhibition Assay (LEIA) and Egg Hatching Inhibition Assay (EHIA). Pistacia lentiscus, Limoniatrum monopetalum, Cladium mariscus and Helychrisum italicum picardi were the most active in both GIN and life stages. To investigate the role of polyphenols in the anthelmintic activity, four selected extracts were treated with polyvinylpolypyrrolidone (PVPP), and non-treated and treated samples were further characterized by high-performance liquid chromatography with electrospray ionization mass spectrometric detection (HPLC-ESI-MSn). While polyphenols seem responsible for the EHIA properties, they are partially accountable to LEIA results. Several phenolics involved in the anthelmintic effects were identified and discussed. In sum, these species are rich sources of anthelmintic compounds and, therefore, are of major interest for nutraceutical and/or phytotherapeutic applications against GIN in ruminants.


Independent pharmacist prescribing in Canada.
While pharmacists are trained in the selection and management of prescription medicines, traditionally their role in prescribing has been limited. In the past 5 years, many provinces have expanded the pharmacy scope of practice. However, there has been no previous systematic investigation and comparison of these policies. We performed a comprehensive policy review and comparison of pharmacist prescribing policies in Canadian provinces in August 2010. Our review focused on documents, regulations and interviews with officials from the relevant government and professional bodies. We focused on policies that allowed community pharmacists to independently continue, adapt (modify) and initiate prescriptions. Pharmacists could independently prescribe in 7 of 10 provinces, including continuing existing prescriptions (7 provinces), adapting existing prescriptions (4 provinces) and initiating new prescriptions (3 provinces). However, there was significant heterogeneity between provinces in the rules governing each function. The legislated ability of pharmacists to independently prescribe in a community setting has substantially increased in Canada over the past 5 years and looks poised to expand further in the near future. Moving forward, these programs must be evaluated and compared on issues such as patient outcomes and safety, professional development, human resources and reimbursement.


Real-time observation of protein aggregates in pharmaceutical formulations using liquid cell electron microscopy.
Understanding the properties of protein-based therapeutics is a common goal of biologists and physicians. Technical barriers in the direct observation of small proteins or therapeutic agents can limit our knowledge of how they function in solution and in the body. Electron microscopy (EM) imaging performed in a liquid environment permits us to peer into the active world of cells and molecules at the nanoscale. Here, we employ liquid cell EM to directly visualize a protein-based therapeutic in its native conformation and aggregate state in a time-resolved manner. In combination with quantitative analyses, information from this work contributes new molecular insights toward understanding the behaviours of immunotherapies in a solution state that mimics the human body.


Testosterone therapy--what, when and to whom?
Testosterone therapy has been used for more than 60 years in the treatment of male hypogonadism. The classical forms of hypogonadism are comprised of primary testicular failure or insufficient testicular stimulation due to the lack of pituitary gonadotropins. Typical causes of primary hypogonadism are Klinefelter's syndrome, anorchia or acquired disturbances of testicular function. Secondary hypogonadism is characterized by insufficient production of pituitary gonadotropins, due either to pituitary failure or defects at the hypothalamic level. It is unequivocally accepted in clinical practice that any male with inadequately low testosterone production for his age will require androgen therapy. In addition to the classical forms of hypogonadism, the past decade of research has clearly demonstrated that, with increasing age, many men will suffer from decreasing testosterone production. About 15-25% of men over the age of 50 years will experience serum testosterone levels well below the threshold considered normal for men between 20 and 40 years of age. Studies substituting testosterone in elderly men with low serum testosterone have shown that men with clinical symptoms identical to the symptomatology of classical hypogonadism will benefit most from such therapy. Therefore, it is the general consensus to treat men with age-related hypogonadism only when clinical symptoms are present that can be potentially corrected by testosterone administration. Until recently, intramuscular injections of esters, such as testosterone enanthate, have been the mainstay of testosterone therapy. The introduction of testosterone patches has not challenged this approach, since many users of patches suffer from moderate to severe skin reactions. Some oral testosterone formulations have proven to be problematic, as absorption can be variable, bioavailability is frequently poor, due to the first-pass effect of the liver, and frequent administration is often required. Oral testosterone undecanoate avoids, at least partially, the first-pass effect of the liver. However, plasma testosterone levels generally undergo large fluctuations. The large fluctuations in serum testosterone levels caused by conventional intramuscular injections result in unsatisfactory shifts in mood and sexual function in some men, which, combined with the frequency of injections, make the intramuscular mode of delivery far from ideal. Recently, a hydroalcoholic gel containing 1% testosterone has proven to be as efficient as a testosterone patch, but with fewer side-effects and a higher grade of patient satisfaction. Doses of 50-100 mg gel applied once daily on the skin deliver sufficient amounts of testosterone to restore normal hormonal values and correct the signs and symptoms of hypogonadism. The gel has been shown to be effective and successful in patients in the United States, who have benefited from its availability for almost 3 years. In the near future, intramuscular injections of testosterone undecanoate will become commercially available. Such injections have a very favorable pharmacokinetic profile, with one injection every 3 months maintaining serum testosterone well within the normal range. In phase III studies, intramuscular testosterone undecanoate proved to be as efficient as testosterone enanthate, with only one-quarter of the number of injections required and more stable serum testosterone levels. Thus, the new application modes--hydroalcoholic gel (for example, Testogel, Schering AG, Germany) and intramuscular testosterone undecanoate (Nebido, Schering AG, Germany)--appear to be the methods of choice in the near future, one being very suitable for hormone therapy in elderly men, the other for long-term substitution in classical forms of hypogonadism.


TGN38-green fluorescent protein hybrid proteins expressed in stably transfected eukaryotic cells provide a tool for the real-time, in vivo study of membrane traffic pathways and suggest a possible role for ratTGN38.
The green fluorescent protein (GFP) of Aquorea victoria is fluorescent when expressed as a recombinant protein in eukaryotic cells and has been used as a convenient marker of gene expression in vivo. It has also been used as a marker of the intracellular targeting of recombinant fusion proteins (part GFP, part protein of interest) which have been transiently expressed in eukaryotic cells grown in tissue culture. Thus, the use of GFP has proved a useful tool to study intracellular events in real-time. However, some transiently transfected cells fail to express, or localise correctly, the GFP-tagged protein. Therefore the production of stable cell lines expressing GFP-tagged integral membrane proteins may be essential for long-term studies. The generation of stably transfected eukaryotic cells expressing an integral membrane protein with a known, but poorly characterised intracellular trafficking pathway, would provide useful reagents for future, more precise, analysis of that pathway. TGN38 is a type I integral membrane protein which cycles between the trans-Golgi network (TGN) and cell surface; at steady state it is localised to the TGN. As such, TGN38 is an ideal candidate for tagging with GFP. We have generated cDNA constructs encoding ratTGN38 tagged at either the N- or C terminus with GFP. Transiently transfected rat (NRK) cells expressed active fluorophore, but failed to show correct localisation of the fusion protein. In contrast, both constructs are appropriately localised in stably transfected NRK cells and both are fluorescent. Furthermore, the recombinant GFP-tagged proteins and the endogenous TGN38 molecules show identical responses to drugs and temperature blocks known to perturb intracellular morphology and membrane traffic pathways. In fact morphological changes to the TGN induced by brefeldin A were observed at earlier time points than had been described previously using immunofluorescence analysis of fixed cells, thus validating the use of in vivo, real-time analysis of GFP-tagged proteins. In addition, we show that (in contrast to the situation in COS cells) elevated expression of ratTGN38 in NRK cells does not lead to a fragmentation of the TGN; this has implications for the role which TGN38 is playing in the maintenance of the morphology of the TGN. The data we present demonstrate that: (i) it is possible to generate stable cell lines expressing integral membrane proteins tagged with GFP; (ii) the GFP tag remains fluorescent when expressed on either the cytosolic or the lumenal side of all membranes of the secretory pathway up to and including that of the TGN; (iii) the GFP tag does not interfere with the transport of TGN38 along the secretory pathway or its retention in the TGN; (iv) GFP remains fluorescent in cells which have been processed for immunofluorescence analysis (using either paraformaldehyde or methanol fixation); and (v) TGN38 plays a role in maintaining the morphology of the TGN. Thus, stably transfected cells expressing GFP-tagged integral membrane proteins can be used as effective tools for the real-time study of intracellular morphology and membrane traffic pathways in eukaryotic cells.


