Does a One-Size-Fits-All Cost-Sharing Approach Incentivize Appropriate Medication Use? A Roundtable on the Fairness and Ethics Associated with Variable Cost Sharing.
Tiered formularies, in which patients pay copays or coinsurance out-of-pocket (OOP), are used to manage costs and encourage more efficient health care resource use. Formulary tiers are typically based on the cost of treatment rather than the medical appropriateness for the patient. Cost sharing may have unintended consequences on treatment adherence and health outcomes. Use of higher-cost, higher-tier medications can be due to a variety of factors, including unsuccessful treatment because of lack of efficacy or side effects, patient clinical or genetic characteristics, patient preferences to avoid potential side effects, or patient preferences based on the route of administration. For example, patients with rheumatoid arthritis may be required to fail low-cost generic treatments before obtaining coverage for a higher-tier tumor necrosis factor alpha inhibitor for which they would have a larger financial burden. Little is known about stakeholders' views on the acceptability of greater patient cost sharing if the individual patient characteristics lead to the higher-cost treatments. To identify and discuss the trade-offs associated with variable cost sharing in pharmacy benefits. To discuss the trade-offs associated with variable cost sharing in pharmacy benefits, we convened an expert roundtable of patient, payer, and employer representatives (panelists). Panelists reviewed background white papers, including an ethics framework; actuarial analysis; legal review; and stakeholder perspectives representing health plan, employer, and patient views. Using case studies, panelists were asked to consider (a) when it would be more (or less) acceptable to require higher cost sharing; (b) the optimal distribution of financial burdens across patients, all plan members, and employers; and (c) the existing barriers and potential solutions to align OOP costs with medically appropriate treatments. Panelists felt it was least acceptable for patients to have greater OOP costs if the use of the higher-cost treatment was due to biological reasons such as step therapy (6 = unacceptable, 9 = neutral, 2 = acceptable) or diagnostic results (5 = unacceptable, 10 = neutral, and 2 = acceptable). In contrast, panelists felt it was more acceptable for patients to pay greater OOP costs when treatment choice was based on preferences to avoid a side-effect risk (1 = unacceptable, 3 = neutral, and 13 = acceptable) or the route/frequency of administration (1 = unacceptable, 1 = neutral, and 15 = acceptable). Five guiding principles emerged from the discussion: When patients have tried lower-cost therapies unsuccessfully, the benefits of higher-cost treatments were certain and significant, the cost difference between treatments was aligned with improved benefits, and penalties due to bad luck were mitigated, then cost-sharing differences should be minimized but not eliminated. Patient OOP costs can affect the use of both inappropriate and appropriate medications. This study identified 5 guiding principles to determine when it was more (or less) acceptable for patients with the same or similar conditions to have different OOP costs. Barriers that hinder the alignment of care and patient cost sharing exist. Policies that facilitate the alignment of patient cost sharing with appropriate care are needed. Funding for this roundtable was provided by the National Pharmaceutical Council (NPC). Graff and Dubois are employed by the NPC. Shih was employed by the NPC at the time of this study. Barker, Dieguez, Sherman, and Larson received consulting fees for participation in this study. Larson also reports receiving grants and other payment from multiple major pharmaceutical manufacturers outside of this study. The NPC employees developed the study design and chose the case studies in collaboration with the white paper authors. The roundtable was facilitated by Dubois, and the meeting summary and manuscript were written by Graff and Shih, with revisions by all roundtable participants. The abstract for this article was previously presented as a poster at the following meetings: Stakeholder perspectives on balancing patient-centeredness and drug costs in the design of pharmacy benefits. Presented at: Academy of Managed Care Pharmacy 27th Annual Meeting & Expo; San Diego, California; April 8, 2015. Considering efficiency and fairness in the design of prescription drug benefits: seeking a balanced approach to improve patient access to medically appropriate medication and manage drug costs. Presented at: AcademyHealth Annual Research Meeting; Minneapolis, Minnesota; June 15, 2015. Study concept and design were contributed by Shih, Dubois, and Graff, along with Barker and Dieguez. Barker and Dieguez took the lead in data collection, assisted by Graff, Shih, and Dubois. Data interpretation was performed by Shih, Larson, Sherman, and Graff, with assistance from Dubois. The manuscript was written and revised by Graff and Shih, with assistance from the other authors.


[Advance in studies on pathological mechanism of Parkinson's disease and traditional Chinese medicine experiments in prevention and treatment of Parkinson's disease].
This article summarizes the current studies on the pathological mechanism of Parkinson's disease as well as the advance in studies traditional Chinese medicine (TCM) experiments in prevention and treatment of Parkinson's disease in the latest decade in terms of prevention and treatment of PD by TCM, inhibition of oxidative stress, improving mitochondrial energy metabolism, inhibition of neural immune and inflammatory responses, reduction of neural toxicity, inhibition of apoptosis and abnormal protein aggregation.


Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation.
The objective of this prospective study was to assess overall survival and event-free survival in patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary enucleation with or without adjuvant therapy depending on histopathologic risk factors. Patients (n = 123) were divided into three groups on the basis of risk factors for extraocular relapse and metastasis assessed on centralized histologic examination of enucleated eyes. Group 1 (n = 70) had minimal or no choroidal involvement and/or prelaminar or no optic nerve involvement and received no adjuvant therapy. Group 2 (n = 52) had massive choroidal involvement and/or intra- or retrolaminar optic nerve involvement and/or anterior segment involvement and received four courses of adjuvant chemotherapy. Group 3 (n = 1) had invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement and received six courses of adjuvant chemotherapy with intrathecal thiotepa, consolidation chemotherapy, and autologous stem-cell rescue. Genetic testing was also performed. Median follow-up for the 123 patients was 71 months. No disease progression, relapse, or distant metastasis occurred during follow-up. No second malignancies occurred. This requires confirmation with longer follow-up. Secondary bilateralization occurred in two patients with identified RB1 germline mutation. Adjuvant chemotherapy was well tolerated, with limited toxicity. Molecular testing found constitutional RB1 gene mutations in only nine of 100 evaluated patients. The survival rate of 100% was excellent, including 57% of patients who received no adjuvant therapy, suggesting that chemotherapy could be de-escalated in some patients, especially those with massive choroidal involvement.


Relative and interacting effects of sex, race, and environment upon body cell mass in healthy adults.
Most epidemiologic studies in nutrition have concentrated on body fat and obesity because of associated health risks, while few studies have examined factors that influence body cell mass (BCM). The relative influences of sex, race, environment, and age upon BCM were compared by analyzing the results of bioimpedance analyses in two cohorts of 1094 healthy adults, including Africans in Zaire, plus African Americans and Caucasians in New York City. Men were taller, heavier, and had a larger BCM and fat-free mass (FFM) than women, while women had more fat than men. African American men and women had more BCM, FFM, and fat than Africans. In contrast, BCM and FFM were not different in African Americans and Caucasians, and body fat was higher only in African American than in Caucasian women. Sex influenced the effects of environment and race, since the majority of the weight differences in men were in FFM, while the majority of the weight differences in women were in fat. The effect of sex upon BCM was stronger than the effects of environment (p < 0.001) or race (p < 0.001), and the effect of environment was stronger than the effect of race (p = 0.012), so that the relative strengths were sex > environment > race. Race had a stronger effect upon FFM than upon BCM. Since race did not affect BCM significantly, it may affect other components of FFM, e.g., extracellular water or solids, such as skeletal mass. The results demonstrate that sex affects normal body composition to a greater degree than race or environment. Am. J. Hum. Biol. 10:259-268, 1998. © 1998 Wiley-Liss, Inc.


Improvement of the hematologic toxicities of ruxolitinib in patients with MPN-associated myelofibrosis using a combination of thalidomide, stanozolol and prednisone.
Objective: Anemia and thrombocytopenia are the most frequently reported adverse events of ruxolitinib in patients with MPN-associated myelofibrosis (MPN-MF). Although thalidomide, androgens and prednisone have previously demonstrated improvements in myelofibrosis-associated anemia, it is unclear whether these drugs are effective in patients taking ruxolitinib. Method: We conducted a retrospective cohort study to evaluate the efficacy and tolerability of combination therapy with low dose thalidomide, stanozolol and prednisone (TSP) in patients with IPSS intermediate-2 or high-risk myelofibrosis (MF) who received ruxolitinib treatment. Results: Sixty-five patients with MPN-MF who took ruxolitinib were enrolled in this retrospective study, of which 46 patients also took TSP while 19 did not take TSP (TSP and non-TSP groups). Within the first 24 weeks, the proportion of patients with anemia response and platelet count increase ≥50 × 109/L were 45.7% and 67.4% in the TSP group as compared to 0% and 10.5% in the non-TSP group (p < 0.001). The mean hemoglobin level in the non-TSP group reached the nadir after approximately 12-16 weeks of therapy, but gradually increased in the TSP group. Conclusion: In summary, TSP regimen can improve anemia and thrombocytopenia during ruxolitinib treatment in patients with MPN-MF, and the associated adverse events were manageable.


Pyloric stenosis: a 13-year experience in operative management.
Infantile hypertrophic pyloric stenosis is best treated surgically, after an appropriate period of rehydration and resuscitation. Our experience with this entity has resulted in the performance of fewer contrast studies to establish the diagnosis as well as the use of an operative technique which can be safely applied to the teaching environment.


Learning Hamiltonian Monte Carlo in R.
Hamiltonian Monte Carlo (HMC) is a powerful tool for Bayesian computation. In comparison with the traditional Metropolis-Hastings algorithm, HMC offers greater computational efficiency, especially in higher dimensional or more complex modeling situations. To most statisticians, however, the idea of HMC comes from a less familiar origin, one that is based on the theory of classical mechanics. Its implementation, either through Stan or one of its derivative programs, can appear opaque to beginners. A lack of understanding of the inner working of HMC, in our opinion, has hindered its application to a broader range of statistical problems. In this article, we review the basic concepts of HMC in a language that is more familiar to statisticians, and we describe an HMC implementation in R, one of the most frequently used statistical software environments. We also present hmclearn, an R package for learning HMC. This package contains a general-purpose HMC function for data analysis. We illustrate the use of this package in common statistical models. In doing so, we hope to promote this powerful computational tool for wider use. Example code for common statistical models is presented as supplementary material for online publication.


