Induction of mutagenesis and transformation in BALB/c-3T3 clone A31-1 cells by diverse chemical carcinogens.
BALB/c-3T3 cells were employed to examine the genotoxic potential of a variety of known chemical carcinogens. BALB/c-3T3 cells displayed a dose-dependent transformation response to a variety of carcinogens (polycyclic hydrocarbons, methylating agents, ethylating agents, aflatoxin B1 [AFB1], and 4-nitroquinoline-N-oxide [4-NQO]). When the ability of these compounds to induce mutagenesis to resistance to the cardiac glycoside ouabain (OUAR) was examined, we found the short chain alkylating agents to be particularly effective mutagens, causing biologic effects at doses below those necessary to induce a transformation response. In contrast, the polycyclic hydrocarbons which were potent transforming agents were weaker, albeit significant, mutagens for the OUAR locus in this system, while AFB1 was quite weak. Further studies were performed with 5-azacytidine (5-AZA) and the nongenotoxic carcinogen cinnamyl anthranilate (ClN). 5-AZA was a potent transforming agent, but failed to cause mutagenesis. ClN similarly caused in vitro transformation. When a series of eight structurally diverse compounds were examined in both the BALB/c-3T3 and C3H10T1/2 mouse fibroblast transformation systems, the BALB/c-3T3 system was shown to be sensitive to a wide variety of potential carcinogens, whereas the C3H10T1/2 system proved routinely sensitive only to the polycyclic hydrocarbons.


Multiple personality disorder and borderline personality disorder. Distinct entities or variations on a common theme?
We report data from a comparison of 14 subjects with multiple personality disorder (MPD) and 13 subjects with borderline personality disorder (BPD). There were few significant differences between the groups. The authors discuss the concept of MPD as an epiphenomenon of BPD, and argue their fundamental similarity.


Rheumatoid arthritis: previously untreated early disease.
Rheumatoid arthritis is a chronic autoimmune disease, which most often presents as a symmetrical polyarthritis of the hands and feet. Pharmacological treatments include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs) and other disease-modifying anti-rheumatoid drugs (DMARDs), which may be synthetic (either conventional [csDMARDs] or targeted [tsDMARDs]) or biological (bDMARDs). We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of methotrexate in combination with other csDMARDs versus methotrexate monotherapy in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? What are the effects of bDMARDs as monotherapy versus methotrexate or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? What are the effects of bDMARDs in combination with methotrexate versus methotrexate monotherapy or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? What are the effects of glucocorticoids in combination with methotrexate or with other csDMARDs versus methotrexate or other csDMARDs in people with rheumatoid arthritis who have not previously received any DMARD treatment (first-line treatment)? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). At this update, searching of electronic databases retrieved 2058 studies. Of the full articles evaluated, 10 systematic reviews, 22 RCTs, and one follow-up report were added at this update. We performed a GRADE evaluation for 18 PICO combinations. In this systematic overview, we categorised the efficacy for 22 comparisons based on information about the effectiveness and safety of bDMARDs (monotherapy or combined with csDMARDs), csDMARDs (monotherapy or combined with other csDMARDs), glucocorticoids combined with methotrexate or other csDMARDs, and methotrexate (monotherapy or combined with other csDMARDs), identifying interventions which were likely or unlikely to be beneficial.


Preliminary evaluation of 18F‑AlF‑NOTA‑MAL‑Cys40‑Exendin‑4 in rodent heart after myocardial ischemia and reperfusion.
Glucagon‑like peptide‑1 (GLP‑1) and its receptor (GLP‑1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non‑invasive method for monitoring GLP‑1R expression. In the present study, a fluorine‑18‑labeled aluminum fluoride exendin‑4 analog [18F‑AlF conjugated with 1,4,7‑triazacyclononanetriacetic acid (NOTA)‑maleimide (MAL)‑Cys40‑exendin‑4] was synthesized and evaluated in a rat MI/R model for GLP‑1R imaging. NOTA‑MAL‑Cys40‑exendin‑4 was synthesized by coupling Cys40‑exendin‑4 with NOTA‑MAL. NOTA‑MAL‑Cys40‑exendin‑4 was then conjugated with 18F‑AlF to obtain 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4. The yield of 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP‑1R and an appropriate signal‑to‑noise ratio. At 8 h post‑MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post‑MI/R compared with 8 h post‑MI/R, but still remained higher compared with sham‑operated groups (0.06±0.012 %ID/g; n=6). Pre‑injected unlabeled exendin‑4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 demonstrated favorable characteristics for GLP‑1R imaging following MI/R. PET imaging using 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 in rodent hearts after MI/R revealed a dynamic pattern of GLP‑1R upregulation.


Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling.
Changes in the hypothalamic-pituitary-adrenal (HPA) axis activity constitute a key component of bipolar mania, but the extent and nature of these alterations are not fully understood. We use here the lateral hypothalamic-kindled (LHK) rat model to deliberately induce an acute manic-like episode and measure serum corticosterone concentrations to assess changes in HPA axis activity. A mathematical model is developed to succinctly describe the entwined biochemical transformations that underlay the HPA axis and emulate by numerical simulations the considerable increase in serum corticosterone concentration induced by LHK. Synergistic combination of the LHK rat model and dynamical systems theory allows us to quantitatively characterize changes in HPA axis activity under controlled induction of acute manic-like states and provides a framework to study in silico how the dynamic integration of neurochemical transformations underlying the HPA axis is disrupted in these states.


[Human microbiomes--normal microbiota underlying a growing number of diseases].
Human microbiomes refer to complex bacterial communities colonizing the skin and the mucous membranes of various body cavities. Microbiomes and especially their aberrations have recently been linked to numerous local and systemic diseases. Identification of factors regulating the composition and function of microbiomes is therefore medically highly relevant, but still in its infancy. With the exception of fecal transplantation, microbiome-based medical applications do not yet exist. The active research in the field is expected to provide better understanding on the role of microbiomes in human health, and enable their clinical utilization in the future.