Gender differences in mathematics anxiety and the relation to mathematics performance while controlling for test anxiety.
Mathematics anxiety (MA), a state of discomfort associated with performing mathematical tasks, is thought to affect a notable proportion of the school age population. Some research has indicated that MA negatively affects mathematics performance and that girls may report higher levels of MA than boys. On the other hand some research has indicated that boys' mathematics performance is more negatively affected by MA than girls' performance is. The aim of the current study was to measure girls' and boys' mathematics performance as well as their levels of MA while controlling for test anxiety (TA) a construct related to MA but which is typically not controlled for in MA studies. Four-hundred and thirty three British secondary school children in school years 7, 8 and 10 completed customised mental mathematics tests and MA and TA questionnaires. No gender differences emerged for mathematics performance but levels of MA and TA were higher for girls than for boys. Girls and boys showed a positive correlation between MA and TA and a negative correlation between MA and mathematics performance. TA was also negatively correlated with mathematics performance, but this relationship was stronger for girls than for boys. When controlling for TA, the negative correlation between MA and performance remained for girls only. Regression analyses revealed that MA was a significant predictor of performance for girls but not for boys. Our study has revealed that secondary school children experience MA. Importantly, we controlled for TA which is typically not controlled for in MA studies. Girls showed higher levels of MA than boys and high levels of MA were related to poorer levels of mathematics performance. As well as potentially having a detrimental effect on 'online' mathematics performance, past research has shown that high levels of MA can have negative consequences for later mathematics education. Therefore MA warrants attention in the mathematics classroom, particularly because there is evidence that MA develops during the primary school years. Furthermore, our study showed no gender difference in mathematics performance, despite girls reporting higher levels of MA. These results might suggest that girls may have had the potential to perform better than boys in mathematics however their performance may have been attenuated by their higher levels of MA. Longitudinal research is needed to investigate the development of MA and its effect on mathematics performance.


The yin and yang of solubilization and stabilization for wild-type and full-length membrane protein.
Membrane proteins (MP) are stable in their native lipid environment. To enable structural and functional investigations, MP need to be extracted from the membrane. This is a critical step that represents the main obstacle for MP biochemistry and structural biology. General guidelines and rules for membrane protein solubilization remain difficult to establish. This review aims to provide the reader with a comprehensive overview of the general concepts of MP solubilization and stabilization as well as recent advances in detergents innovation. Understanding how solubilization and stabilization are intimately linked is key to facilitate MP isolation toward fundamental structural and functional research as well as drug discovery applications. How to manage the tour de force of destabilizing the lipid bilayer and stabilizing MP at the same time is the holy grail of successful isolation and investigation of such a delicate and fascinating class of proteins.


Estrogen plus progestin and colorectal cancer in postmenopausal women.
Although the Women's Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. We analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants. In the WHI trial, 16,608 postmenopausal women who were 50 to 79 years of age and had an intact uterus were randomly assigned to a combination of conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The main outcome measures were the incidence, stages, and types of colorectal cancer, as determined by blinded central adjudication. There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean +/-SD, 3.2+/-4.1 vs. 0.8+/-1.7; P=0.002) and were more advanced (regional or metastatic disease, 76.2 percent vs. 48.5 percent; P=0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8+/-4.3 vs. 0.7+/-1.5 nodes, P=0.006). Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. However, colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.


Study of graphene plasmons in graphene-MoS2 heterostructures for optoelectronic integrated devices.
The performance of electronic circuits is becoming limited by on-chip digital information transmission. Graphene plasmons with ultra-high confinement and low damping rates offer an effective solution to this problem as they allow for the implementation of optical interconnects. However, direct contact with the semiconductor always deteriorates the plasmonic properties due to large damping of the plasmon in the semiconductor. Here, we studied graphene plasmons in heterostructures of graphene and monolayer MoS2 which represents a promising semiconductor for next-generation electronic devices. The graphene plasmons in the heterostructures were systematically evaluated in terms of their resonance frequency, intensity, lifetime and electrical tunability and were found to keep their main characteristics. Experimental results exhibited both a redshift in the plasmon frequencies and a decrease in the resonance intensity for both graphene/MoS2 and MoS2/graphene devices when compared with graphene devices at the same gate bias. These results could be attributed to changes in the dielectric constant and effective doping of graphene. Furthermore, the conductivity saturation on the electron branch in the back-gated graphene/MoS2 device cancelled the electron plasmons. These findings demonstrate that electrically tunable graphene plasmons can be realized in contact with semiconducting MoS2. Our results provide a platform for the investigation of the integration of semiconductor-based electronic and optoelectronic devices with plasmonic devices through van der Waals heterostructures.


Immobilized metal affinity chromatography of histidine-tagged lentiviral vectors using monolithic adsorbents.
Histidine-tagged lentiviral vectors were separated from crude cell culture supernatant using labscale monolithic adsorbents by immobilized metal affinity chromatography. The capture capacity, concentration factor, purification factor, and elution efficiency of a supermacroporous cryogel monolith were evaluated against the BIA Separations convective interaction media (CIM) disc, which is a commercial macroporous monolith. The morphology of the polymeric cryogel material was characterised by scanning electron microscopy. Iminodiacetic acid was used as the metal chelating ligand in both monoliths and the chelating capacity for metal ions was found to be comparable. The CIM-IDA-Ni(2+) adsorbent had the greatest capture capacity (6.7 x 10(8) IU/ml of adsorbent), concentration factor (1.3-fold), and elution efficiency (69%). Advantages of the cryogel monoliths included rapid, low pressure processing as well low levels of protein and DNA in the final purified vector preparations.