Profilin as a regulator of the membrane-actin cytoskeleton interface in plant cells.
Membrane structures and cytoskeleton dynamics are intimately inter-connected in the eukaryotic cell. Recently, the molecular mechanisms operating at this interface have been progressively addressed. Many experiments have revealed that the actin cytoskeleton can interact with membranes through various discrete membrane domains. The actin-binding protein, profilin has been proven to inhibit actin polymerization and to promote F-actin elongation. This is dependent on many factors, such as the profilin/G-actin ratio and the ionic environment of the cell. Additionally, profilin has specific domains that interact with phosphoinositides and poly-L-proline rich proteins; theoretically, this gives profilin the opportunity to interact with membranes, and a large number of experiments have confirmed this possibility. In this article, we summarize recent findings in plant cells, and discuss the evidence of the connections among actin cytoskeleton, profilin and biomembranes through direct or indirect relationships.


GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.
Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.


Recapitulating the Size and Cargo of Tumor Exosomes in a Tissue-Engineered Model.
There is a growing interest in the pivotal role of exosomes in cancer and in their use as biomarkers. However, despite the importance of the microenvironment for cancer initiation and progression, monolayer cultures of tumor cells still represent the main in vitro source of exosomes. As a result, their environmental regulation remains largely unknown. Here, we report a three-dimensional tumor model for studying exosomes, using Ewing's sarcoma type 1 as a clinically relevant example. The bioengineered model was designed based on the hypothesis that the 3-dimensionality, composition and stiffness of the tumor matrix are the critical determinants of the size and cargo of exosomes released by the cancer cells. We analyzed the effects of the tumor microenvironment on exosomes, and the effects of exosomes on the non-cancer cells from the bone niche. Exosomes from the tissue-engineered tumor had similar size distribution as those in the patients' plasma, and were markedly smaller than those in monolayer cultures. Bioengineered tumors and the patients' plasma contained high levels of the Polycomb histone methyltransferase EZH2 mRNA relatively to their monolayer counterparts. Notably, EZH2 mRNA, a potential tumor biomarker detectable in blood plasma, could be transferred to the surrounding mesenchymal stem cells. This study provides the first evidence that an in vitro culture environment can recapitulate some properties of tumor exosomes.


Investigation of poly[oligo(ethylene glycol)diacrylates] as potential stationary phases in GC.
Poly[oligo(ethylene glycol)diacrylate]s were investigated as potential candidates for application as stationary phases in capillary gas chromatography. Depending on the molar mass of the monomer, up to three different phase transitions were observed in calorimetric scans of the polymers. Two transitions have been identified as the glass transition and melting of crystallites while the nature of the third effect remains unknown. The new stationary phases demonstrate a good separating ability and selectivity in the viscous-elastic state, i.e. at temperatures above the glass transition and melting points. The new polymeric stationary phases possess selectivity similar to conventional PEG columns but provide better thermal stability than conventional PEG stationary phases.


Semitendinosus regrowth: biochemical, ultrastructural, and physiological characterization of the regenerate tendon.
Previous studies have suggested that hamstring tendons can regenerate following harvesting for anterior cruciate ligament reconstruction. This "neo-tendon" is a true, functional tendon, not scar tissue. Controlled laboratory study. Semitendinosus tendons were harvested from 35 New Zealand white rabbits using a standard tendon stripper. The rabbits were sacrificed 9 to 12 months following the index procedure and thoroughly evaluated. Thirty-one rabbits were available at the time of sacrifice. The neo-tendon was present in 26 rabbits but was highly variable in size and location of its tibial insertion. Histologic and immunohistochemical staining confirmed that the regenerate tissue was indeed tendon with normal cellularity, organization, and immunolocalization of type I collagen. Electron microscopy showed regeneration of organized collagen tissue that simulated native tendon but with a smaller cross-sectional diameter. Functionally, the neo-tendon was able to transmit force across the musculotendinous junction but at a significantly slower rate than the opposite, control leg. Biomechanical properties of the neo-tendon were significantly less than the control side. Biochemical analysis revealed that the neo-tendons contained glycosaminoglycans and collagen, but levels were significantly lower than normal tendons. Semitendinosus tendons regenerate with biologically reactive tendinous tissues in an animal model. This tissue has many of the characteristics of a normal tendon but appears to be inferior to the original musculotendinous unit at 9- to 12-month evaluation. Further characterization of the "lizard tail phenomenon" is still needed. Hamstring tendon regrowth may have a dramatic impact on postoperative function of patients who undergo anterior cruciate ligament reconstruction with these tendons. Further modulation of this regeneration may further reduce graft harvesting morbidity.


Assessment of clinical usefulness of parametric clearance images in diagnosis of kidney cicatrisation in children with chronic infections of the urinary tract.
Cicatrisation of the renal cortex is closely related to chronic infections of the urinary system. Static renal scintigraphy is used as the method enabling detection of local defects of radiopharmaceutical uptake, and is treated as the "gold standard" in the diagnosis of renal scars. The aim of the reported investigation was a comparison of the diagnostic efficacy of parametric clearance images and the conventional summation images - obtained from dynamic scintigraphy - in the detection of local defects of renal function. As the "gold standard" for the above comparison, the static scintigraphy of kidneys was accepted. Forty-one patients (age 4-19 years), 28 girls and 13 boys, participated in the study. Altogether, 73 kidneys were analyzed (in 9 patients, only one kidney). In each patient dynamic renal scintigraphy was performed after IV administration of 99mTc EC (ethylenedicysteine) and static planar renal scintigraphy using 99mTc-DMSA (dimercaptosuccinic acid) as a reference method. From the dynamic study, summation and parametric clearance images were generated. Each kidney was divided into 3 segments (upper, middle, lower); altogether 219 segments were evaluated by modified Howard's scale. Planar and oblique projection images were compared with corresponding summation and parametric clearance images. Parametric clearance imaging has a higher sensitivity and accuracy for detection of regional post-inflammatory changes in the kidneys than conventional summation images (p < 0.05) and shows parenchymal changes similarly to static scintigraphy (high Cohen's kappa index).


Prevalence of consumption of addictive substances amongst Moroccan fishermen.
The prevalence of toxic habits is constantly increasing in developing countries and all professional sectors are concerned. Seafarers are a particular target because of the dangerousness and complexity of their work. However, few studies have investigated toxic habits in this population. The aim of the study was to determine the prevalence of the use and misuse of addictive substances in seafarers and to appreciate poly-consumptions according to socio-demographic and occupational characteristics. This cross-sectional study was conducted amongst 1,219 fishermen. Subjects filled a questionnaire during their medical examination. The questionnaire covered socio-demographic and occupational characteristics, toxic habits (tobacco, alcohol, cannabis and others psychotropic substances). The misuse was assessed by specific tests: dependence on smoking tobacco (Fagerstrom), Cannabis Abuse Screening Test (CAST) and Alcohol Use Disorders Identification Test (AUDIT). The prevalence of consumption was 58.5% for smoking tobacco, 36.2% for cannabis, and 36.5% for alcohol. Amongst consumers, the prevalence of dependence or misuse was 49% for smoking tobacco, 61.2% for cannabis and 86% for alcohol. Only 115 (9.4%) people had no toxic habit. 56.4% had one toxic habit, 20.4% had two toxic habits, 11.9% had three toxic habits and 1.9% had four toxic habits. The most frequent associations were tobacco-cannabis (10.5%) and tobacco-alcohol (6.1%). In this sector, occupational health physicians have to play a key role in raising awareness and fighting against toxic habits.


Bone marrow transplantation for adults and children with poor risk acute lymphoblastic leukaemia in first complete remission.
Thirty-two patients with poor risk acute lymphoblastic leukaemia in first complete remission received bone marrow transplants (BMT) from fully matched family donors. Their ages ranged from 7 to 41 (median 23) years. Nine patients were aged 16 years or less. Patients were selected for BMT because they had risk factors for relapse with standard treatment approaches. In particular the children who were selected for BMT had presenting blast counts of greater than or equal to 90 x 10(9)/l or null immunophenotypes. The overall disease-free survival was 50% with a relapse risk of 31% at 9 years. Patients aged less than 16 years had a much lower risk of both graft-related disease and relapse than did older patients (disease-free survival 89% for those aged 7-16, 48% for those aged 17-26, 24% for those aged 26-41). We conclude that selection of BMT for young patients with poor risk features is entirely justified but that the prognosis for older patients is poor even after BMT.


Field testing of genetically engineered microorganisms.
The first approved field releases of microorganisms genetically altered in the laboratory have been initiated in the past several years. While most introductions have been carried out in the United States, several tests have also occurred in the United Kingdom and Australia. Although such releases remain controversial in some areas, these pioneering studies have provided significant insight into the environmental behavior and relative safety of applying these microbes in a well-planned and carefully monitored program.


Long Range Corrections for Inhomogeneous Simulations of Mie n-m Potential.
The long-range correction scheme for dispersion interactions in inhomogeneous simulations is generalized to Mie n-m potential. The influence of the cutoff distance and lateral dimensions of the simulation box are studied for 8-6, 12-6, and 20-6 Mie fluids at two different temperatures (close and far from the critical point). For sufficiently large systems (2400 particles, Rc = 3.5σ) equilibrium properties are simulated over the whole vapor-liquid coexistence using the inhomogeneous Monte Carlo simulations, and the results are compared with the Gibbs Ensemble technique and with the square gradient theory combined with the SAFT Mie equation of state.