Rat liver 4S-benzo[a]pyrene-binding protein is distinct from glycine N-methyltransferase.
Rat liver 4S-benzo[a]pyrene-binding protein (BAP) was reported to be identical to the subunit (Mr 32,500) of the tetrameric glycine N-methyltransferase (GNMT). We have reevaluated this study. When a liver cytosol was subjected to Sephacryl S-200 gel permeation chromatography, enzyme activity as well as cross-reactivity with anti-GNMT antibody were found only at the elution position of the purified GNMT. Chromatograph of the cytosol pretreated with [3H]benzo[a]pyrene showed two peaks in the void volume and at the position of an approximate Mr of 40,000. The latter, corresponding to the 4 S BAP, did not cross-react with the anti-GNMT antibody. An extract of nuclei in which GNMT was proposed to act as a mediator of cytochrome P4501A1 gene expression contained the tetrameric GNMT but no binding activity. The lung, in which no GNMT mRNA occurred, had the 4 S BAP. Extracts of Escherichia coli and COS-7 cells expressing large amounts of GNMT showed no 4 S BAP. These findings suggest that the 4 S BAP is distinct from the subunit of GNMT.


PVL-positive MRSA in Austria.
The objective of this study was to present, for the first time, an overview of the existing Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) strains in Austria and to compare the situation with that found in other countries. Between 2001 and 2006 we analysed 1150 MRSA isolates - from infections as well as from colonisation - for the presence of PVL genes. The most common multilocus sequence types of the 94 PVL-positive MRSA strains were ST8, ST152, ST30, ST80, and ST5; the ST22, and ST777 sequences were also detected. During 2005 and 2006, 3.7-7.7% of the isolates were PVL-positive. The age distribution of the patients revealed that nosocomial MRSA mainly occurs in elderly people, whereas PVL-positive MRSA mainly appears in younger people. We observed a relatively high prevalence of PVL-positive isolates. Several MRSA clones containing the PVL genes are spreading throughout Austria, including two strains not yet widespread in Western Europe.


A new quantitative analysis system for the evaluation of coronary bifurcation lesions: comparison with current conventional methods.
Objective conventional quantitative angiographic systems are designed to automatically follow the contours of straight vascular segments and not of bifurcations. Recently a new analysis method was specifically developed for bifurcation lesions, able to automatically divide the lesion into three separate segments. In this study, we aimed to assess whether the smaller interaction required by the analyst could reduce the analysis time and inter and intra observer variability when compared with a conventional analysis. We used a dedicated system (QVA-CMS V. 6.0 with the Bifurcation Module, MEDIS, Leiden, The Netherlands) applying a minimum cost algorithm tuned to detect the contours of the proximal main vessel (PMV), distal main vessel (DMV), and side-branch (SB). We assessed the intra- and the interobserver agreement in measurements of minimal lumen diameter (MLD) and percentage diameter stenosis (%DS) of the PMV and DMV, as well as of the SB ostium in 30 angiograms of patients before and after percutaneous coronary angioplasty with stenting of both branches. The consensus between measurements by two observers and by the same observer was analyzed using the intra- and interclass correlation coefficient and the reliability coefficients for all measurements. Bland-Altman plots before and after PCI were also generated to assess the relationship between variability and absolute measurements. Before PCI, intra- and interobserver variabilities were consistently lower for the new QVA system, with a significant difference for lesion length in the SB. Post-PCI data showed a greater variability in the assessment of diameter stenosis with both techniques. The time for analysis was significantly lower both before and after PCI for QVA compared with quantitative coronary angiography (QCA) (4.7 +/- 1.1 min versus 6.2 +/- 1.3 min, P < 0.0001). Our results demonstrate that this new quantitative bifurcation analysis system can be consistently applied to the analysis of bifurcation lesions before and after angioplasty, with an intra- and interobserver reproducibility equal to or better than the conventional analysis system with a significantly shorter analysis time.


Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes.
Cyclooxygenase-2 (COX-2) inhibitors exert antitumor activity via COX-2-dependent and independent pathways. We wished to evaluate the antitumor activity of meloxicam, a preferential COX-2 inhibitor, in osteosarcoma, the most common primary malignant bone tumor, and determine whether its antitumor effect is COX-2-dependent. COX-2 expression in the osteosarcoma cell lines MG-63, HOS and U2-OS was determined by real-time RT-PCR and western blotting. Subsequently, the inhibitory effects of meloxicam on osteosarcoma cell growth and invasiveness were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and matrigel invasion assays, respectively. Apoptotic activity was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining and semi-quantification of Bax and Bcl-2 expression by real time RT-PCR and western blotting. Prostaglandin-E(2) (PGE(2)) production in the presence and absence of meloxicam was analyzed by enzyme immunoassay, and to determine whether the effects of meloxicam are COX-2-dependent or independent, PGE(2) was added to see if it reversed the effects of meloxicam. In addition, the effects of meloxicam on tumor growth and metastasis were evaluated in an in vivo mouse model using grafted LM-8 mouse osteosarcoma cells, together with immunohistochemical analysis for vascular endothelial growth factor in lung metastatic lesion. Meloxicam inhibited PGE(2) production, proliferation and invasiveness especially in MG-63 cells, which express relatively high levels of COX-2. Only high concentrations of meloxicam caused apoptosis and upregulated Bax mRNA and protein in MG-63 cell culture. In contrast, meloxicam did not induce apoptosis in HOS and U2-OS cells, expressing relatively low levels of COX-2. Exogenous PGE(2) reduced the effects of meloxicam on cell viability and invasiveness, but not its effect on Bax mRNA. In vivo, high doses of meloxicam suppressed LM-8 tumor growth and lung metastasis. Meloxicam, may have both COX-2-dependent and independent inhibitory actions on osteosarcoma. Its effects are more prominent in osteosarcoma cells that have relatively high levels of COX-2.