Accounting for the increase of children in care in western Australia: What can a client information system tell us?
This paper analyses a fourteen-year period of Western Australian data from the client information system of the Department for Child Protection and Family Support. Western Australia saw a large increase in the number of children in state care similar to trends across Australia as a whole. The study shows the following trends: changes in response to 'referrals' with particular increases in the number of findings of neglect and increasing proportions of these followed swiftly by entry to care; changes in patterns of entry to care with more children under one-year-old entering; increased length of stay of children in care; and, the high incidence of Aboriginal children entering and remaining in care. The data demonstrate unequivocally that increased 'referrals' are not associated with increased substantiations of harm or 'acts of commission with dangerous intent', but that neglect assessed early in the lives of children was the major precipitant for entry to care and particularly so for Aboriginal infants.


A requirement for trypsin-sensitive cell-surface components for cell-cell interactions of embryonic neural retina cells.
A quantitative assay was used to measure the rate of collection of a population of embryonic neural retina cells to the surface of cell aggregates. The rate of collection of freshly trysinized cells was limited in the initial stages by the rate of replacement of trypsin-sensitive cell- surface components. When cells were preincubated, or "recovered," and then added to cell aggregates, collection occurred at a linear rate and was independent of protein and glycoprotein synthesis. The adhesion of recovered cells was temperature and energy dependent, and was reversibly inhibited by cytochalasin B. Colchicine had little effect on collection of recovered cells. Antiserum directed against recovered cell membranes was shown to bind to recovered cells by indirect immunofluorescence. The antiserum also was shown to inhibit collection of recovered cells to aggregates, suggesting that at least some of the antigens identified might be involved in the adhesion process. The inhibitory effect of the antiserum was dose dependent . Freshly trypsinized cells absorbed neither the immunofluorescence activity nor the adhesion-inhibiting activity. Recovered cells absorbed away both activities. In specificity studies, dorsal neural retina cells adhered to aggregates of ventral optic tectum in preference to aggregates of dorsal optic tectum. The adhesive specificity of the dorsal retina cells was less sensitive to trypsin than the adhesive specificity of ventral retina cells which adhered preferentially to dorsal tectal aggregates only after a period of recovery.


Shift work increases the frequency of duodenal ulcer in H pylori infected workers.
To evaluate whether shift work is associated with an increased rate of peptic ulcer in H pylori infected workers. During a two year period, consecutive dyspeptic workers underwent non-invasive evaluation of H pylori status by means of urea 13C breath test or stool testing. Those testing positive were included in the study and divided into two main categories: day-time workers and shift workers. An upper gastrointestinal endoscopy was performed in all workers, and biopsy specimens were taken from the stomach to confirm the presence of H pylori infection (culture and histology). A total of 247 day-time workers and 101 shift workers were included. The prevalence of duodenal ulcer was significantly higher in shift workers than in day-time workers (29 of 101 v 23 of 247; OR = 3.92, 95% CI 2.13 to 7.21), and persisted after multivariate analysis, taking into account possible confounding factors (OR = 3.96, 95% CI 2.10 to 7.47). Shift work increases the ulcerogenic potential of H pylori infection and should be considered a risk factor for duodenal ulcer in infected shift workers. Treatment of infection in this high risk group may improve the health of workers and may reduce the economic impact of peptic ulcer.


Molecular self-assembly into one-dimensional nanostructures.
Self-assembly of small molecules into one-dimensional nanostructures offers many potential applications in electronically and biologically active materials. The recent advances discussed in this Account demonstrate how researchers can use the fundamental principles of supramolecular chemistry to craft the size, shape, and internal structure of nanoscale objects. In each system described here, we used atomic force microscopy (AFM) and transmission electron microscopy (TEM) to study the assembly morphology. Circular dichroism, nuclear magnetic resonance, infrared, and optical spectroscopy provided additional information about the self-assembly behavior in solution at the molecular level. Dendron rod-coil molecules self-assemble into flat or helical ribbons. They can incorporate electronically conductive groups and can be mineralized with inorganic semiconductors. To understand the relative importance of each segment in forming the supramolecular structure, we synthetically modified the dendron, rod, and coil portions. The self-assembly depended on the generation number of the dendron, the number of hydrogen-bonding functions, and the length of the rod and coil segments. We formed chiral helices using a dendron-rod-coil molecule prepared from an enantiomerically enriched coil. Because helical nanostructures are important targets for use in biomaterials, nonlinear optics, and stereoselective catalysis, researchers would like to precisely control their shape and size. Tripeptide-containing peptide lipid molecules assemble into straight or twisted nanofibers in organic solvents. As seen by AFM, the sterics of bulky end groups can tune the helical pitch of these peptide lipid nanofibers in organic solvents. Furthermore, we demonstrated the potential for pitch control using trans-to-cis photoisomerization of a terminal azobenzene group. Other molecules called peptide amphiphiles (PAs) are known to assemble in water into cylindrical nanostructures that appear as nanofiber bundles. Surprisingly, TEM of a PA substituted by a nitrobenzyl group revealed assembly into quadruple helical fibers with a braided morphology. Upon photocleavage of this the nitrobenzyl group, the helices transform into single cylindrical nanofibers. Finally, inspired by the tobacco mosaic virus, we used a dumbbell-shaped, oligo(phenylene ethynylene) template to control the length of a PA nanofiber self-assembly (<10 nm). AFM showed complete disappearance of long nanofibers in the presence of this rigid-rod template. Results from quick-freeze/deep-etch TEM and dynamic light scattering demonstrated the templating behavior in aqueous solution. This strategy could provide a general method to control size the length of nonspherical supramolecular nanostructures.


An evaluation of the effectiveness of four mechanical plaque-removal devices when used by a trained care-provider.
Many care-dependent elderly individuals live in nursing homes and must depend on nursing home aides for oral hygiene care. It is generally agreed that the level of oral hygiene care among care-dependent nursing home residents is less than optimal. Two reasons are time constraints and the difficulty involved in brushing other individuals' teeth. The identification of effective and efficient plaque-removal devices for use by care-providers should make it easier for nursing home aides to incorporate effective oral hygiene care into their daily routines. This pilot study was undertaken to determine the relative effectiveness of four plaque removal devices with different basic designs when used by a non-professional care-provider on 10 healthy volunteers. A brush with curved bristles on the lateral aspect of the brush head and short straight bristles in the center (Collis-curve) and an electric toothbrush with tufts that rotate reciprocally (Interplak) were the most effective, a conventional brush (Oral-B) was somewhat less effective, and a disposable foam brush (Abco) was least effective and similar to the prebrushing plaque score (baseline). All the volunteers reported that the Collis-curve was the most comfortable brush, and the care-provider reported that it was the easiest to use.