Poly D,L-Lactide-Co-Glycolic Acid Grafting Material in Sinus Lift.
The poly D,L-lactide-co-glycolic acid (PLGA) is a copolymer used in many therapeutic devices for its high rates of biodegradability and biocompatibility. The principal aim of the research was to evaluate the new bone formation, after 16 (T1) and 28 weeks (T2), in sheep maxillary sinus lift in vivo model using PLGA.Computerized tomography analysis, X-ray microanalysis, and scanning electron microscope analysis of secondary electrons (SE) and the backscattered electrons (BSE) of the samples were detected.After 28 weeks, the computed tomography analysis showed a 22% increase of UH density in the grafting areas. The X-ray microanalysis of the samples showed calcium and phosphorus increase at T1 and T2 follow-up period and the carbon and oxygen concentration decrease. The SE evaluation showed a rapid superficial resorption of the biomaterials at T1 and a completely bone reorganization of biomaterial at T2. The BSE analysis confirmed the SE data and showed the direct and intimate contact between bone and PLGA with a higher calcification in T2 compared to T1.Certainly, still other experiments and a larger number of samples will be necessary to be analyzed to determine the behavior of the PLGA in the bone regeneration; however, the PLGA used in maxillary sinus lift animal model, seem to promote new bone formation that continues increase at 28 weeks after grafting.


Towards weighing individual atoms by high-angle scattering of electrons.
We consider theoretically the energy loss of electrons scattered to high angles when assuming that the primary beam can be limited to a single atom. We discuss the possibility of identifying the isotopes of light elements and of extracting information about phonons in this signal. The energy loss is related to the mass of the much heavier nucleus, and is spread out due to atomic vibrations. Importantly, while the width of the broadening is much larger than the energy separation of isotopes, only the shift in the peak positions must be detected if the beam is limited to a single atom. We conclude that the experimental case will be challenging but is not excluded by the physical principles as far as considered here. Moreover, the initial experiments demonstrate that the separation of gold and carbon based on a signal that is related to their mass, rather than their atomic number.


Influence of genetics and the pre-vaccination blood transcriptome on the variability of antibody levels after vaccination against Mycoplasma hyopneumoniae in pigs.
The impact of individual genetic and genomic variations on immune responses is an emerging lever investigated in vaccination strategies. In our study, we used genetic and pre-vaccination blood transcriptomic data to study vaccine effectiveness in pigs. A cohort of 182 Large White pigs was vaccinated against Mycoplasma hyopneumoniae (M. hyo) at weaning (28 days of age), with a booster 21 days later. Vaccine response was assessed by measuring seric M. hyo antibodies (Ab) at 0 (vaccination day), 21 (booster day), 28, 35, and 118 days post-vaccination (dpv). Inter-individual variability of M. hyo Ab levels was observed at all time points and the corresponding heritabilities ranged from 0.46 to 0.57. Ab persistence was higher in females than in males. Genome-wide association studies with a 658 K SNP panel revealed two genomic regions associated with variations of M. hyo Ab levels at 21 dpv at positions where immunity-related genes have been mapped, DAB2IP on chromosome 1, and ASAP1, CYRIB and GSDMC on chromosome 4. We studied covariations of Ab responses with the pre-vaccination blood transcriptome obtained by RNA-Seq for a subset of 82 pigs. Weighted gene correlation network and differential expression analyses between pigs that differed in Ab responses highlighted biological functions that were enriched in heme biosynthesis and platelet activation for low response at 21 dpv, innate antiviral immunity and dendritic cells for high response at 28 and 35 dpv, and cell adhesion and extracellular matrix for high response at 118 dpv. Sparse partial least squares discriminant analysis identified 101 genes that efficiently predicted divergent responders at all time points. We found weak negative correlations of M. hyo Ab levels with body weight traits, which revealed a trade-off that needs to be further explored. We confirmed the influence of the host genetics on vaccine effectiveness to M. hyo and provided evidence that the pre-vaccination blood transcriptome co-varies with the Ab response. Our results highlight that both genetic markers and blood biomarkers could be used as potential predictors of vaccine response levels and more studies are required to assess whether they can be exploited in breeding programs.


GnRH antagonist for patients with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer in fresh cycles.
The aim of the present study was to evaluate the influence of a gonadotropin-releasing hormone (GnRH) antagonist compared with a GnRH agonist on the in vitro fertilization cycle outcome in patients with polycystic ovary syndrome. The outcomes of pregnancy were evaluated. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was also used to evaluate whether the endometrial thickness (cm) and estradiol (E2) level (pg/ml) on the day of human chorionic gonadotropin (hCG) administration (the hCG day) had the best sensitivity and specificity for predicting a clinical pregnancy. The results demonstrated that there were significant differences in the E2 and progesterone levels between the two treatment groups on the hCG day. Furthermore, the mean number of total oocytes retrieved, mean number of 2 pronuclei oocytes, mean number of oocytes cleaved (P<0.05), mean number of embryos available (P=0.022) and mean number of embryos transferred (P=0.014) were significantly different. Additionally, the rates of ectopic pregnancy (P=0.984) and ovarian hyperstimulation syndrome (P=0.976) did not differ significantly between the treatment groups. Although the biochemical pregnancy (P=0.592), clinical pregnancy (P=0.617) and live birth (P=0.365) rates were lower with the GnRH antagonist than with the GnRH agonist, there were no significant differences in the outcomes between the two groups. Analysis of the influence of endometrial thickness with respect to the clinical pregnancy using the ROC (AUC) method revealed that when the best cutoff of 9.75 cm was used, the sensitivity was 62.5%, the specificity was 43.1% and the AUC was 0.53. Additionally, the Youden index was 0.056. Analysis of the influence of the E2 level on the hCG day on clinical pregnancy, using the ROC (AUC) method showed that the best cutoff was 2,984.5 pg/ml, which had a sensitivity of 68.8% and specificity of 52.9%, while the AUC was 0.573 (with a Youden index of 0.217). Furthermore, the results demonstrated that neither the endometrial thickness nor the E2 level on the hCG day had the best sensitivity and specificity for predicting a clinical pregnancy.


Desensitization of postsynaptic glutamate receptors contributes to high-frequency homosynaptic depression of aplysia sensorimotor connections.
Withdrawal reflexes of Aplysia are mediated in part by a monosynaptic circuit of sensory (SN) and motor (MN) neurons. A brief high-frequency burst of spikes in the SN produces excitatory postsynaptic potentials (EPSPs) that rapidly decrease in amplitude during the burst of activity. It is generally believed that this and other (i.e., low-frequency) forms of homosynaptic depression are entirely caused by presynaptic mechanisms (e.g., depletion of releasable transmitter). The present study examines the contribution that desensitization of postsynaptic glutamate receptors makes to homosynaptic depression. Bath application of cyclothiazide, an agent that reduces desensitization of non-NMDA glutamate receptors, reduced high-, but not low-frequency synaptic depression. Thus, a postsynaptic mechanism, desensitization of glutamate receptors, can also contribute to homosynaptic depression of sensorimotor synapses.


The use of rapid-rate transcranial magnetic stimulation (rTMS) in refractory depressed patients.
Rapid-rate transcranial magnetic stimulation (rTMS) allows for the noninvasive examination of the cerebral cortex. Recent studies have begun to investigate whether rTMS may be therapeutic for the treatment of depression. In the present study, the authors report on the safety and efficacy of rTMS in treating 50 patients with refractory depression. Overall, there were 21 responders (42%). Interestingly, 56% of the young patients responded, but only 23% of the elderly patients responded to rTMS. Overall, rTMS was well tolerated in all patients. Specifically, no patient developed a new onset of seizures during rTMS. The authors discuss the extant literature on rTMS for the treatment of depression along with future areas of research.


Economic Burden of Illness in Adult Patients with Nocturia.
Nocturia is considered to be a very bothersome lower urinary tract disorder. Yet, to date, the economic burden attributable to this poor health condition remains less well known. To compare differences in health care resource utilization (HCRU), health care costs, and work productivity in adult patients with differing frequencies of nocturia episodes (i.e., < 2 vs. ≥ 2 nocturia episodes per night). Adult patients with nocturia enrolled in an integrated proprietary database were recruited to complete a survey on their demographics, nocturia characteristics, and work productivity. Using patients' survey data and health care claims from the previous 6 months, those with < 2 (n = 197; 21.9%) versus ≥ 2 (n = 702; 78.1%) nocturia episodes per night were compared for differences in HCRU, health care costs, and work productivity after adjusting for potential confounders. HCRU was reported as the mean number per patient per month (PPPM) for outpatient visits (all types), physician office visits, and prescriptions filled and the proportion of patients with ≥1 hospitalization or emergency department visit in the previous 6 months. Health care costs were reported as mean PPPM. Work productivity was assessed via patient survey and reported as a mean percentage for absenteeism, presenteeism, overall work impairment, and activity impairment during the past week. 899 adult patients (mean age = 71.4 years; 57.2% men) were enrolled and analyzed. Compared with patients with <2 nocturia episodes per night, patients with ≥ 2 nocturia episodes had more outpatient health care visits (unadjusted mean visits PPPM: 2.1 vs. 1.6; P < 0.001; adjusted mean visits PPPM: 2.1 vs. 1.6; P = 0.017), office visits (unadjusted and adjusted mean visits PPPM: 0.9 vs. 0.7; P < 0.001), and prescriptions filled (unadjusted mean prescription fills PPPM: 3.1 vs. 2.1; P < 0.001; adjusted mean prescription fills PPPM: 3.2 vs. 2.2; P = 0.027). Patients with ≥ 2 nocturia episodes per night also displayed significantly higher outpatient health care costs (unadjusted mean PPPM costs: $676 vs. $516; P = 0.028; adjusted mean PPPM costs: $678 vs. $506; P = 0.017). In terms of work productivity impairment, patients with ≥ 2 nocturia episodes per night experienced higher rates of unadjusted (20% vs. 10%; P = 0.002) and adjusted presenteeism (20% vs. 10%; P = 0.004) and unadjusted (20% vs. 10%; P = 0.002) and adjusted overall work impairment (20% vs. 10%; P = 0.001). Study findings demonstrate that nocturia was associated with higher outpatient encounters and related costs in the presence of a greater occurrence of nocturic episodes. This study was funded by Allergan plc, Dublin, Ireland. Neither honoraria nor payments were provided for authorship. Dmochowski is a consultant and speaker for Allergan plc and a consultant for Serenity Pharmaceuticals. Brucker is a consultant and speaker for Allergan plc, a consultant for Watkins-Conti and Avadel, and an investigator for Medtronic and Ipsen. Cole is a consultant for Allergan plc and an employee of Sharp Rees-Stealy Medical Group. Kawahara and Pulicharam are full-time employees of DaVita Medical Group. Burk is a consultant for Allergan plc and a health outcomes consultant. Tung is an employee of Allergan plc. Hale has served as a consultant/advisor to and has received research funding from Allergan plc. The data from this manuscript were previously presented in poster format by Steve Kawahara at the Academy of Managed Care & Specialty Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, CA.