Blunting Neuroinflammation by Targeting the Immunoproteasome with Novel Amide Derivatives.
Neuroinflammation is an inflammatory response of the nervous tissue mediated by the production of cytokines, chemokines, and reactive oxygen species. Recent studies have shown that an upregulation of immunoproteasome is highly associated with various diseases and its inhibition attenuates neuroinflammation. In this context, the development of non-covalent immunoproteasome-selective inhibitors could represent a promising strategy for treating inflammatory diseases. Novel amide derivatives, KJ3 and KJ9, inhibit the β5 subunit of immunoproteasome and were used to evaluate their possible anti-inflammatory effects in an in vitro model of TNF-α induced neuroinflammation. Differentiated SH-SY5Y and microglial cells were challenged with 10 ng/mL TNF-α for 24 h and treated with KJ3 (1 µM) and KJ9 (1 µM) for 24 h. The amide derivatives showed a significant reduction of oxidative stress and the inflammatory cascade triggered by TNF-α reducing p-ERK expression in treated cells. Moreover, the key action of these compounds on the immunoproteasome was further confirmed by halting the IkB-α phosphorylation and the consequent inhibition of NF-kB. As downstream targets, IL-1β and IL-6 expression resulted also blunted by either KJ3 and KJ9. These preliminary results suggest that the effects of these two compounds during neuroinflammatory response relies on the reduced expression of pro-inflammatory targets.


The DSM-IV panic disorder field trial: panic attack frequency and functional disability.
The goal of the DSM-IV panic disorder field trial was to provide an empirical basis for choosing between alternate proposals (DSM-III-R and proposed DSM-IV) for the diagnostic threshold for panic disorder, in particular the number and frequency of panic attacks required for diagnosis. The two criteria sets were compared with respect to their ability to identify individuals whose panic attacks were associated with distress, impairment, or help-seeking. Subjects were a convenience sample screened in three geographically diverse primary care clinics for presence (past 6 months) or absence (lifetime) of panic attacks. Each underwent a clinician-administered semistructured interview which included assessment of panic frequency, panic-related impairment, psychiatric diagnosis, health services utilization, and medical illness. Self-perceived health-related quality of life was assessed using the Medical Outcome Study SF-36 Health Survey Questionnaire. Although both proposals diagnosed the same proportion of panic-impaired individuals, they were not completely overlapping. Twenty percent of subjects diagnosed by each criteria set were excluded by the other. Subjects who had been excluded by the DSM-III-R but included by the DSM-IV proposal were those with fewer than 4 attacks in 4 weeks who also denied worry about the "next" attack. Broadening the worry criterion to include concerns about the health implications of attacks enabled diagnosis of this group. Subjects who met DSM-III-R, but not the proposed DSM-IV criteria, had 4 attacks in 4 weeks but denied any panic related worry. Modification of the DSM-IV proposal to include a month of worry or "a significant change in behavior related to the attacks" allowed inclusion of this group in the diagnostic category. These data suggest that the finalized DSM-IV panic disorder criteria will diagnose a greater proportion of individuals whose panic attacks are associated with impairment without inflating the diagnostic category or significantly reducing specificity.


Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera.
The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.


Outcomes of laparoscopic hepatic resection for colorectal cancer metastases.
The role of laparoscopic liver resection for cancer remains controversial. This review summarizes the expanding literature on outcomes of minimally invasive hepatic resection for colorectal cancer liver metastases. Four recent studies (in more than 300 patients) show 5-year overall-survival rates of 46-64%, which are comparable to results in modern open hepatic resection series. The advantages of laparoscopic liver resection include smaller incisions, less pain, less narcotic requirements, and shorter length of stay.


Revealing the lytic mechanism of the antimicrobial peptide gomesin by observing giant unilamellar vesicles.
Gomesin (Gm) is a potent cationic antimicrobial peptide from a Brazilian spider. Here we use optical and fluorescence microscopy to study the interaction of Gm, its low active linear analogue, [Ser(2,6,11,15)]-Gm (GmL), and a fluorescent labeled analogue, Gm-Rh, with giant unilamellar vesicles (GUVs) composed of mixtures of the neutral lipid palmitoyloleoyl phosphatidylcholine (POPC) with the negatively charged lipid palmitoyloleoyl phosphatidylglycerol (POPG) or cholesterol, so as to mimic bacterial and mammalian cell membranes, respectively. We observed the effect of injecting a peptide solution with a micropipet close to GUVs. As a result of peptide-lipid interaction, GUVs burst suddenly. Stable pores, which result in leaky vesicles, were not observed. Fluorescence microscopy of Gm-Rh injected on GUVs confirmed the high peptide/lipid affinity. These facts lead us to suggest that Gm and GmL disrupt the membrane via the carpet model. In order to quantify the lytic activity of both peptides against different membrane composition, a solution of GUVs was diluted in increasing concentration of peptides and the fraction of burst GUVs was measured as a function of time. The lytic activity of both peptides was enhanced by the presence of POPG and decreased upon addition of cholesterol. GmL exhibited lower lytic activity as compared to Gm, but this difference vanished at high POPG molar fraction.