LCA case study on lawn establishment and maintenance with various peat and compost contents in substrates.
The environmental impacts of the establishment and maintenance of lawn, including the production and use of various substrates, were analyzed by life cycle assessment (LCA). The project focused on comparing substrates with different peat and compost contents using pilot substrates and developed a calculation tool to optimize landscaping from an ecological perspective. The impact categories were climate change, aquatic eutrophication, acidification, and use of primary energy. Life cycle assessment methodology and ISO standards 14040 and 14044 were used. Two thousand tons of substrates per hectare of lawn area were assumed to be needed; this large amount explains the importance of the substrate properties for all of the impact categories. Degradation of peat was the most significant factor of the influence of climate; thus, the most effective means of reducing the impact of landscaping on climate is to replace peat with compost. Nitrous oxide and methane emissions were related to the use of compost, but most of these emissions will occur regardless of how the sludge or biowaste is treated. Ammonia emissions from composting were the most important factor for acidification. The significance of fuel consumption by machinery in lawn establishment and mowing was low. The high contents of N and P in compost-based substrates may lead to high nutrient emissions into water systems, which can have significant local impact. The tool helps optimize substrate contents to minimize the environmental effects. Integr Environ Assess Manag 2016;12:459-464. © 2016 SETAC.


Pulmonary function one and four years after a deep saturation dive.
The pulmonary function of 24 Norwegian divers who had participated in a deep saturation dive to pressures of 3.1-4.6 MPa was reevaluated one and four years later. Twenty-eight divers performing ordinary saturation diving to pressures of 0.8-1.6 MPa and followed over a three-year period served as referents. A significant reduction in forced expiratory volume in 1 s (FEV1.0) of 210 (SD 84) ml (P < 0.001) occurred the first year after the dive. Thereafter the annual reduction in FEV1.0 was 28 (SD 62) ml.year-1; this value did not differ from the 35 (SD 80) ml.year-1 of the referents. The forced midexpiratory flow rate and forced expiratory flow rates at low lung volumes were also significantly reduced one year after the deep dive, and the closing volume was increased. No significant changes occurred in forced vital capacity. The results agree with those of cross-sectional studies on divers' lung function and indicate the development of airflow limitation in relation to diving exposure.


Mediterranean diet and longevity.
Mortality statistics from the WHO database covering the period 1960 to 1990 have provided intriguing evidence that something unusual has been affecting in a beneficial way the health of the Mediterranean population. In recent papers, which evaluated the evidence accumulated over the last three decades, it was concluded that the traditional Mediterranean diet meets several important criteria for a healthy diet. Direct evidence in support of the beneficial properties of the Mediterranean diet has also become available. These data were derived from three studies, which have used a diet score, devised a priori on the basis of eight desirable key features of the traditional common diet in the Mediterranean region. The conclusion of these studies is that a diet that adheres to the principles of the traditional Mediterranean one is associated with longer survival. The Greek version of the Mediterranean diet is dominated by the consumption of olive oil and by high consumption of vegetables and fruits. Antioxidants represent a common element in these foods and an antioxidant action provides a plausible explanation for the apparent benefits. Wild edible greens frequently eaten in rural Greece in the form of salads and pies contain very high quantities of flavonoids-- considerably higher than those found in red wine or black tea. While there is no direct evidence that these antioxidants are central to the benefits of the Mediterranean Diet, indirect evidence from epidemiological data and the increasing understanding of their mechanisms of action suggest that antioxidants may play a major role.


[3H]epibatidine labels nicotinic receptors in rat brain: an autoradiographic study.
Epibatidine, a frog skin alkaloid, is a nicotinic receptor agonist with potent analgesic activity. We used in vitro receptor autoradiographic techniques to map binding sites for [3H]epibatidine in rat brain, and those for another nicotinic agonist, [3H]cytisine. Both [3H]epibatidine and [3H]cytisine are excellent radioligands for autoradiography. [3H]Epibatidine in particular binds with very high affinity and extremely low nonspecific binding. In the present study, the distribution of binding was almost identical for both radioligands and closely resembled that of previously published autoradiographic studies with two other nicotinic ligands, [3H]acetylcholine and [3H]nicotine. Brain regions demonstrating the highest levels of [3H]epibatidine binding included the interpeduncular nucleus, medial habenular nucleus, fasciculus retroflexus, superficial gray layer of the superior colliculus and numerous thalamic nuclei, including the anteroventral, dorsal lateral geniculate and gelatinosus nuclei. Quantitative analysis revealed that [3H]epibatidine binding was greater than [3H]cytisine binding in several regions. In particular, [3H]epibatidine clearly labeled the optic nerve, optic chiasm and optic tract, whereas [3H]cytisine binding to these structures did not exceed background levels. Other regions in which [3H]epibatidine binding was greater than that of [3H]cytisine included the medial habenula, fasciculus retroflexus, olivary pretectal nucleus and superficial gray layer of the superior colliculus. The differences in labeling between these two nicotinic ligands may arise from receptor heterogeneity in brain nicotinic receptors and the ability of [3H]epibatidine to label more than one subtype of nicotine receptor.


Compact beveled fiber optic probe design for enhanced depth discrimination in epithelial tissues.
We report the development and evaluation of a simple compact probe that incorporates multiple beveled fibers for depth sensitive detection of spectroscopic signals in vivo. We evaluated three probes with bevel angles 35, 40, and 45 degrees for their collection efficiency and depth resolution using a thin highly scattering white substrate and found that a 40 degree bevel provides the best characteristics for depth-resolved spectroscopy. The depth sensitivity of the probe with 40 degree beveled fibers was then evaluated using multilayer phantoms with scattering properties mimicking precancerous tissue and in vivo on normal human oral mucosa. The results demonstrate that the use of multiple beveled fibers has the capability to simultaneously collect scattering spectra from a range of depths within epithelial tissue that has the potential to provide further significant improvement of detection and monitorin of epithelial precancers.


When proton pumps go sour: Urinary acidification and kidney stones.
H(+)-ATPases mediate urinary acidification along the collecting duct, and mutations in their B1 and a4 subunits result in distal renal tubular acidosis. The pathomechanisms by which these mutations affect pump activity are only poorly understood. Common polymorphisms may impair pump activity and may link the pump to a higher risk for alkaline urine and the development of kidney stones.


Amino acid transport in Pseudomonas aeruginosa.
Properties of the transport systems for amino acids in Pseudomonas aeruginosa were investigated. Exogenous (14)C-labeled amino acids were shown to equilibrate with the internal native amino acid pool prior to incorporation into protein. When added at low external concentrations, the majority of the amino acids examined entered the protein of the cell unaltered. The rates of amino acid transport, established at low concentrations with 18 commonly occurring amino acids, varied as much as 40-fold. The transport process became saturated at high external amino acid concentrations, was temperature-sensitive, and was inhibited by sodium azide and iodoacetamide. Intracellular to extracellular amino acid ratios of 100- to 300-fold were maintained during exponential growth of the population in a glucose minimal medium. When the medium became depleted of glucose, neither extracellular nor intracellular amino acids could be detected.