Analysis of heavy metals from water, sediment, and tissues of Labeo angra (Hamilton, 1822), from an Ox-box lake- an wetland site from Assam, India.
The aim of this study was to assess the regional impacts of heavy metals (Mn, Fe, Mg, Ca, Cu, Zn, Cd, Cr, Pb and Ni) on water, sediment and a native, teleost fish species, Labeo angra, inhabiting a flood plain wetland of Barak River in Assam, India. Heavy metal concentrations in the water, sediments and fish were measured; bioaccumulation factor, metal pollution index as well as condition indices were calculated, to assess the pollution load and health status of the fish. Multivariate statistical analysis was used on wetland water and sediment heavy metals to ascertain the possible sources and seasonal variations of the pollutants. Results showed that most heavy metals in the wetland water and sediments exceeded the water (drinking and irrigation) and sediment quality guidelines, respectively. Seasonal variations were observed for geogenic heavy metals, Mn, Fe, Mg and Ca while no seasonal variations were observed for anthropogenic heavy metals, Cu, Cd, Cr, Pb and Ni. Multivariate statistical analysis showed that there was strong correlation between geogenic and anthropogenic heavy metals in water and sediment, both originating from the common anthropogenic sources. Accumulation of most of the metals in all the tissues was above the safe limits as recommended by the Food and Agriculture Organization. High bioaccumulation factors and metal pollution index for these metals in the different tissues revealed that metals were extensively bio-accumulated and bioconcentrated. Condition indices in fish from the wetland suggested metabolic abnormalities.


A hundred years in the elucidation of the structures of natural products.
The development in the strategies for elucidating the structures of natural products from 1916 to 2016 are reviewed revealing the transition from chemical to spectroscopic methods and using examples drawn from the chemistry of terpenoids and steroids.


Modified effective dielectric function for metallic granular composites with high percolation threshold.
We propose the effective dielectric function theory of metal granular composites modified with the metal particle size. The modified theory is used to explain the electrical conductivity, resonant plasmon absorption, and large nonlinear absorption of Au-TiO2 granular composite films with high-density metallic particles and a high electric percolation threshold. It is revealed that the decreasing metal particle size leads to an increasing percolation threshold and large enhancement of optical nonlinearity of the composites.


Arabidopsis thaliana ALG3 mutant synthesizes immature oligosaccharides in the ER and accumulates unique N-glycans.
The core oligosaccharide Glc(3)Man(9)GlcNAc(2) is assembled by a series of membrane-bound glycosyltransferases as the lipid carrier dolichylpyrophosphate-linked glycan in the endoplasmic reticulum (ER). The first step of this assembly pathway on the ER luminal side is mediated by ALG3 (asparagine-linked glycosylation 3), which is a highly conserved reaction among eukaryotic cells. Complementary genetics compared with Saccharomyces cerevisiae ALG gene families and bioinformatic approaches have enabled the identification of ALG3 from other species. In Arabidopsis thaliana, AtALG3 (At2g47760) was identified as alpha1,3-mannosyltransferase. Complementation analysis showed that AtALG3 rescued the temperature-sensitive phenotype, that lipid-linked oligosaccharide assemblies and that protein underglycosylation of S. cerevisiae ALG3-deficient mutant. In Arabidopsis ALG3 mutant, an immature lipid-linked oligosaccharide structure, M5(ER), was synthesized, and used for protein N-glycosylation, resulting in the blockade of subsequent maturation with the concanavalin A affinoactive and Endo H-insensitive structure. N-Glycan profiling of total proteins from alg3 mutants exhibited a unique structural profile, alg3 has rare N-glycan structures including Man(3)GlcNAc(2), M4(ER), M5(ER) and GlcM5(ER), which are not usually detected in Arabidopsis, and a much less amount of complex-type N-glycan than that in wild type. Interestingly, despite protein N-glycosylation differences compared with wild type, alg3 showed no obvious phenotype under normal and high temperature or salt/osmotic stress conditions. These results indicate that AtALG3 is a critical factor for mature N-glycosylation of proteins, but not essential for cell viability and growth in Arabidopsis.


Risk factors of postoperative atrial fibrillation after cardiac surgery.
Postoperative atrial fibrillation (AF) occurs in up to 50% of cardiac surgery patients and represents the most common postoperative arrhythmic complication. The etiology of AF after open-heart surgery is incompletely understood and its prevention remains suboptimal. Identification of patients vulnerable for postoperative AF would allow targeting of those most likely to benefit from aggressive prophylactic intervention. The aim of the present study was to evaluate clinical predictors of postoperative AF. Patients undergoing elective cardiac surgery in the absence of significant left ventricular dysfunction (n = 253; average age 65 +/- 11 years) were recruited to the present prospective study. Ninety-nine patients (39.1%) of the total study population developed AF during the postoperative period. The median age for patients with postoperative AF was 69 years compared with 64 years for patients without (p < 0.001). In addition to advanced age, AF patients were more likely to have surgery for valvular heart disease and less likely to have preoperative beta-adrenergic blockers than patients without AF. Multivariate logistic regression analysis (odds ratio, +/-95% CI, p value) was used to identify the following independent clinical predictors of postoperative AF: increasing age (above vs. below median [OR = 2.6; CI, 1.2 to 3.9; p < 0.01]), and surgery for valvular heart disease (vs. coronary artery bypass grafting [OR 2.8; CI, 1.1 to 3.5; p < 0.01)]). Additionally, postoperative complications (stroke, infections, unstable hemodynamics [OR = 1.9; CI, 1.0 to 7.5; p < 0.05]), and preoperative nonuse of beta-adrenergic blockers (OR = 1.7; CI, 1.1 to 4.9; p < 0.05) were associated with increased risk for postoperative AF. Both, patients with and without AF had similar body mass index, preoperative heart rate, preoperative blood pressure, and duration of surgery. Male sex did not identify patients at high risk for development of AF after cardiac surgery. Postoperative AF remains the most common complication after cardiac surgery. A combination of advanced age and type of surgery identifies patients at high risk for development of AF after cardiac surgery.


[The first finding of Giardia spp. in roebucks (Capreolus capreolus L.)].
Roe deer (Capreolus capreolus L.) is a representative of the new host of an intestinal flagellate of the genus Giardia. Giardia spp. was found during autopsy in three dead head of roe deer (roe deer calf 7-8 months, doe, buck) sent for examination to the State Veterinary Institute, Praha, from three different localities of the Czech Republik. Localization of the Giardia spp. was studied in the intestinal tract of the roe deer calf in native preparations in the intestinal contents and in the smears of intestinal mucosa stained after Giemsa (at a distance of 30-40 cm along the whole length of the small intestine). Giardia trophozoites were found in the small intestine in the section of 280-770 cm from the caudal part of duodenum. The trophozoites occurred most intensively within the section of 350-420 cm. The trophozoites showed active, motility in this part of the small intestine as late as in more than 48 hours after the death of the row calf. Their size (obtained by measuring 30 trophozoites) was from 12.4-16.2 to 8-11.5 microns with the mean of 14.5 to 9.4 microns. In the contents of the caeca and colons of all three animals after death numerous Giardia cysts were found, in the caecum of the roe calf trophozoites were detected rarely. Most of the cysts were of ovoid shape. Their size, by measuring 50 cysts from each of the animals, was from 11.2-14.4 to 8-10.4 microns with the mean of 13.3 x 9.1 microns. Sporadically, nearly spherical cysts occurred (12.8-13.6 to 9.6-10.4 microns).(ABSTRACT TRUNCATED AT 250 WORDS)


High-capacity wavelength demultiplexer with a large-diameter GRIN rod lens.
A high capacity (twelve-channel) fiber optic wavelength demultiplexer incorporating a large diameter GRIN rod lens and grating was developed and fully characterized. The demultiplexer operates over the 740-930-nm wavelength range with an average channel spacing of 17 nm. The insertion loss, measured and averaged over all twelve channels, was approximately 3 dB, and the average adjacent channel optical cross talk was 32 dB.


Reduced error signalling in medication-naive children with ADHD: associations with behavioural variability and post-error adaptations.
We examined the blood-oxygen level-dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention-deficit/hyperactivity disorder (ADHD). We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8-12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations. We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to task-driven connectivity between the cingulo-opercular system and the VAN. Our study was limited by the modest sample size and imperfect matching across groups. Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD.