Bioethics and law: a developmental perspective.
In most Western countries, health law [and] bioethics are strongly intertwined. This strong connection is the result of some specific factors that, in the early years of these disciplines, facilitated a rapid development of both. In this paper, I analyze these factors and construe a development theory existing of three phases, or ideal-typical models. In the moralistic-paternalistic model, there is almost no health law of explicit medical ethics, and the little law there is is usually based on traditional morality, combined with paternalist motives. The objections to this model are that its paternalism and moralism are unacceptable, that it is too static and knows no external control mechanisms. In the liberal model, which is now dominant in most Western countries, law and ethics closely cooperate and converge, both disciplines use the same framework for analysis: they are product-oriented rather than practice-oriented; they use the same conceptual categories, they focus on minimally decent rather than the ideal, and they are committed to the same substantive normative theory in which patient autonomy and patient rights are central. However, each of these four characteristics also results in a certain one-sidedness. In some countries, a third model is emerging. In this postliberal model, health law is more modest and acknowledges its inherent and normative limits, whereas ethics takes a richer and most ambitious self image. As a result health law and ethics will partly diverge again.


Sodium maleopimaric acid as pseudostationary phase for chiral separations of amino acid derivatives by capillary micellar electrokinetic chromatography.
A new type of chiral surfactant, sodium maleopimaric acid (SMA), was synthesized, and employed for the enantioselective micellar electrokinetic chromatographic (MEKC) separation of amino acid enantiomers derivatized with naphthalene-2,3-dicarboxaldehyde (NDA-D/L-AAs). The effect of the surfactant concentration, type and concentration of the BGE, and buffer pH on the resolution was studied, and optimized conditions were used to evaluate the ability of this new surfactant to perform chiral separations toward NDA-D/L-AAs by MEKC. Enantiomeric separations of NDA-D/L-AAs were achieved with a running buffer consisting of 100 mM borate (pH 9.5) and 20 mM SMA in a 58.5 cm length x 50 microm id capillary. Under the conditions selected, two pairs of tested amino acid enantiomers including NDA-D/L-trptophan (Trp) and NDA-D/L-kynurenine (Kyn) were resolved.


[Cervicothoracic cystic lymphangioma: about a case].
Cervicothoracic cystic lymphangiomas are rare benign tumors developing from sequestration of embryonic lymph sac which is gradually filled with lymph fluid. The diagnosis is based on clinical signs (laterocervical swelling) and imaging (ultrasound and CT scan), then confirmed by histology after surgery which constitutes the basis of treatment. We here report a case of cervicothoracic cystic lymphangioma and review of the literature.


Aggressive early reconstruction in open foot trauma: a case report.
Open fracture-dislocation of the lower extremity poses a serious risk, has a high incidence of complications, and necessitates prompt surgical intervention. Patients need to be evaluated on presentation to the emergency department for neurovascular injury, soft-tissue insult, stability of the fracture, concomitant injuries, and overall medical/nutritional status. Implementation of a specific treatment protocol will decrease time to operative management and increase the overall success rate. Success after treatment of lower-extremity trauma should be defined as a noninfected, functional limb with optimal tissue preservation allowing ambulation. We present a case of open fracture-dislocation of the first ray treated with prompt debridement, skeletal stabilization, and immediate soft-tissue reconstruction.


Characteristics of a human prostate stromal cell line related to its use in a stromal-epithelial coculture model for the study of cancer chemoprevention.
An immortalized human prostate stromal cell line (PS30) was previously established using recombinant retrovirus encoding human papillomavirus 16 gene products. In this study, we further characterize this stromal cell line for its potential use in a stromal-epithelial coculture model for prostate cancer prevention. Using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry, we examined expression of androgen receptor (AR), vitamin D receptor (VDR), prostate-specific antigen (PSA), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGF) families and their receptors, metalloproteinases (MMP) MMP-2 and MMP-9, as well as the cells' ability to respond to the synthetic androgen R1881. The PS30 stromal cells do not express PSA, confirming their stromal origin. They are positive for both AR messenger ribonucleic acid (mRNA) and protein; however, they do not respond to growth stimulation by the synthetic androgen R1881. The PS30 cells express mRNA for VDR, TGF-betas, IGFs and their receptors, as well as the MMPs. Moreover, they produce significant amounts of TGF-beta1, TGF-beta2, IGFBP-3, and MMP-2 proteins. Our observations confirm the use of PS30 for the study of stromal-epithelial interactions in the modulation of prostate carcinogenesis.


NF-κB in the regulation of epithelial homeostasis and inflammation.
The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.


Cell survival in V79 multicell spheroids treated with dehydroascorbate, 5-thio-D-glucose and 2-deoxy-D-glucose.
We found that dehydroascorbic acid (DHA), 5-thio-D-glucose (5TG) and 2-deoxy-D-glucose (2DG) were toxic to monolayers of V79 cells under hypoxic conditions at 37 degree C but not at 0 degree C. Very little toxicity was observed at either temperature under aerobic conditions. When spheroids (600 micrometer diameter) were treated with 7.5 mM of these chemicals for periods up to 3 days, the number of viable cells per spheroid dropped to 70% for DHA, 50% for 5TG and 25% for 2DG relative to controls. These survivals were reduced to much lower values when the experiments were repeated in glucose-free medium.