Rapid detection of Mycobacterium tuberculosis Beijing genotype strains by real-time PCR.
Mycobacterium tuberculosis strains of the Beijing genotype were first identified in China and neighboring countries and have attracted special attention due to their global emergence and association with drug resistance. To further analyze the spread and special characteristics of Beijing genotype strains, accurate, rapid and sensitive methods that overcome the drawbacks of the classical methods such as IS6110 DNA fingerprinting or spoligotyping for the identification of strains of this genotype are needed. Based on the nucleotide sequences of M. tuberculosis SAWC0780 and H37Rv, primers and fluorogenic 5' nuclease (TaqMan) probes for real-time PCR assays specific for Beijing and non-Beijing strains, respectively, were designed. The detection limits for the real-time PCR assays were about 5 and 10 copies of chromosomal DNA, respectively. In mixtures of Beijing and non-Beijing DNA, a multiplex assay was able to detect (i) one copy of Beijing DNA in approximately 1,000 copies of non-Beijing DNA and (ii) one copy of non-Beijing DNA in approximately 2,000 copies of Beijing DNA. In a blinded analysis of a collection of 103 multidrug-resistant strains isolated in Germany in 2001, all 62 Beijing and all 41 non-Beijing strains were correctly identified. In conclusion, the real-time assay allows for the rapid and specific detection of Beijing and non-Beijing strains. The major advantages of this test in comparison to other methods used for the identification of Beijing strains are its simplicity and sensitivity and the fact that amplification and detection occur within one reaction tube.


Use of Sentinel blood culture system for analysis of specimens from potentially infected prosthetic joints.
The Sentinel blood culture system was used for the analysis of 657 specimens from infected prosthetic joints and blood cultures (83 from prosthetic joints and 574 from standard blood cultures). The positivity rate was similar for specimens from prosthetic joints and blood cultures (18% compared with 14%). However, there was an unacceptable rate of false positive results with specimens from prosthetic joints (58% compared with 8%). This high false positivity rate was due to (i) prolonged incubation and (ii) the lack of blood in these specimens. It is therefore recommended that the Sentinel system should only be used for the initial seven days of incubation of specimens taken from prosthetic joints. Further incubation should take place in a standard incubator and a terminal subculture performed after 21 days.


Have hospital inpatient cost containment programs contributed to the growth in outpatient expenditures? Analysis of the substitution effect associated with hospital utilization review.
The rapid increase in outpatient expenditures has been the focus of growing attention in recent years. This increase has corresponded with public and private efforts to contain hospital inpatient costs, prompting some analysts to suggest that outpatient expenditure growth is the result of a substitution effect; that is, the substitution of outpatient for inpatient care associated with hospital cost containment programs. Claims data on 43 privately insured groups that adopted utilization review (UR) during the latter part of 1984 or early 1985 were analyzed, comparing outpatient expenditures before and after adoption of hospital inpatient UR to quantify the substitution effect associated with UR. UR was not associated with higher physician office expenditures nor with higher outpatient diagnostic expenditures. UR was related to significantly higher hospital outpatient department expenditures. On average, these expenditures were approximately 20% higher (P = 0.01) after the adoption of UR. However, outpatient department expenditures of the groups analyzed represented a fairly small percentage of total medical expenditures; hence, the absolute expenditure increase was quite modest, on the order of $9 per insured person per year. This analysis, admittedly limited in scope, suggests that UR is associated with a measurable substitution effect. It is likely that inpatient hospital cost containment programs have resulted in some substitution of outpatient for inpatient care and thus have played a role in fostering outpatient expenditure growth during recent years.


The health concerns and behaviours of primigravida: comparing advanced age pregnant women with their younger counterparts.
This study was to describe and compare the health concerns, behaviours and anxiety of advanced age pregnant women (35 years and older) with their younger counterparts. Women have specific health concerns and behaviours during pregnancy. Delayed childbearing has an increased risk of adverse pregnancy outcomes and advanced age pregnant women may have more health concerns than younger ones. A cross-sectional study. Primigravidae Chinese women aged 35 or older (n = 47) and 188 younger than aged 35 were recruited in February and March of 2005 by convenient sampling from the antenatal clinic of a regional hospital in Hong Kong to complete a questionnaire. Advanced age pregnant women when compared with their counterparts were more likely to have tertiary education (42·6% vs. 28·7%) and a higher family monthly income of Hong Kong $40,001 or more (40·5% vs. 15·4%). They were more likely to be concerned the possibility of miscarriage (63·8% vs. 45·9%) and the physical demands of caring for the newborn (61·7% vs. 45·4%) but were more likely to take up healthy behaviours such as 'eating nutritious food' (100%) and avoiding 'wearing tight clothing and high-heel shoes'(100%). Advanced age women were more likely to be concerned about their 'recovery after childbirth' (63·8% vs. 42·7%), Down's syndrome (70·2% vs. 37·8%) and structural defects of their foetus (78·7% vs. 54·1%). The results of this study provide a background for improving prenatal care catering for the specific health concerns of the advanced aged and promotion of health behaviours among younger pregnant women. Antenatal, obstetric and community health nurses have the responsibility to provide education and support services catering to the special concerns of pregnant women at different ages. Health professionals should promote the prime time for childbearing and deliver messages regarding the potential problems associated with later childbearing at premarital counselling.


Effect of sugammadex on chest radiographic abnormality in the early postoperative period after video-assisted thoracoscopic lobectomy
Sugammadex, which offsets the effects of neuromuscular blocking agents (NMBs), has advantages over traditional reversal agents like pyridostigmine, as it enables fast and reliable recovery from neuromuscular blockade. This study compared the incidence of early postoperative chest radiographic abnormalities (CRA) between sugammadex (group S) and pyridostigmine (group P) following video-assisted thoracoscopic (VAT) lobectomy for lung cancer. We performed a retrospective cohort analysis by reviewing the medical records of patients who underwent VAT lobectomy at a single university medical center. We defined the early postoperative CRA as a characteristic appearance on chest radiograph up to 2 days after surgery. Arterial blood gas analysis (ABGA), surgical time, anaesthesia time, extubation time, and the total dose of rocuronium were analysed. Postoperative nausea and vomiting (PONV) and pain scores were observed until 2 days after surgery. A total of 257 patients underwent VAT lobectomy during the study period; 159 were included in the final analysis. Ninety patients received sugammadex while 69 received pyridostigmine. The incidence of early postoperative atelectasis was significantly lower in group S than in group P (26.7%, 95% CI: 17.5%‒35.8% and 43.5%, 95% CI: 31.8%‒55.2%, respectively, P = 0.013). The median dose of rocuronium was higher in group S than in group P (120 mg vs. 90 mg, P < 0.001). ABGA, extubation time, and PONV were similar in both groups. Sugammadex decreased the incidence of CRA in the early postoperative period despite higher NMB consumption.