Isolation of the GFA1 gene encoding glucosamine-6-phosphate synthase of Sporothrix schenckii and its expression in Saccharomyces cerevisiae.
Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is an essential enzyme involved in cell wall biogenesis that has been proposed as a strategic target for antifungal chemotherapy. Here we describe the cloning and functional characterization of Sporothrix schenckii GFA1 gene which was isolated from a genomic library of the fungus. The gene encodes a predicted protein of 708 amino acids that is homologous to GlcN-6-P synthases from other sources. The recombinant enzyme restored glucosamine prototrophy of the Saccharomyces cerevisiae gfa1 null mutant. Purification and biochemical analysis of the recombinant enzyme revealed some differences from the wild type enzyme, such as improved stability and less sensitivity to UDP-GlcNAc. The sensitivity of the recombinant enzyme to the selective inhibitor FMDP [N(3)-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid] and other properties were similar to those previously reported for the wild type enzyme.


Helical plating - a novel technique to increase stiffness in defect fractures.
Single-plate fixation bridging bone defects provokes nonunion and risks plate-fatigue failure due to under- dimensioned implants. Adding a helical plate to bridge the fracture increases stiffness and balances load sharing. This study compares the stiffness and plate surface strain of different constructs in a transverse contact and gap femoral shaft fracture model. Eight groups of six synthetic femora each were formed: intact femora; intact femora with lateral locking plate; contact and gap transverse shaft osteotomies each with lateral locking plate, lateral locking plate and helical locking plate, and long proximal femoral nail. Constructs underwent non-destructive quasi-static axial and torsional loading. Plate surface strain evaluation was performed under 200 N axial loading. Constructs with both lateral and helical plates demonstrated similar axial and torsional stiffness- independent of the contact or gap situations - being significantly higher compared to lateral plating (p < 0.01). Torsional stiffness of the constructs, with both lateral and helical plates in the gap situation, was significantly higher compared to this situation stabilised by a nail (p < 0.01). Plate surface strain dropped from 0.3 % in the gap situation with a lateral plate to < 0.1 % in this situation with both a lateral and a helical plate. Additional helical plating increases axial and torsional construct stiffness in synthetic bone and seems to provide well-balanced load sharing. Its use should be considered in very demanding situations for gap or defect fractures, where single-plate osteosynthesis provides inadequate stiffness for fracture healing and induces nonunion.


Paradoxical nasal obstruction: analysis of characteristics using acoustic rhinometry.
The aim of this study was to determine the characteristics of acoustic rhinometric parameters in patients with paradoxical nasal obstruction. The medical records of 1844 patients who had nasal septal deviation between 1998 and 2004 at our institute were assessed retrospectively. The authors selected 31 subjects for the experimental group and 256 subjects for the control group. Minimal cross-sectional area (MCA), volume, and degree of mucosal change at baseline and decongested phase were analyzed. MCA of the convex side in the baseline state for the experimental (paradoxical) group is wider than that for the control group (p = 0.005). Degree of mucosal change of the experimental group is smaller than that of the control group in the convex side (p = 0.001). Other parameters are similar for the two groups. Patients with paradoxical nasal obstruction might be explained by less degree of mucosal change in the concave side of the nasal cavity during nasal cycle than the control group.


Organocatalyzed Atom Transfer Radical Polymerization: Perspectives on Catalyst Design and Performance.
The recent development of organocatalyzed atom transfer radical polymerization (O-ATRP) represents a significant advancement in the field of controlled radical polymerizations. A number of classes of photoredox catalysts have been employed thus far in O-ATRP. Analysis of the proposed mechanism gives insight into the relevant photophysical and chemical properties that determine catalyst performance. Discussion of each of the classes of O-ATRP catalysts highlights their previous uses, their roles in the development of O-ATRP, and the distinctive properties that govern their polymerization behavior, leading to a set of design principles for O-ATRP catalysts. Remaining challenges for O-ATRP are presented, as well as prospects for further improvement in the application scope of O-ATRP.


Effective use of chemodenervation and chemical neurolysis in the management of poststroke spasticity.
Chemodenervation with botulinum toxin (BTX) and chemical neurolysis with phenol can be used alone or in combination to effectively manage focal spasticity after a stroke. As with other treatments, these interventions must be done the right way, at the right time, in the right patient, and for the right reason. The proper use of these treatments requires careful patient assessment and realistic goals, knowledge of the peripheral functional anatomy, and an understanding of how these treatments work and how to best to administer them. This article reviews how BTX and phenol can be used in the management of poststroke spasticity.


Detection of linkage for heterogeneous disorders by using multipoint linkage analysis.
We have compared the efficiency of the lod score test which assumes heterogeneity (lod2) to the standard lod score test which assumes homogeneity (lod1) when three-point linkage analysis is used in successive map intervals. If it is assumed that a gene located midway between two linked marker loci is responsible for a proportion of disease cases, then the lod1 test loses power relative to the lod2 test, as the proportion of linked families decreases, as the flanking markers are more closely linked, and as more map intervals are tested. Moreover, when multipoint analysis is used, linkage for a disease gene is more likely to be incorrectly excluded from a complete and dense linkage map if true genetic heterogeneity is ignored. We thus conclude that, in general, the lod2 linkage test is more efficient for detecting a true linkage when a complete genetic marker map is screened for a heterogeneous disorder.


Coarctation of the Aorta: Diagnosis and Management.
Coarctation of the aorta (CoA) accounts for approximately 5-8% of all congenital heart defects. Depending on the severity of the CoA and the presence of associated cardiac lesions, the clinical presentation and age vary. Developments in diagnosis and management have improved outcomes in this patient population. Even after timely repair, it is important to regularly screen for hypertension. Patients with CoA require lifelong follow-up with a congenital heart disease specialist as these patients may develop recoarctation and complications at the repair site and remain at enhanced cardiovascular risk throughout their lifetime.


Lymphadenopathy, elevated serum IgE levels, autoimmunity, and mast cell accumulation in flaky skin mutant mice.
The autosomal recessive mutation "flaky skin" (fsn) causes pleiotropic abnormalities in the immune and hematopoietic systems accompanied by pathologic changes in the skin. Homozygotes (fsn/fsn) showed increased size and histological alterations in the spleen and lymph nodes. Abnormalities in lymphoid architecture of the spleen in fsn/fsn mice were accompanied by marked increases in total numbers of B cells, macrophages, and immature erythroid cells. Splenic B cells displayed elevated MHC class II expression. Serum IgE levels were greater than 100 microg/ml by 10 weeks of age, representing > 7000-fold increase compared with normal littermates. This increased IgE level was associated with elevated IL-4 production by spleen cells and with increased amounts of serum IL-4. Serum IgM, IgG1, and IgG2b levels were also increased in fsn/fsn mice while IgG3 was decreased. Autoimmunity in fsn/fsn mice was evidenced by glomerulonephritis accompanied by immune complex deposition in the kidneys, increased serum blood urea nitrogen levels, and the presence of circulating anti-double-stranded DNA autoantibodies. Pathological changes in the skin of fsn/fsn mice were characterized by epidermal hyperplasia and mixed dermal inflammation. Increased numbers of mast cells were also observed in the dermis of the truncal skin as well as in the epithelial stomach. These marked immunological abnormalities suggest that the fsn locus encodes a major immunoregulatory molecule important in multiple immune and hematopoietic functions.


Endoscopic removal of pedunculated leiomyoma of the sigmoid colon (case report and literature review of dignostic and treatment options).
Colonic leiomyoma are remarkably rare cause of colonic symptoms in clinical practice. They constitute only 3% of gastrointestinal leiomyomas and complete endoscopic removal of the tumour can be a problem because of its submucosal origin. We describe a 62-year female patient with a 8 mm leiomyoma of sigmoid colon that was successfully removed by conventional endoscopic snare electrocauterisation, without complications.


Exome Capture with Heterologous Enrichment in Pig (Sus scrofa).
The discovery of new protein-coding DNA variants related to carcass traits is very important for the Italian pig industry, which requires heavy pigs with higher thickness of subcutaneous fat for Protected Designation of Origin (PDO) productions. Exome capture techniques offer the opportunity to focus on the regions of DNA potentially related to the gene and protein expression. In this research a human commercial target enrichment kit was used to evaluate its performances for pig exome capture and for the identification of DNA variants suitable for comparative analysis. Two pools of 30 pigs each, crosses of Italian Duroc X Large White (DU) and Commercial hybrid X Large White (HY), were used and NGS libraries were prepared with the SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing Library (Agilent). A total of 140.2 M and 162.5 M of raw reads were generated for DU and HY, respectively. Average coverage of all the exonic regions for Sus scrofa (ENSEMBL Sus_scrofa.Sscrofa10.2.73.gtf) was 89.33X for DU and 97.56X for HY; and 35% of aligned bases uniquely mapped to off-target regions. Comparison of sequencing data with the Sscrofa10.2 reference genome, after applying hard filtering criteria, revealed a total of 232,530 single nucleotide variants (SNVs) of which 20.6% mapped in exonic regions and 49.5% within intronic regions. The comparison of allele frequencies of 213 randomly selected SNVs from exome sequencing and the same SNVs analyzed with a Sequenom MassARRAY® system confirms that this "human-on-pig" approach offers new potentiality for the identification of DNA variants in protein-coding genes.


Developing Correctional Policy, Practice, and Clinical Care Considerations for Incarcerated Transgender Patients Through Collaborative Stakeholder Engagement.
Transgender persons are at increased risk of victimization during incarceration and have unique health care needs. We convened a symposium of 27 key stakeholders to develop consensus on correctional policy, practice, and clinical care considerations for incarcerated transgender persons. Participants included formerly justice-involved transgender persons, correctional leaders, government authorities, academicians, advocates, health care providers, and expert consultants. Consensus considerations were developed in four areas: correctional practices that promote safety and respectful interactions with transgender inmates, training of correctional staff, health care delivery, and reentry to the community. Gaps in knowledge and practice in these four areas were also identified. A collaborative stakeholder model is an effective strategy to convene disparate groups who infrequently communicate with one another to help advance correctional policies and clinical care.