Incidence of delirium after cardiac surgery: protocol for the DELIRIUM-CS Canada cross-sectional cohort study.
Delirium is a recognized complication of cardiac surgery and is the focus of increasing attention owing to its negative effect on postoperative outcomes. However, little is known about the actual incidence of delirium following cardiac surgery, with published rates ranging widely, from 3%-78%. We describe the protocol for the DELIRIUM-CS Canada study, which will use validated and easily implementable bedside tools to determine the incidence of postoperative delirium in a contemporary cardiac surgery population. We hypothesize that delirium, identified through a systematic and standardized screening protocol, is a highly prevalent, though variable, condition following cardiac surgery. The DELIRIUM-CS Canada study is a multicentre cross-sectional cohort study. Over a 3-month period, all patients undergoing major cardiac surgical procedures at 10 participating centres will be screened for postoperative delirium by means of the Intensive Care Delirium Screening Checklist or the Confusion Assessment Method for the Intensive Care Unit. Delirium screening will be conducted for 7 days following the date of surgery or until the initial discharge from the intensive care unit. In addition to reporting an overall rate of delirium, we will report unadjusted and adjusted incidence rates of delirium by institution and for the entire cohort. Risk adjustment will be performed with the use of multivariate regression modelling techniques. The results of this study will provide valuable insight into the true burden of delirium among patients having undergone a major cardiac surgical procedure in the current era. This is the first step in creating a multifaceted delirium prevention/treatment clinical pathway for patients undergoing cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT02206880.


Scleritis, keratitis, and orbital cellulitis: isolated ocular manifestation of systemic lupus erythematosus.
Systemic autoimmune diseases are associated with ocular inflammatory conditions such as episcleritis, scleritis, keratitis, and uveitis. However, ocular manifestations have been reported to correlate with the extent of systemic disease. We present a patient with scleritis, keratitis, and orbital cellulitis, as the isolated manifestation of systemic lupus erythematosus (SLE). No microbial etiology was identified and antibiotics did not produce clinical improvement. The patient improved significantly with steroids and disease-modifying antirheumatic drugs. Although ocular inflammation has been previously remarked in SLE of systemic severity, in this case there were no other organs with SLE involvement. We briefly discuss the ocular manifestations of SLE, which can involve all segments of the eye, including cornea, sclera, retina, uvea, optic nerve, and orbit.


Using behavioral and electrophysiological measures to assess the effects of a preventive intervention: a preliminary study with preschool-aged foster children.
The current study was designed to explore the use of behavioral (i.e., accuracy and reaction times) and electrophysiological measures (i.e., event-related potentials) to assess the impact of a family-based preventive intervention for preschool-aged, maltreated children in foster care. These measures were recorded during a computerized flanker task designed to assess cognitive control and response monitoring. The sample was recruited from a larger randomized efficacy trial of Multidimensional Treatment Foster Care for Preschoolers (MTFC-P) and included foster children assigned to the intervention condition (n = 10), foster children assigned to a services-as-usual comparison condition (n = 13), and low-income, nonmaltreated community children (n = 11). The children's behavioral and electrophysiological performance on the task was generally consistent with previous research with adults and older children. There were no group differences on the behavioral measures of cognitive control or response monitoring. Notably, however, group differences were observed on the electrophysiological measures of response monitoring. Specifically, the foster children who received services as usual were significantly less responsive to performance feedback about errors than the foster children who received the intervention and the nonmaltreated children. Applications of this methodology and implications of the results for future prevention research are discussed.


[Iniencephaly: four cases and a review of the literature].
Iniencephaly is a rare malformation of the base of the skull. The brain is involved and prognosis is almost invariably lethal. We identified 202 reports in the literature up through 2000. Ultrasound morphology explorations now provide the diagnosis making it possible to propose pregnancy termination. We report four cases of iniencephaly diagnosed between 1992 and 1999.


Changes in erythropoiesis assessed by reticulocyte parameters during ultralong distance running.
To investigate the possibility of early changes in erythropoiesis during prolonged exercise being reflected in reticulocyte parameters. This was a case-control field study of hematological variables in a group of ultramarathon runners competing in a 6-day track race. A 6-day ultramarathon in Colac, Australia. 7 male and 1 female experienced ultramarathon runners. A track race of 6 days' duration. A wide range of red cell and reticulocyte parameters. Resting red cell parameters were within normal clinical limits. However, except for the expected findings typical of hemodilution, red cell parameters were relatively unchanged during and after the event, with the exception of small but statistically significant changes in number and percentage of macrocytic, microcytic, hypochromic, and hyperchromic red cells. No reticulocytosis was found in an event that would have been expected to be associated with significant foot-strike hemolysis; however, an increase in the percentage of reticulocytes with high RNA content late in the event indicates early release from the marrow. Reduction in reticulocyte mean cell volume, which is consistent with functional iron deficiency, was demonstrated during the event. This finding is consistent with changes in some of the iron-related parameters associated with the acute phase response, but the dissociation in time between these changes makes a causal relationship unlikely. Other changes such as those in reticulocyte hemoglobin distribution width, reticulocyte distribution width, cell hemoglobin concentration mean, and lack of change in corpuscular hemoglobin are not typical of true iron deficiency, and the mechanism of these changes is currently unknown. The hematopoietic system demonstrates remarkable stability in the face of very significant exercise stress. No reticulocyte response was demonstrated in this study, but reticulocyte changes both consistent with and contrary to early release from the marrow were demonstrated after several days of strenuous running. The significance of several newly developed ratios of red cell and reticulocyte parameters in conditions of exercise stress requires further investigation.