Effects of a self-determination theory-based mail-mediated intervention on adults' exercise behavior.
To examine the effect of a mail-mediated intervention, based on self-determination theory, on adults'exercise behavior. The study was a randomized control trial conducted over a 2-month period. Of the initial 185 volunteer participants, 126 (68.1%) completed questionnaires at baseline, 1 month, and 2 months. Participants in intervention-only and intervention-plus-booster groups received a mail-delivered packet containing strategies designed to promote perceptions of autonomy, competence, and relatedness regarding exercise. Those in a control group received an American Heart Association physical-activity facts packet. After 1 month, those in the intervention-plus-booster group received a booster postcard, reiterating the main points of the initial intervention packet. Exercise behavior was the primary outcome variable. Perceptions of autonomy, competence, and relatedness were evaluated as mediating variables. Separate 3 (group) x 3 (time) repeated measures analyses of variance conducted for men and women revealed that for women, all three groups significantly increased exercise levels over the 2-month period. No significant interactions were found regarding the influence of the intervention on the mediating variables. A process evaluation indicated a lack of compliance regarding completing intervention-packet worksheets. Findings suggested that more intensive interventions and greater fidelity of treatment may be needed to evidence change in exercise behavior.


A focus group study of the use of video-recorded simulated objective structured clinical examinations in nurse practitioner education.
The objective structured clinical examination (OSCE) is a common method of clinical skills assessment used for advanced nurse practitioner students across the United Kingdom. The purpose of an advanced nursing OSCE is to assess a nurse practitioner student's competence and safety in the performance of commonly used advanced clinical practice skills. Students often feel nervous when preparing for and participating in an OSCE. Consideration of these identified anxieties led to the development of an alternative method of meeting students' OSCE learning and preparation needs; namely video-recorded simulated OSCEs. Video-recording was appealing for the following reasons: it provides a flexible usage of staff resources and time; OSCE performance mistakes can be rectified; it is possible to use the same video-recordings with multiple cohorts of students, and the recordings can be made conveniently available for students with video streaming on internet-based video-sharing sites or virtual learning environments. The aim of the study was to explore the value of using such recordings amongst nurse practitioner students, via online and face-to-face focus groups, to see if they are a suitable OSCE educational preparation technique. The study findings indicate that simulated OSCE video-recordings are an effective method for supporting nurse practitioner educational development.


A biotin-conjugated glutathione-responsive FRET-based fluorescent probe with a ferrocenyl BODIPY as the dark quencher.
An efficient ferrocenyl BODIPY based dark quencher has been developed and employed to construct a FRET-based fluorescent probe that contains a biotin moiety as a potential directing ligand for cancer cells and a glutathione-cleavable disulfide linker connecting the quencher and a distyryl BODIPY fluorophore. This molecular probe is deactivated in the native form through FRET followed by intramolecular charge transfer due to the ferrocenyl unit. However, upon interaction with glutathione in phosphate buffered saline and inside cancer cells, the fluorescence emission is significantly increased due to detachment of the fluorophore from the quencher. As shown by flow cytometry, this probe also exhibits preferential uptake by the biotin-receptor-expressing A549 human lung adenocarcinoma epithelial cells over the Chinese hamster ovary CHO-K1 cells used as the negative control. On the basis that both biotin receptor and GSH level are often overexpressed or elevated in cancer cells, this dual functional fluorescent probe serves as a promising agent for cancer imaging.


Protective effect of Urtica dioica L. on renal ischemia/reperfusion injury in rat.
Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions. This study was designed to investigate the effect of Urtica dioica L. (UD), in I/R induced renal injury. A total of 32 male Sprague-Dawley rats were divided into four groups: control, UD alone, I/R and I/R + UD; each group contain 8 animals. A rat model of renal I/R injury was induced by 45-min occlusion of the bilateral renal pedicles and 24-h reperfusion. In the UD group, 3 days before I/R, UD (2 ml/kg/day intraperitoneal) was administered by gastric gavage. All animals were sacrificed at the end of reperfusion and kidney tissues samples were obtained for histopathological investigation in all groups. To date, no more histopathological changes on intestinal I/R injury in rats by UD treatment have been reported. Renal I/R caused severe histopathological injury including tubular damage, atrophy dilatation, loss of brush border and hydropic epithelial cell degenerations, renal corpuscle atrophy, glomerular shrinkage, markedly focal mononuclear cell infiltrations in the kidney. UD treatment significantly attenuated the severity of intestinal I/R injury and significantly lowered tubulointerstitial damage score than the I/R group. The number of PCNA and TUNEL positive cells in the control and UD alone groups was negligible. When kidney sections were PCNA and TUNEL stained, there was a clear increase in the number of positive cells in the I/R group rats in the renal cortical tissues. However, there is a significant reduction in the activity of PCNA and TUNEL in kidney tissue of renal injury induced by renal I/R with UD therapy. Our results suggest that administration of UD attenuates renal I/R injury. These results suggest that UD treatment has a protective effect against renal damage induced by renal I/R. This protective effect is possibly due to its ability to inhibit I/R induced renal damage, apoptosis and cell proliferation.


Six degrees of separation: the oxygen effect in the development of radiosensitizers.
The popular theory six degrees of separation is used in this review as an analogy to relate all radiosensitization to oxygen. As the prime mover of all radiosensitizers, the pervasive influence of oxygen has consciously or unconsciously influenced the direction of research and development and provided the benchmark against which all other compounds and approaches are measured. It is the aim of this review to develop the six degrees of separation from oxygen analogy as a unifying framework for conceptually organizing the field and for giving context to its varied subspecializations and theories. Under such a framework, it would become possible for one area to consider questions and problems found in other areas of radiosensitization, using a common analogy, that would allow for further development and unification of this multifaceted discipline. In this review, approaches to the development of radiosensitizers and the current state of research in this field are discussed, including promising new agents in various stages of clinical development.


Processing quantum information with relativistic motion of atoms.
We show that particle detectors, such as two-level atoms, in noninertial motion (or in gravitational fields) could be used to build quantum gates for the processing of quantum information. Concretely, we show that through suitably chosen noninertial trajectories of the detectors the interaction Hamiltonian's time dependence can be modulated to yield arbitrary rotations in the Bloch sphere due to relativistic quantum effects.


Ideal observer analysis for continuous tracking experiments.
Continuous tracking is a newly developed technique that allows fast and efficient data acquisition by asking participants to "track" a stimulus varying in some property (usually position in space). Tracking is a promising paradigm for the investigation of dynamic features of perception and could be particularly well suited for testing ecologically relevant situations difficult to study with classical psychophysical paradigms. The high rate of data collection may be useful in studies on clinical populations and children, who are unable to undergo long testing sessions. In this study, we designed tracking experiments with two novel stimulus features, numerosity and size, proving the feasibility of the technique outside standard object tracking. We went on to develop an ideal observer model that characterizes the results in terms of efficiency of conversion of stimulus strength into responses, and identification of early and late noise sources. Our ideal observer closely modeled results from human participants, providing a generalized framework for the interpretation of tracking data. The proposed model allows to use the tracking paradigm in various perceptual domains, and to study the divergence of human participants from ideal behavior.