Histopathologic considerations in the management of skin cancer.
A knowledge of the pathology and biologic behavior of skin cancers is essential for accurate diagnosis and effective treatment. The dual nature and newer concepts of squamous-cell carcinoma and basal-cell epithelioma are reviewed. Some difficulties encountered in differentiating the two are discussed, including the "basosquamous" problem, squamous metaplasia, and pseudoepitheliomatous hyperplasia. Sclerosis within basal-cell epitheliomas is discussed, specifically relating to its importance in treatment. Follicular involvement in epidermal malignant and pre-malignant lesions is presented as a possible cause of recurrence.


Ultrathin self-assembled fibrin sheets.
Fibrin polymerizes into the fibrous network that is the major structural component of blood clots and thrombi. We demonstrate that fibrin from three different species can also spontaneously polymerize into extensive, molecularly thin, 2D sheets. Sheet assembly occurs in physiologic buffers on both hydrophobic and hydrophilic surfaces, but is routinely observed only when polymerized using very low concentrations of fibrinogen and thrombin. Sheets may have been missed in previous studies because they may be very short-lived at higher concentrations of fibrinogen and thrombin, and their thinness makes them very difficult to detect. We were able to distinguish fluorescently labeled fibrin sheets by polymerizing fibrin onto micro-patterned structured surfaces that suspended polymers 10 microm above and parallel to the cover-glass surface. We used a combined fluorescence/atomic force microscope system to determine that sheets were approximately 5 nm thick, flat, elastic and mechanically continuous. Video microscopy of assembling sheets showed that they could polymerize across 25-microm channels at hundreds of microm(2)/sec (approximately 10(13) subunits/s x M), an apparent rate constant many times greater than those of other protein polymers. Structural transitions from sheets to fibers were observed by fluorescence, transmission, and scanning electron microscopy. Sheets appeared to fold and roll up into larger fibers, and also to develop oval holes to form fiber networks that were "pre-attached" to the substrate and other fibers. We propose a model of fiber formation from sheets and compare it with current models of end-wise polymerization from protofibrils. Sheets could be an unanticipated factor in clot formation and adhesion in vivo, and are a unique material in their own right.


The glass transition and the Jarzynski equality.
A simple model featuring a double well potential is used to represent a liquid that is quenched from an ergodic state into a history-dependent glassy state. Issues surrounding the application of the Jarzynski equality to glass formation are investigated. We demonstrate that the Jarzynski equality gives the free energy difference between the initial state and the state we would obtain if the glass relaxed to true thermodynamic equilibrium. We derive new variations of the Jarzynski equality which are relevant to the history-dependent glassy state rather than the underlying equilibrium state. It is shown how to compute the free energy differences for the nonequilibrium history-dependent glassy state such that it remains consistent with the standard expression for the entropy and with the second law inequality.


[Apamin--a highly specific and effective blockader of calcium-dependent potassium conductance].
Apamin is a toxic polypeptide extracted from bee venom. It has been considered as a neurotoxin with central action, but its low concentrations (10(-8)-10(-7) M) were shown to reversibly block the nonadrenergic inhibition and effects of externally applied ATP, noradrenaline and caffeine in smooth muscles of the gastrointestinal tract. All these processes are related to the activation of Ca-dependent potassium permeability. Current-clamp, voltage-clamp and patch-clamp experiments have also shown that apamin blocks specifically some types of these conductances in other tissues: skeletal muscles, mammalian neurons and neuroblastoma, hepatocytes. Nowadays apamin is the most specific but not a universal blocker of the Ca-activated potassium conductance.


Stable transfection of mammalian cells by syringe-mediated mechanical loading of DNA.
We show that mammalian cells can be stably transfected by a mechanical loading procedure in which cells are forced through a small opening in the presence of DNA. A suspension of cells and plasmid DNA in growth medium was passed up and down through a 30-gauge needle attached to a 1-ml syringe. Cells were immediately plated at appropriate densities for subsequent selection for stable expression of a marker gene. Two rodent cell lines, Chinese hamster ovary and mouse Ltk- cells, were successfully transfected with an efficiency of about one transfectant per 5 x 10(4) cells. The human HeLa cell line was transfected with a somewhat lower efficiency. Pluronic F-68, a detergent believed to aid in healing of membrane injuries, had no beneficial effect when present during the loading procedure. Successful transfection was accomplished using three different genes as selectable markers. Southern blotting analysis revealed that transfectants contained one or very few copies of the introduced DNA construct integrated into the genome. Several transfectants were demonstrated to remain stable for more than 20 generations of growth in the absence of selection. This procedure is fast, economical, and of general utility.


A predicted organometallic series following a 32-electron principle: An@C28 (An = Th, Pa+, U2+, Pu4+).
The spectroscopic and thermodynamic properties of the molecules M@C28 (M = Ce, Th, Pa+, U2+, Pu4+) are calculated using density functional theory. The systems have considerable energetic stability. It is shown that the actinide cases can be classified as "32-electron" systems, using the bonding s-, p-, d-, and f-type orbitals of the central metal. The rest of the valence molecular orbitals have purely carbon character.


Patient navigation for pregnant individuals with opioid use disorder: Results of a randomized multi-site pilot trial.
Patient navigation (PN) may benefit pregnant individuals with opioid use disorder (OUD) by improving treatment adherence. We examined participant enrollment, session delivery and assessment feasibility for a PN intervention among pregnant participants and compared PN preliminary effectiveness for OUD treatment engagement with participants in usual care (UC). This study was a pilot single-blinded multi-site randomized trial. Two academic medical centers in Pennsylvania (n = 57) and Utah (n = 45), United States participated. One hundred and two pregnant adult participants unestablished (fewer than 6 weeks) on medication for OUD (MOUD) were randomized to PN (n = 53) or UC (n = 49). PN was composed of 10 prenatal sessions (delivered after baseline but before the prenatal assessments) and four postnatal sessions (delivered before the 2- and 6-month postpartum assessments) focused upon OUD treatment and physical/mental health needs. UC involved brief case management. Feasibility assessments included consent, session delivery and assessment rates. Mixed-effect models for intent-to-treat (ITT) and per protocol (PP, received six or more sessions) populations were estimated to compare outcomes of MOUD use, secondary outcomes of substance use disorder (SUD) treatment attendance and non-prescribed opioid use, and exploratory outcome of overdose at baseline, predelivery and 2 and 6 months postpartum. We consented 87% (106 of 122) of the proposed target, delivered ~60% of sessions delivered and completed ≥ 75% assessments. PN ITT and PP had better MOUD adherence, SUD treatment attendance, non-prescribed opioid use and overdose outcomes than UC. Notable changes included good evidence for greater percentage change in days for PN PP MOUD use from baseline to 2 months postpartum [PN = 28.0 versus UC = -10.9, 95% confidence interval (CI) = 9.7, 62.1] and some evidence for baseline to 6 months postpartum (PN = 45.4 versus UC = 23.4, 95% CI = -0.7, 48.2). PN PP percentage change in days for SUD treatment attendance also showed good evidence for improvements from baseline to prenatal assessment (PN = 7.4 versus UC = -21.3, 95% CI = 3.3, 53.5). PN compared to UC participants reported fewer overdoses at 2 months (PN = 11.9%/UC = 16.1%) and at 6 months postpartum (PN = 3.8%/UC = 6.2%). Patient navigation appears to be associated with improvements in opioid use disorder treatment engagement and overdoses during pregnancy. This pilot trial shows the feasibility of the intervention and a future large-scale trial.


Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.
Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy using different pharmaceuticals has been proven highly effective due to the ability to affect multiple cellular pathways involved in the disease progression. However, the currently used drug combination designs are primarily based on empirical clinical studies, and little attention has been given to dosage regimens, i.e. how administration routes, onsets, and durations of the combinations influence the therapeutic outcome. This is partly because combination therapy is challenged by distinct physicochemical properties and in vivo pharmacokinetics/pharmacodynamics of the individual pharmaceuticals, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials.


Calculating the Position of the Joint Line of the Knee Using Anatomical Landmarks.
Restoration of the joint line of the knee during primary and revision total knee arthroplasty is a step that directly influences patient outcomes. In revision total knee arthroplasty, necessary bony landmarks may be missing or obscured, so there remains a lack of consensus on how to accurately identify and restore the joint line of the knee. In this study, 50 magnetic resonance images of normal knees were analyzed to determine a quantitative relationship between the joint line of the knee and 6 bony landmarks: medial and lateral femoral epicondyles, medial and lateral femoral metaphyseal flares, tibial tubercle, and proximal tibio-fibular joint. Wide variability was found in the absolute distance from each landmark to the joint line of the knee, including significant differences between the sexes. Normalization of the absolute distances to femoral or tibial diameters revealed reliable spatial relationships to the joint line of the knee. The joint line was found to be equidistant from the lateral femoral epicondyle and the proximal tibio-fibular joint, representing a reproducible point of reference for joint line restoration. The authors propose a simple 3-step algorithm that can be used with magnetic resonance imaging, computed tomography, or radiography to reliably determine the anatomical location of the joint line of the knee relative to the surrounding bony anatomy. [Orthopedics. 2016; 39(6):381-386.].


[Recovery from unconsciousness following severe hemodilution and hypotension caused by intraoperative massive hemorrhage: a case report].
A 75-year-old female with a history of cerebral infarction fell into sudden hypotension (mean blood pressure of around 46 mmHg) and severe anemia (hematocrit < or = 10%; minimum hemoglobin concentration of 2.0 g.dl-1) of approximately one hour due to massive hemorrhage during surgical removal of pheochromocytoma originated in the right adrenal gland. Nevertheless, she recovered from the unconsciousness after over 9 hours postoperatively. It is suggested that major reasons for her escaping from the brain damage, in spite of the low cerebral perfusion pressure, might be the decreased cerebral oxygen consumption due to the intraoperative mild hypothermia (31.5 degrees C) and the avoidance due to hemodilution of the extremely low cerebral blood flow.