Impact of Diabetes on Extracellular Volume Status in Patients Initiating Peritoneal Dialysis.
Recent reports have highlighted that diabetic patients with kidney failure are at increased risk of technique failure and transfer to haemodialysis within 90 days of initiating peritoneal dialysis (PD). We wished to determine whether there were differences between diabetic and non-diabetic patients within the first 3 months of starting PD. We reviewed results of corresponding bioimpedance and the 1st test of peritoneal membrane function (PET) in consecutive patients, 6-10 weeks after initiating PD electively. Adult patients numbering 386 - 230 males (59.6%), 152 (39.4%) diabetic, 188 (48.7%) white, mean age 57.3 ±16.9 years - were studied. Although weight, residual renal function and peritoneal clearances were not different, diabetic patients had greater extracellular water to total body water (ECW/TBW; 40.4 ± 1.1 vs. 39.2 ± 1.4) and % ECW excess (9.6 [6.3-12.3] vs. 4.9 [0.7-8.9]), lower serum albumin (35.2 ± 4.7 vs. 37.8 ± 4.9 g/L), greater fat mass index (9.5 ± 4.2 vs. 7.7 ± 4.2), and although mean arterial blood pressure was similar, arterial pulse pressure was greater (66.9 ± 10.8 vs. 54.3 ± 17.3 mm Hg, all p < 0.001). On multivariate analysis, glycated haemoglobin was associated with pulse pressure (standardised β 0.24, p < 0.001), N terminal brain natriuretic peptide (β 0.24, p < 0.001), ECW/TBW (β 0.19, p = 0.012) and negatively with serum albumin (β -0.14, p = 0.033) and creatinine (β -0.18, p = 0.02). Diabetic patients electively starting PD were found to have greater ECW/TBW ratios and ECW excess 6-10 weeks after starting PD compared to non-diabetics, despite similar PET. Increased ECW could predispose diabetic patients to be at greater risk of volume overload.


Observation of ballistic avalanche phenomena in nanoscale vertical InSe/BP heterostructures.
Impact ionization, which supports carrier multiplication, is promising for applications in single photon detection1 and sharp threshold swing field effect devices2. However, initiating the impact ionization of avalanche breakdown requires a high applied electric field in a long active region, which hampers carrier multiplication with a high gain, low bias and superior noise performance3,4. Here we report the observation of ballistic avalanche phenomena in sub-mean free path (MFP) scaled vertical InSe/black phosphorus (BP)5-9 heterostructures10. We use these heterojunctions to fabricate avalanche photodetectors (APDs) with a sensitive mid-infrared light detection (4 μm wavelength) and impact ionization transistors with a steep subthreshold swing (<0.25 mV dec-1). The devices show a low avalanche threshold (<1 V), low noise figure and distinctive density spectral shape. Our transport measurements suggest that the breakdown originates from a ballistic avalanche phenomenon, where the sub-MFP BP channel support the lattice impact ionization by electrons and holes and the abrupt current amplification without scattering from the obstacles in a deterministic nature. Our results provide new strategies for the development of advanced photodetectors1,11,12 via efficient carrier manipulation at the nanoscale.


A library of 3-aryl-4,5-dihydroisoxazole-5-carboxamides.
Parallel solution phase methods for the preparation of a 72-membered 3-aryl-4,5-dihydroisoxazole-5-carboxamide library is reported. The reaction order (nitrile oxide 1,3-dipolar cycloaddition followed by amide formation, or vice versa) was investigated both experimentally and computationally to determine which route would result in the highest yields, minimize purification efforts, and give higher 1,3-dipolar cycloaddition regioselectivity. Automated preparative HPLC was used to purify the final products to >or=90% purity on a 10+ mg scale.


Leveraging nonlinear dynamic models to predict progression of neuroimaging biomarkers.
Using biomarkers to model disease course effectively and make early prediction is a challenging but critical path to improving diagnostic accuracy and designing preventive trials for neurological disorders. Leveraging the domain knowledge that certain neuroimaging biomarkers may reflect the disease pathology, we propose a model inspired by the neural mass model from cognitive neuroscience to jointly model nonlinear dynamic trajectories of the biomarkers. Under a nonlinear mixed-effects model framework, we introduce subject- and biomarker-specific random inflection points to characterize the critical time of underlying disease progression as reflected in the biomarkers. A latent liability score is shared across biomarkers to pool information. Our model allows assessing how the underlying disease progression will affect the trajectories of the biomarkers, and, thus, is potentially useful for individual disease management or preventive therapeutics. We propose an EM algorithm for maximum likelihood estimation, where in the E step, a normal approximation is used to facilitate numerical integration. We perform extensive simulation studies and apply the method to analyze data from a large multisite natural history study of Huntington's Disease (HD). The results show that some neuroimaging biomarker inflection points are early signs of the HD onset. Finally, we develop an online tool to provide the individual prediction of the biomarker trajectories given the medical history and baseline measurements.


Whole-Genome Sequence Analysis of Antimicrobial Resistance Genes in Streptococcus uberis and Streptococcus dysgalactiae Isolates from Canadian Dairy Herds.
The objectives of this study are to determine the occurrence of antimicrobial resistance (AMR) genes using whole-genome sequence (WGS) of Streptococcus uberis (S. uberis) and Streptococcus dysgalactiae (S. dysgalactiae) isolates, recovered from dairy cows in the Canadian Maritime Provinces. A secondary objective included the exploration of the association between phenotypic AMR and the genomic characteristics (genome size, guanine-cytosine content, and occurrence of unique gene sequences). Initially, 91 isolates were sequenced, and of these isolates, 89 were assembled. Furthermore, 16 isolates were excluded due to larger than expected genomic sizes (>2.3 bp × 1,000 bp). In the final analysis, 73 were used with complete WGS and minimum inhibitory concentration records, which were part of the previous phenotypic AMR study, representing 18 dairy herds from the Maritime region of Canada (1). A total of 23 unique AMR gene sequences were found in the bacterial genomes, with a mean number of 8.1 (minimum: 5; maximum: 13) per genome. Overall, there were 10 AMR genes [ANT(6), TEM-127, TEM-163, TEM-89, TEM-95, Linb, Lnub, Ermb, Ermc, and TetS] present only in S. uberis genomes and 2 genes unique (EF-TU and TEM-71) to the S. dysgalactiae genomes; 11 AMR genes [APH(3'), TEM-1, TEM-136, TEM-157, TEM-47, TetM, bl2b, gyrA, parE, phoP, and rpoB] were found in both bacterial species. Two-way tabulations showed association between the phenotypic susceptibility to lincosamides and the presence of linB (P = 0.002) and lnuB (P < 0.001) genes and the between the presence of tetM (P = 0.015) and tetS (P = 0.064) genes and phenotypic resistance to tetracyclines only for the S. uberis isolates. The logistic model showed that the odds of resistance (to any of the phenotypically tested antimicrobials) was 4.35 times higher when there were >11 AMR genes present in the genome, compared with <7 AMR genes (P < 0.001). The odds of resistance was lower for S. dysgalactiae than S. uberis (P = 0.031). When the within-herd somatic cell count was >250,000 cells/mL, a trend toward higher odds of resistance compared with the baseline category of <150,000 cells/mL was observed. When the isolate corresponded to a post-mastitis sample, there were lower odds of resistance when compared with non-clinical isolates (P = 0.01). The results of this study showed the strength of associations between phenotypic AMR resistance of both mastitis pathogens and their genotypic resistome and other epidemiological characteristics.