Unexpected insights into antibacterial activity of zinc oxide nanoparticles against methicillin resistant Staphylococcus aureus (MRSA).
Zinc oxide nanoparticles (ZnO-NPs) are attractive as broad-spectrum antibiotics, however, their further engineering as antimicrobial agents and clinical translation is impeded by controversial data about their mechanism of activity. It is commonly reported that ZnO-NP's antimicrobial activity is associated with the production of reactive oxygen species (ROS). Here we disprove this concept by comparing the antibacterial potency of ZnO-NPs and their capacity to generate ROS with hydrogen peroxide (H2O2). Then, using gene transcription microarray analysis, we provide evidence for a novel toxicity mechanism. Exposure to ZnO-NPs resulted in over three-log reduction in colonies of methicillin resistant S. aureus with minimal increase in ROS or lipid peroxidation. The amount of ROS required for the same amount of killing by H2O2 was much greater than that generated by ZnO-NPs. In contrast to H2O2, ZnO-NP mediated killing was not mitigated by the antioxidant, N-acetylcysteine. ZnO-NPs caused significant up-regulation of pyrimidine biosynthesis and carbohydrate degradation. Simultaneously, amino acid synthesis in S. aureus was significantly down-regulated indicating a complex mechanism of antimicrobial action involving multiple metabolic pathways. The results of this study point to the importance of specific experimental controls in the interpretation of antimicrobial mechanistic studies and the need for targeted molecular mechanism studies. Continued investigation on the antibacterial mechanisms of biomimetic ZnO-NPs is essential for future clinical translation.


Phylogeny of the mega-diverse Gelechioidea (Lepidoptera): adaptations and determinants of success.
The Gelechioidea, with 18,000 described and many more unnamed species ranks among the most diverse lepidopteran superfamilies. Nevertheless, their taxonomy has remained largely unresolved, and phylogenetic affinities among gelechioid families and lower taxa have been insufficiently understood. We constructed, for the first time, a comprehensive molecular phylogeny for the Gelechioidea. We sampled seven genes, in total 5466 base pairs, of 109 gelechioid taxa representing 32 of 37 recognized subfamilies, and two outgroup taxa. We used maximum likelihood methods and Bayesian inference to construct phylogenetic trees. We found that the families Autostichidae, Lecithoceridae, Xyloryctidae, and Oecophoridae s. str., in this order, are the most basally arising clades. Elachistidae s. l. was found to be paraphyletic, with families such as Gelechiidae and Cosmopterigidae nested within it, and Parametriotinae associated with several families previously considered unrelated to them. Using the phylogenetic trees, we examined patterns of life history evolution and determinants of the success of different lineages. Gelechioids express unusually wide variability in life-history strategies, including herbivorous, saprophagous, fungivorous, and carnivorous lineages. Most species are highly specialized in diet and other life history traits. The results suggest that either saprophagy was the ancestral feeding strategy from which herbivory evolved independently on multiple occasions, or that the ancestor was herbivorous with repeated origins of saprophagy. External feeding is an ancestral trait from which internal feeding evolved independently several times. In terms of species number, saprophages are dominant in Australia, while elsewhere several phytophagous lineages have extensively specialized and diversified. Internal feeding has remained a somewhat less generally adopted feeding mode, although in a few lineages significant radiations of leaf mining species have occurred. We conclude that diverse feeding modes, specialization among saprophages, repeated shifts to phytophagy, and a generally high specialization rate on single plant species (monophagy) are the major factors behind the success of the Gelechioidea.


A mutant of DNA polymerase I (Klenow fragment) with reduced fidelity.
The kinetic parameters governing incorporation of correct and incorrect bases into synthetic DNA duplexes have been investigated for Escherichia coli DNA polymerase I [Klenow fragment (KF)] and for two mutants, Tyr766Ser and Tyr766Phe. Tyr766 is located at the C-terminus of helix O in the DNA-binding cleft of KF. The catalytic efficiency for correct incorporation of dNTP is reduced 5-fold for Tyr766Ser. The catalytic efficiencies of all 12 possible misincorporations have been determined for both KF and Tyr766Ser by using single-turnover kinetic conditions and a form of the enzyme that is devoid of the 3'-5' exonuclease activity because of other single amino acid replacements. Tyr766Ser displays an increased efficiency of misincorporation (a reduction in fidelity) for several of the 12 mismatches. The largest increase in efficiency of misincorporation for Tyr766Ser occurs for the misincorporation of TMP opposite template guanosine, a 44-fold increase. In contrast, the efficiencies of misincorporation of dAMP opposite template A, G, or C are little affected by the mutation. A determination of the kinetic parameters associated with a complete kinetic scheme has been made for Tyr766Ser. The rate of addition of the next correct nucleotide onto a preexisting mismatch is decreased for Tyr766Ser. The fidelity of Tyr766Phe was not substantially different from that of KF for the misincorporations examined, indicating that it is the loss of the phenolic ring of the side chain of Tyr766 that leads to the significant decrease in fidelity. The results indicate that KF actively participates in the reduction of misincorporations during the polymerization event and that Tyr766 plays an important role in maintaining the high fidelity of replication by KF.


Implementation Quality: Implications for Intervention and Translational Science.
Implementation quality (IQ), a critical concept for translational science, measures the discrepancy between an intervention's intended design and its implementation. Quantifying the impact of IQ on intervention outcomes informs efforts to improve intervention translatability. The purpose of this article is to define and describe IQ and its dimensions (content adherence, quality of delivery, and engagement) with a focus on individualized interventions being delivered in research and practice settings. We apply IQ concepts from intervention science in two contexts: (a) an intervention currently being investigated in an efficacy trial, and (b) a practice situation involving the application of evidence-based practice guidelines during clinic visits. IQ measurement approaches are presented using a study protocol, progress notes, interdisciplinary meeting notes, or clinical guidelines, depending upon whether the intervention is delivered during a research study or a clinical encounter. The investigators describe the necessary infrastructure and support for capturing IQ data and the subsequent complexities and challenges of collecting, measuring, and analyzing these data. Understanding IQ is critical to advancing translational science. Such understanding informs application of appropriate IQ measures, and promotes effective translation of evidence-based interventions into practice. Policy changes are needed to promote IQ assessment to ensure high-quality clinical encounters during which interventions are effectively delivered. In both research and practice settings, the conceptualization and measurement of IQ will improve patient outcomes by advancing translational science and integrating evidence-based interventions into nursing practice.


Why is allergy increasing?--environmental factors.
Data from epidemiological studies have shown that allergic conditions have increased over the last 30-40 years, particularly in developed countries, despite a decrease in the severity of grass pollen seasons. Other epidemiological studies suggest an interaction between allergic diseases and traffic pollution, and laboratory findings indicate that diesel exhaust particles enhance sensitivity to allergens. In an in vitro study, we found evidence to suggest that cigarette smoke may render the airway epithelium more susceptible to adverse effects of allergens. Evidence from other studies indicates that O3 and NO2, with or without SO2, can enhance the airway allergic response in susceptible individuals such as those with asthma and rhinitis. Studies investigating cellular and subcellular mechanisms suggest that pollutants are likely to influence the actions and interactions of a variety of cells, and lead to the synthesis of proinflammatory mediators that modulate the activity and functions of inflammatory cells.