Growth inhibition of human breast carcinoma and leukemia/lymphoma cell lines by recombinant interferon-beta 2.
Recombinant human interferon-beta 2 was produced in Escherichia coli by direct expression of cDNA encoding the mature protein sequence. At concentrations that stimulate DNA synthesis and growth in B-cell hybridomas and plasmacytomas, the cytokine was found to exert a strong inhibition on the growth of a number of carcinoma and leukemia/lymphoma cell lines. This antigrowth effect was observed in clonogenic assays and by measurements of cell number and thymidine incorporation in growing cultures. The effect was blocked by antibodies to a synthetic peptide from the N terminus of the molecule. Normal diploid fibroblasts were inhibited at concentrations higher than those needed for breast carcinoma cells.


Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia.
For unclear reasons, life-threatening water intoxication often coincides with acute psychosis in polydipsic schizophrenic patients with chronic hyponatremia. In contrast, most polydipsic schizophrenic patients are normonatremic and never manifest hyponatremia. To explore whether the effect of acute psychosis on water balance differs in these 2 schizophrenic subgroups, we compared their responses to drug-induced psychotic exacerbations. Matched polydipsic schizophrenic patients with (n = 6) and without (n = 8) hyponatremia were identified based on past and current indexes of fluid intake and hydration. A transient psychotic exacerbation was induced with an infusion of the psychotomimetic methylphenidate hydrochloride (0.5 mg/kg of body weight over a 60-second period). Antidiuretic hormone levels, subjective desire for water, and factors known to influence water balance were measured at 15-minute intervals for 2 hours. Except for the expected differences in plasma osmolality and sodium, basal measures were similar in the 2 groups. Following methylphenidate administration, antidiuretic hormone levels increased more in the hyponatremic patients (P < .02), despite their consistently lower plasma osmolality (P < .007). No known or putative antidiuretic hormone stimulus could account for this finding. Only basal positive psychotic symptoms (P < .09) and plasma sodium (P < .18) were even marginally associated with the peak antidiuretic hormone responses, but neither factor could explain the difference in the response by the 2 groups. Psychotic exacerbations are associated with enhanced antidiuretic hormone secretion, for unknown reasons, in schizophrenic patients with hyponatremia and polydipsia, thereby placing them at increased risk of life-threatening water intoxication.


Effectiveness of BNT162b2 vaccine against symptomatic SARS-CoV-2 infection in children aged 5-11 years in Japan during Omicron variant predominate periods.
Although the effectiveness of BNT162b2 messenger RNA vaccines against the Omicron variant has been reported in several countries, data are limited in children living in Asian countries. Therefore, this study aimed to estimate the effectiveness of the pediatric primary two-dose monovalent mRNA vaccine series in preventing symptomatic coronavirus disease 2019 (COVID-19) in Japan. We conducted a test-negative case-control study (262 test-positive cases and 259 test-negative controls) in patients aged 5-11 years who presented with COVID-19-like symptoms during the Omicron BA.2- and BA.5-predominant periods. Vaccination status, demographic data, underlying medical conditions, lifestyle, personal protective health behaviors, living environment, and PCR test results were obtained using parent-administered questionnaires and clinical records. Vaccine effectiveness (VE) against symptomatic COVID-19 was calculated using a multivariate logistic regression analysis. Of the test-positive cases and test-negative controls, 9.2% (n=24) and 12.7% (n=33) received two vaccine doses, respectively. Having siblings and a BA.5-dominant period were significantly associated with symptomatic COVID-19. After adjusting for age, siblings, study period, and duration after the last vaccination, the overall VE of two-dose vaccination was 50.0% (95% confidence interval [CI], 5%-74%). VE was 72% (95%CI: 24%-89%) within 3 months after the two-dose vaccination, while it decreased to 24% (95%CI: -80% to 68%) after 3 months. Two BNT162b messenger RNA vaccine doses provided moderate protection against symptomatic COVID-19 during the Omicron variant period. A time-dependent decrease in VE was noted after the second dose; thus, a booster dose 3 months after the second dose is warranted.


Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses.
Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs) to the post-synaptic membrane, and is developmentally regulated. How enhanced sensory experience can alter presynaptic release properties in the developing neocortex has not been investigated. Using paired-pulse stimulation at layer 4-2/3 synapses in acute brain slices, we found that presynaptic release probability progressively increases in the spared-whisker barrel column over the first 24 h of SRE. Enhanced release probability can be at least partly attributed to presynaptic NMDA receptors (NMDARs). We find that the influence of presynaptic NMDARs in enhancing EPSC amplitude markedly increases during SRE. This occurs at the same time when recently potentiated synapses become highly susceptible to a NMDAR-dependent form of synaptic depression, during the labile phase of plasticity. Thus, these data show that augmented sensory stimulation can enhance release probability at layer 4-2/3 synapses and enhance the function of presynaptic NMDARs. Because presynaptic NMDARs have been linked to synaptic depression at layer 4-2/3 synapses, we propose that SRE-dependent up-regulation of presynaptic NMDARs is responsible for enhanced synaptic depression during the labile stage of plasticity.


The accuracy of three impression transfer techniques for implant supported prostheses.
Cast framework for osseointegrated implant retained prostheses need to be passively fitting so as not to place undue forces and stress concentrations around the fixtures. Impression materials and techniques play a key role in the accuracy and fit of the metal framework. In this study, three impression procedures were investigated to establish which was the most accurate, reliable and predictable. This included using smooth sided tapered transfer copings and unsplinted and splinted square undercut transfer copings. A metal plated master model was fabricated and used as the standard against which models poured using the different impression techniques were compared. Readings were taken with a Reflex Microscope and used to calculate the mean, standard deviation and deviation index for each test model. The results of this study suggest that direct coping transfer techniques provide comparable or better results than indirect coping transfers in master cast fabrication. There was no significant difference in impression transfer accuracy between splinted and non-splinted square impression coping transfer techniques.


Deterministic processes vary during community assembly for ecologically dissimilar taxa.
The continuum hypothesis states that both deterministic and stochastic processes contribute to the assembly of ecological communities. However, the contextual dependency of these processes remains an open question that imposes strong limitations on predictions of community responses to environmental change. Here we measure community and habitat turnover across multiple vertical soil horizons at 183 sites across Scotland for bacteria and fungi, both dominant and functionally vital components of all soils but which differ substantially in their growth habit and dispersal capability. We find that habitat turnover is the primary driver of bacterial community turnover in general, although its importance decreases with increasing isolation and disturbance. Fungal communities, however, exhibit a highly stochastic assembly process, both neutral and non-neutral in nature, largely independent of disturbance. These findings suggest that increased focus on dispersal limitation and biotic interactions are necessary to manage and conserve the key ecosystem services provided by these assemblages.


[A course in medical ethics--a pain in the neck for the clinicians?].
Last year, a course in clinical medical ethics for paediatricians had to be cancelled owing to lack of interest. To find the reason for this, and to learn what ethical problems the physicians encountered in the course of their work, how they solved them, and their attitude towards education in medical ethics, a questionnaire was sent to all members of The Norwegian Paediatric Association, to be answered anonymously. The most frequent excuses for not attending the course were pressure of work and lack of time. 37% claimed that they very often or often encountered ethical problems during their work. 20% often solved these problems alone, and two out of three after discussing them with colleagues. 51% felt a need to improve their competence to solve ethical problems. Only 16% reported having no such need. The authors discuss the form and content of the education in medical ethics.


Health-Care Waste Treatment Technology Selection Using the Interval 2-Tuple Induced TOPSIS Method.
Health-care waste (HCW) management is a major challenge for municipalities, particularly in the cities of developing nations. Selecting the best treatment technology for HCW can be regarded as a complex multi-criteria decision making (MCDM) issue involving a number of alternatives and multiple evaluation criteria. In addition, decision makers tend to express their personal assessments via multi-granularity linguistic term sets because of different backgrounds and knowledge, some of which may be imprecise, uncertain and incomplete. Therefore, the main objective of this study is to propose a new hybrid decision making approach combining interval 2-tuple induced distance operators with the technique for order preference by similarity to an ideal solution (TOPSIS) for tackling HCW treatment technology selection problems with linguistic information. The proposed interval 2-tuple induced TOPSIS (ITI-TOPSIS) can not only model the uncertainty and diversity of the assessment information given by decision makers, but also reflect the complex attitudinal characters of decision makers and provide much more complete information for the selection of the optimum disposal alternative. Finally, an empirical example in Shanghai, China is provided to illustrate the proposed decision making method, and results show that the ITI-TOPSIS proposed in this paper can solve the problem of HCW treatment technology selection effectively.


Acute obstructive suppurative cholangitis.
Acute obstructive suppurative cholangitis is an uncommon condition which, if unrecognized, carries a high rate of mortality. This study of 12 patients highlights the clinical features as well as the poor outcome of delayed surgical decompression. Endoscopic and percutaneous drainage of the obstructed biliary tree in acutely ill patients may improve the results of subsequent surgery.


Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer's Disease.
Alzheimer's disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the "amyloid cascade hypothesis". However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca2+) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca2+ signaling may act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump might act as such Ca2+ stabilizing agents. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD.


Clinical evaluation of a true percutaneous technique for antegrade femoral nailing.
From July 1997 to March 2001, 209 consecutive patients with 215 femoral shaft fractures amenable to antegrade femoral nailing were enrolled. A true percutaneous insertion technique was performed using a stab wound incision. One hundred ninety-seven (92%) fractures achieved primary union with anatomic or near anatomic alignment. Eighteen (8%) healing problems and two deep infections (1%) responded to repeat interventions. There was one iatrogenic complication related to an anterior starting point. External blood loss was minimal (generally <100 cc). Incisions averaged 16 mm and healed uneventfully. At one-year follow-up only 10% of patients had hip abductor pain. The percutaneous technique appears to be a safe and effective alternative to the standard technique. Hip pain at one year appears decreased compared to reports using a traditional approach.