Individual Traits, Personal Values, and Conflict Resolution in an Isolated, Confined, Extreme Environment.
The study of personality traits, personal values, and the emergence of conflicts within groups performing in an isolated, confined, and extreme environment (ICE) may provide insights helpful for the composition and support of space crews for long duration missions. Studied pre/post and over the 2-yr period of the investigation were 10 Danish military personnel deployed to stations in Greenland on a 26-mo staggered rotation. Subjects completed the NEO PI-R, Triarchic Psychopathy Measure, and Portrait Values Questionnaire, and participated in structured interviews. During deployment, questionnaires were completed biweekly and a cognitive function test once a month. Personality findings indicated a generally well-adjusted group, above average in positive personality traits [Conscientiousness T-score = 59.4 (11.41); Agreeableness T-score = 54.4 (9.36)] and boldness. Personal values of benevolence and self-direction were highly rated. The decision when to "pick sides" and intervene during disagreements between group members was viewed as an important component of conflict resolution. There were no changes in positive/negative affect or cognitive function over the annual light/dark cycle. The personal values of group members appear highly compatible for living in a small group ICE environment for an extended period. Disagreements between group members impact the functioning of the entire group, particularly in regard to decisions whether to support one of the individuals or let the argument run its course. Extended training in strategies for conflict resolution are needed in planning for future long duration missions to avoid fault lines forming within the group.Corneliussen JG, Leon GR, Kjærgaard A, Fink BA, Venables NC. Individual traits, personal values, and conflict resolution in an isolated, confined, extreme environment. Aerosp Med Hum Perform. 2017; 88(6):535-543.


Quantitative assessment of mast cells in recurrent aphthous ulcers (RAU).
Previous studies on the frequency of mast cells (MCs) in recurrent aphthous ulcers (RAU) have yielded conflicting results. Monoclonal antibodies specific for tryptase (AA1) and anti-IgE (polyclonal antibody) were used to identify density and distribution of MCs in an immunohistochemical study of RAU (n=15), induced oral traumatic ulcers (TUs) (n=9), and control clinically healthy oral mucosa (n=15). Results were quantified by means of a VIDAS image analyzer. In all sections studied, IgE-positive cells showed similar frequency and distribution to tryptase-positive MCs. In RAU lesions, numerous tryptase-positive MCs were found in the sub-epithelial lamina propria, but MC numbers in the epithelium were low and present only in some RAU biopsies. MCs were also more numerous in RAU-inflammatory infiltrates (118+/-31 cells/mm2) than those seen in TU-inflammatory infiltrates (75+/-18 cells/mm2, P<0.001). MC activation/degranulation, as judged by diffuse extracellular tryptase staining, was a common feature within RAU-inflammatory infiltrates and at RAU-inflammatory infiltrates-connective tissue interfaces, which were often associated with connective tissue disruption. MC counts in the RAU connective tissue, lateral to the inflammatory infiltrates, were significantly greater than in the connective tissue of TUs and of control biopsies (124+/-36 vs 73+/-13 vs 69+/-21 cells/mm2, respectively; P<0.001). Overall, MCs were significantly increased in aphthae (116+/-26 cells/mm2) compared with TU lesions (72+/-11 cells/mm2, P<0.001) and controls (71+/-16 cells/mm2, P<0.001). In conclusion, MC numbers are increased in a typical topographical pattern, and the local MCs show signs of activation/degranulation suggesting active involvement of this cell type in RAU pathogenesis.


Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex.
A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q(o) site inhibitors of the cytochrome bc(1) complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K(i) = 881.80 nM, porcine bc(1)), the most potent compound 4f displayed 20 507-fold improved binding affinity (K(i) = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K(i) = 83.00 pM) bound to the chicken bc(1) at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques.


Hemofiltration and inflammatory mediators.
Hemofiltration used in conjunction with cardiac surgery and cardiopulmonary bypass (CPB) was first reported in 1976. Since then, the technology has been routinely used in this context. This review attempts to restate the basic principles governing hemofiltration, the strategies or timing of the use of the technology, and the indications. Particular attention will be focused on the role of hemofiltration in an attempt to reduce the plasma levels of some of the mediators of the Systemic Inflammatory Response Syndrome (SIRS).


[Interactions between naltrexone, an opioid antagonist, and opioids administered during general anesthesia].
We report a case of a probable interaction between sufentanil and naltrexone, an oral long acting opioid antagonist, prescribed for maintenance of abstinence in alcoholics and opioid addicts. The interaction resulted in an antagonisation of the effects of sufentanil and the necessity to increase the dosage. Anaesthetists should be aware of this potential drug interaction.