Mapping the key issues shaping the landscape of global public health.
A survey of global health experts attending an invited meeting provided a means to map key issues perceived to be shaping emerging global public health agendas. Eighty-five participants proposed three major issues likely to have the most significant impact on the field of global health in the coming years. Six raters grouped the resultant items, with multi-dimensional scaling (MDS) analysis producing a composite two-dimensional map depicting the overall patterning of items. Thematic clusters were incorporated within four major domains: changing health and prevention needs (15% of items), globalisation and global health governance (33% of items), transforming health systems (30% of items) and innovations in science and technology (7% of items). The remaining 15% of items addressed forms of environmental change. The distribution of items across domains was not significantly influenced by the current professional role of participants, their current location in the 'global north' or 'global south' or their region of focus (although the latter approached threshold significance). The constraints on interpretation imposed by the biases influencing participation in the survey are noted. However, the exercise suggests the potential for coherently defining shared agendas for diverse stakeholders to address emerging priorities. The closer integration of environmental concerns with other global public issues is clearly warranted.


Cardiovascular indices of challenge and threat states predict competitive performance.
Cardiovascular (CV) reactivity is proposed by both the Biopsychosocial Model and the Theory of Challenge and Threat States in Athletes to predict competitive performance. The association between CV reactivity and competitive performance was examined in cognitive (Study 1) and motor (Study 2) tasks. In Study 1, 25 participants (9 female) completed a modified Stroop Test, and in Study 2, 21 female netballers completed a netball shooting task, under competition. Measures of CV reactivity, self-report measures of self-efficacy, control, achievement-goals and emotions along with baseline and competitive task performance were taken. CV reactivity indicative of a challenge state predicted superior performance in both tasks compared to CV reactivity indicative of a threat state. In both studies the purported relationships between CV reactivity and the psychological and emotional responses were weak or absent. The mechanisms for the observed association between CV reactivity and task performance are discussed alongside implications of the findings for future research and practice.


Serum creatinine as marker of kidney function in South Asians: a study of reduced GFR in adults in Pakistan.
Migrant populations of South Asian origin have a higher risk for chronic kidney disease than the native whites. Several formulas have been developed to estimate kidney function from serum creatinine concentration. However, none of these has been validated in the South Asian population, which generally has different muscle mass composition than whites. A population-based cross-sectional study was performed on 262 individuals who were aged > or = 40 yr in Karachi, Pakistan. Reduced GFR was defined as creatinine clearance (Ccr) measured in 24-h urine collection of <60 ml/min per 1.73 m2. Creatinine excretion was compared with age- and gender-matched white individuals by comparison of observed versus expected results on the basis of a formula using t test. The agreement among Cockcroft Gault (CG) Ccr and Modification of Diet in Renal Disease (MDRD) Study GFR equations was assessed by regression analyses, and the degree of accuracy of estimated versus measured GFR was determined. Mean (95% confidence interval) creatinine excretion was 1.7 (1.0 to 2.4) mg/kg per d lower than expected for age- and gender-matched white individuals (P < 0.001). The coefficient of determination for measured Ccr on the logarithmic scale was 66.7 and 55.6% for the CG and MDRD Study equations, respectively. The proportion of estimates within 20, 30, and 50% of measured Ccr values was 47.7 versus 32.8% (P < 0.001), 64.9 versus 49.6% (P < 0.001), and 79.4 versus 72.9 (P = 0.07) for CG versus MDRD Study equations, respectively. Lower mean creatinine excretion in these individuals may explain, in part, suboptimal agreement between estimated versus measured GFR. Inclusion of terms for ethnic and racial groups other than white and black might improve the performance of GFR estimating equations.


Diaphragmatic breathing reduces exercise-induced oxidative stress.
Diaphragmatic breathing is relaxing and therapeutic, reduces stress, and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices. Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant; therefore, in this study, we investigated the effects of diaphragmatic breathing on exercise-induced oxidative stress and the putative role of cortisol and melatonin hormones in this stress pathway. We monitored 16 athletes during an exhaustive training session. After the exercise, athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1 h relaxing performing diaphragmatic breathing and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.


Chlorinated persistent organic pollutants, obesity, and type 2 diabetes.
Persistent organic pollutants (POPs) are lipophilic compounds that travel with lipids and accumulate mainly in adipose tissue. Recent human evidence links low-dose POPs to an increased risk of type 2 diabetes (T2D). Because humans are contaminated by POP mixtures and POPs possibly have nonmonotonic dose-response relations with T2D, critical methodological issues arise in evaluating human findings. This review summarizes epidemiological results on chlorinated POPs and T2D, and relevant experimental evidence. It also discusses how features of POPs can affect inferences in humans. The evidence as a whole suggests that, rather than a few individual POPs, background exposure to POP mixtures-including organochlorine pesticides and polychlorinated biphenyls-can increase T2D risk in humans. Inconsistent statistical significance for individual POPs may arise due to distributional differences in POP mixtures among populations. Differences in the observed shape of the dose-response curves among human studies may reflect an inverted U-shaped association secondary to mitochondrial dysfunction or endocrine disruption. Finally, we examine the relationship between POPs and obesity. There is evidence in animal studies that low-dose POP mixtures are obesogenic. However, relationships between POPs and obesity in humans have been inconsistent. Adipose tissue plays a dual role of promoting T2D and providing a relatively safe place to store POPs. Large prospective studies with serial measurements of a broad range of POPs, adiposity, and clinically relevant biomarkers are needed to disentangle the interrelationships among POPs, obesity, and the development of T2D. Also needed are laboratory experiments that more closely mimic real-world POP doses, mixtures, and exposure duration in humans.


Evidence for time-dependent interactions between ritonavir and lopinavir/ritonavir plasma levels following P-glycoprotein inhibition in Sprague-Dawley rats.
The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 µg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.


New criteria for the sonographic diagnosis of a plaque ulcer in the extracranial carotid artery.
The diagnostic power of carotid sonography in detecting plaque ulcers may be inadequate when using the conventional criteria. We aimed to evaluate the usefulness of new criteria that we devised through a preliminary analysis of 50 endarterectomy cases before the present series. Thirty carotid arteries of 30 consecutive patients who underwent endarterectomy (28 men; age range, 46-83 years) were studied. In the long- and short-axis B-mode images of carotid arteries, the concavity of the plaque surface and the surface echo intensity were carefully investigated. The conventional criteria stipulate a concavity larger than 2 × 2 mm with a well-defined back wall and flow reversal within the recess. Our new criteria specify a concavity in the plaque with the basal border echo weaker than that of the adjacent plaque surface, regardless of size. The final diagnosis was based on surgical and histologic findings. Among the 30 carotid arteries, 14 arteries had 14 ulcers at surgery. Seventeen concavities were detected by sonography, and 12 of them, including six smaller than 2 × 2 mm, were truly ulcers. Two concavities with an echo intensity of the basal border equal to or greater than that of the adjacent surface were not true ulcers. Only two of 14 ulcers were not detected by sonography. The sensitivity and specificity of the conventional criteria were 35.7% and 75.0%, respectively, and those of our new criteria were 85.7% and 81.3%, respectively. Our new criteria for the sonographic diagnosis of plaque ulcer are more useful than the conventional ones.