The effect of three angiotensin-converting enzyme inhibitors on kynurenic acid production in rat kidney in vitro.
The renin-angiotensin system (RAS) is commonly known to regulate blood pressure, water and electrolyte homeostasis, however it also exerts paracrine and autocrine actions on the kidney. Angiotensin-converting enzyme inhibitors (ACE-Is), alongside their hypotensive properties, have been shown to decrease kidney function decline in animal models of nephropathy. Glutamate (GLU) is the main stimulatory neurotransmitter in the central nervous system, however its importance in the periphery should also be considered. Activation of renal GLU receptors has been linked to normal kidney function and also renal injury. The wide spectrum GLU receptor antagonist kynurenic acid (KYNA) possesses neuroprotective and central hypotensive effects, however its actions outside the brain are less well recognized. KYNA is a tryptophan metabolite synthesized from kynurenine by kynurenine aminotransferases (KATs). The purpose of this study was to examine the influence of three ACE-Is: lisinopril, perindopril and ramipril on KYNA production and KATs activity in rat kidney in vitro. The effect of ACE-Is on KYNA production and KATs activity was examined in rat kidney homogenates. KYNA was detected by high-performance liquid chromatography (HPLC) and quantified fluorometrically. All examined ACE-Is: lisinopril, perindopril and ramipril decreased KYNA production in rat kidney in vitro. KAT I activity was decreased by lisinopril and ramipril whereas the activity of KAT II was lowered by ramipril. Our study shows that ACE-Is can decrease KYNA production in rat kidney in vitro. Further studies are required to determine the clinical importance of the inhibitory action of ACE-Is on KYNA synthesis in the kidney.


Causes of depression: perceptions among people recovering from depression.
This paper is a report of a study to explore perceptions of the causes of depression among Taiwanese people recovering from depression. Depression is a leading worldwide cause of disability. The prevalence of depression in general, and the incidence of suicide in particular, are causing concern in Taiwan. The suicide rate here has doubled in the last decade and the use of psychotic drugs has also increased. People's perceptions of their condition determine when and how they access and utilize services. A purposive sample of 40 participants (21 women and 19 men) recovering from depression after discharge from four hospitals in Taipei was recruited. In-depth, qualitative interviews using a narrative style were carried out in 2003. The tape-recorded interviews were transcribed and analysed for themes. Participants perceived the causes of their depression as being mainly social and cultural in origin. The main identified causes were: stress in marital relationships; conflict in extended families; changes in life circumstances and early life experiences. Women participants viewed their depression as being caused by their 'dominant' (traditional) husbands, who still thought that women should stay at home to take care of their children and the housekeeping and who refused to share these roles. Women also felt socially isolated when joining their extended marital families. These findings have implications for community nurses' education and practice in relation to depression. Uncovering and addressing conflict and stress in marital relationships and in extended families is challenging, especially for nurses who traditionally work within medical models of care delivery.


Bivalves as Emerging Model Systems to Study the Mechanisms and Evolution of Sex Determination: A Genomic Point of View.
Bivalves are a diverse group of molluscs that have recently attained a central role in plenty of biological research fields, thanks to their peculiar life history traits. Here, we propose that bivalves should be considered as emerging model systems also in sex-determination (SD) studies, since they would allow to investigate: 1) the transition between environmental and genetic SD, with respect to different reproductive backgrounds and sexual systems (from species with strict gonochorism to species with various forms of hermaphroditism); 2) the genomic evolution of sex chromosomes (SCs), considering that no heteromorphic SCs are currently known and that homomorphic SCs have been identified only in a few species of scallops; 3) the putative role of mitochondria at some level of the SD signaling pathway, in a mechanism that may resemble the cytoplasmatic male sterility of plants; 4) the evolutionary history of SD-related gene (SRG) families with respect to other animal groups. In particular, we think that this last topic may lay the foundations for expanding our understanding of bivalve SD, as our current knowledge is quite fragmented and limited to a few species. As a matter of fact, tracing the phylogenetic history and diversity of SRG families (such as the Dmrt, Sox, and Fox genes) would allow not only to perform more targeted functional experiments and genomic analyses, but also to foster the possibility of establishing a solid comparative framework.


Loss of RCC1 leads to suppression of nuclear protein import in living cells.
The role of RCC1-Ran/TC4 in nuclear protein import was examined in living cells using a temperature-sensitive RCC1 mutant cell line, tsBN2, and tsBN2 transformed with a RCC1 cDNA lacking the nuclear localization sequence domain, delta 8-29. Substrate, containing a small number of SV40 T antigen nuclear localization sequence peptides, injected into the cytoplasm of tsBN2 cells cultured at the non-permissive temperature of 39.5 degrees C did not accumulate efficiently in the nucleus. When the same substrate was injected into the cytoplasm of heterokaryons of tsBN2 and wild type BHK21 cells, import efficiency into the tsBN2 nuclei was not restored. Import into the BHK21 nuclei gradually decreased after fusion. In contrast, import efficiency into tsBN2 nuclei gradually recovered after fusion with tsBN2 cells transformed with delta 8-29 in which functional RCC1 was diffusely distributed in both the nuclei and cytoplasm. Substrate did not accumulate in the nuclei of digitonin-permeabilized tsBN2 cells cultured at 39.5 degrees C even in the presence of normal cytosol. These results suggest that loss of RCC1 function leads to the decline of import competence of the nucleus and accumulation of a factor in the cytoplasm that suppresses nuclear import. These results indicate that the RCC1-Ran/TC4 system may regulate nuclear import.


Cathepsin B-like activity as a serum tumour marker in ovarian carcinoma.
Serum cathepsin B-like activity was determined in 75 patients with ovarian carcinomas and in control groups. Ovarian cancers were of FIGO stages I-IV. Control groups consisted of 15 healthy women, 20 patients with myomas of the uterus, and 17 with benign ovarian cysts. Preoperative results showed elevated cathepsin B-like activity in 100% of the patients with ovarian cancers in relation to healthy subjects and patients with myomas, and in 78% in relation to benign ovarian cysts. Cathepsin B activity increased progressively with the FIGO stage of the disease, but the differences among particular stages were not statistically significant. In serous tumours cathepsin activity was significantly higher only in comparison to endometrioid ones (p < 0.001). Antipapain capacity of cystatins in the sera was also determined. No significant correlation between cathepsin B-like, and antipapain activity of cystatins was found. Serum cathepsin B-like activity may be helpful in the preoperative differential diagnosis between ovarian carcinomas and benign ovarian or uterine tumours.


Scanning and War: Utility of FAST and CT in the Assessment of Battlefield Abdominal Trauma.
To determine utilization and accuracy of focused assessment with sonography for trauma (FAST) and computed tomography (CT) in a mature military trauma system to inform service provision for future conflicts. FAST and CT scans undertaken by attending radiologists contribute to surgical decision making for battlefield casualties at the Joint Force, Role 3 Medical Treatment Facility at Camp Bastion (R3), Afghanistan. Registry data for abdominally injured casualties treated at R3 from July to November 2012 were matched to radiological and surgical records to determine diagnostic accuracy for FAST and CT and their influence on casualty management. A total of 468 casualties met inclusion criteria, of whom 85.0% underwent FAST and 86.1% abdominal CT; 159 (34.0%) had abdominal injuries. For detection of intra-abdominal injury, FAST sensitivity (Sn) was 0.56, specificity (Sp) 0.98, positive predictive value (PPV) 0.87, negative predictive value (NPV) 0.90, and accuracy (Acc) 0.89. For CT, Sn was 0.99, Sp 0.99, PPV 0.96, NPV 1.00, and Acc 0.99. Forty-six solid organ injuries were identified in 38 patients by CT; 17 were managed nonoperatively. A further 61 patients avoided laparotomy after CT confirmed extra-abdominal wounds only. The negative laparotomy rate was 3.9%. FAST and CT contribute to triage, guide surgical management, and reduce nontherapeutic laparotomy. When imaging is available, these data challenge current doctrine about inadvisability of nonoperative management of abdominal injury after combat trauma.


Eradication of invasive pneumococcal disease due to the seven-valent pneumococcal conjugate vaccine serotypes in Calgary, Alberta.
The seven-valent pneumococcal conjugate vaccine (PCV7) was licensed in Canada in 2001. Routine infant vaccination programs in Alberta began in 2002. Several years after PCV7 introduction, the routine use of PCV7 in infants and high-risk children has led to near elimination of invasive pneumococcal disease (IPD) caused by vaccine serotypes. Prospective, population-based surveillance of all IPD cases was conducted from January 1998 to December 2010. Demographic, clinical and microbiologic data were collected. There were 1462 IPD cases over 13 years. Comparing PCV7 serotype IPD incidence in the prevaccine period (1998-2001) to the late postvaccine period (2007-2010), there were declines in children 0-5 months (100%), 6-23 months (98%), 2-4 years (97%), 5-15 years (100%) as well as in adults 16-64 years (73%), 65-84 years (90%) and ≥85 years of age (100%). From 2008 to 2010, there were no cases of PCV7 serotype IPD in children under 2 years of age. There have been increases in non-PCV7 serotype IPD; notably, serotypes 5 and 19A have increased significantly in adults and 19A in children. PCV7 serotype IPD has been eliminated in vaccine-eligible young children and nearly eliminated in all other age groups. Serotype 19A increased significantly at all ages before the introduction of an expanded valency pneumococcal conjugate vaccine.


Lithium perspectives.
Progress in lithium treatment and research has been predicated on contributions from scientists of many different kinds. Examples are given of the systematic scientist, the artistic scientist, and the tenacious clinician. Lithium has attracted interest from a wide variety of scientific disciplines, partly because it is a small cation with many biological effects and partly because it counteracts both the manic and the depressive manifestations of manic-depressive illness. The seed John Cade sowed has grown to a large tree.