Altered mechanisms of protein synthesis in frontal cortex in Alzheimer disease and a mouse model.
Expression of the nucleolar chaperones nucleolin (NCL) and nucleophosmin (NPM1), upstream binding transcription factor (UBTF), rRNA18S, rRNA28S, and several genes encoding ribosomal proteins (RPs) is decreased in frontal cortex area 8 at advanced stages of Alzheimer's disease (AD). This is accompanied by reduced protein levels of elongation factors eEF1A and eEF2. Changes are more marked in AD cases with rapid course (rpAD), as initiation factor eIF3η is significantly down-regulated and several RP genes up-regulated in rpAD when compared with typical AD. These changes contrast with those seen in APP/PS1 transgenic mice used as a model of AD-like β-amyloidopathy; Ncl mRNA, rRNA18S, rRNA28S and seven out of fifteen assessed RP genes are up-regulated in APP/PS1 mice aged 20 months; only eEF2 protein levels are reduced in transgenic mice. Our findings show marked altered expression of molecules linked to the protein synthesis machinery from the nucleolus to the ribosome in frontal cortex at terminal stages of AD which differs from that seen in APP/PS1 transgenic mice, thus further suggesting that molecular signals in mouse models do not apply to real human disease counterparts.


Informed consent for chiropractic care: Comparing patients' perceptions to the legal perspective.
This study explored chiropractic patients' perceptions of exchanging risk information during informed consent and compared them with the legal perspective of the informed consent process. Interviews were conducted with 26 participants, recruited from chiropractic clinics. Transcripts were analysed using a constant comparative method of analysis. Participants experienced informed consent as an on-going process where risk information informed their decisions to receive treatment throughout four distinct stages. In the first stage, information acquired prior to arriving at the clinic for treatment shaped perceptions of risk. In stage two, participants assessed the perceived competence of their practitioners. Participants then signed the consent form and discussed the risks with their practitioners. Finally, they communicated with their practitioners during treatment to ensure their pain threshold was not crossed. These findings suggest that chiropractic patients perceive informed consent as a process involving communication with their practitioners, and that it is possible to educate patients about the risks associated with treatment while satisfying the legal requirements of informed consent.


Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study.
Creatine (Cr) is recommended as a dietary supplement especially for athletes but its therapeutic potential is also discussed. It is assumed that human body uses Cr for the formation of phosphocreatine, which is necessary for muscular work as a source of energy. Production of Cr in a body is closely connected to methionine cycle where guanidinoacetate (GAA) is in a final step methylated from S-adenosylmethionine (SAM). Increased availability of SAM for phosphatidylcholine (PC) and sarcosine synthesis can potentially stimulate endogenous production of betaine a thus methylation of homocysteine (HCy) to form methionine. Our subject who was methylenetetrahydrofolate reductase (MTHFR) 677TT homozygote lowered plasma HCy from 33.3 micromol/l to 17.1 micromol/l following one-month Cr supplementation (5 g/day) opposite to 677CC and CT genotypes whose HCy levels tended to increase (but still in normal ranges). We suppose that Cr supplementation stimulates pathways leading to production of sarcosine which can serve to regenerate tetrahydrofolate (THF) to form 5,10-methylene-THF. This could potentially increase MTHFR enzyme activity which may later result in increased HCy methylation. Cr supplementation significantly effects metabolism of one carbon unit and potentially lower body´s demands for methyl groups. This could be beneficial as in the case of reduced enzyme activity such as MTHFR 677C/T polymorphism.


The Emerging Role of Tyrosine Kinase Inhibitors in Ovarian Cancer Treatment: A Systematic Review.
The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs) in ovarian cancer patients. Phase II and III clinical trials were sought in the PubMed database and in the Clinical Trials.gov registry through September 30, 2015. Seventy-five clinical trials regarding TKIs targeting mainly vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and sarcoma tyrosine kinase (Src) were yielded. The most promising results were noted with cediranib, nintedanib, and pazopanib. However, drawing universal conclusions about the potential integration of TKIs in ovarian cancer therapy remains elusive. Furthermore, emerging challenges and directions for the future research are critically discussed.


Siblings of individuals with first-episode psychosis: understanding their experiences and needs.
The growth of early intervention in psychosis services (EIPS) has prompted needed research to provide a robust evidence base to underpin practice. The typical service model embraces key psychosocial interventions, including family interventions. A literature review revealed a number of relevant studies that recognized the role of siblings in families affected by severe mental illness or mental impairment, but little was found about the impact of first-episode psychosis on siblings. To address this apparent oversight, we conducted a study to gain an understanding of sibling experiences. Ten siblings (ages 16 to 30) with a brother or sister diagnosed with first-episode psychosis took part in individual semi-structured interviews. The key findings were grouped in regard to emotional impact, relationships in the family, and siblings' roles and coping patterns. The study also revealed that families are able to identify positive gains out of a fundamentally negative experience.


Hormonal therapy (hCG and rhFSH) for infertile men with adult-onset idiopathic hypogonadotropic hypogonadism.
Adult-onset idiopathic male hypogonadotropic hypogonadism (IMHH) is a very rare but treatable disease. This study was conducted to examine the efficacy and safety of a combination of human chorionic gonadotropin (hCG) and recombinant human follicle-stimulating hormone (rhFSH) for inducing spermatogenesis in men with adult-onset IMHH. Seven men (34-45 years of age) with azoospermia and/or sexual dysfunction, with a low serum testosterone concentration, and apulsatile secretion of luteinizing hormone, were referred to our hospital for infertility. All had normal secondary sexual characteristics. Thorough endocrinologic examination and magnetic resonance imaging revealed no identifiable cause of hypogonadotropic hypogonadism. Adult-onset IMHH was diagnosed in all cases and treatment was started with 150 IU rhFSH and 5,000 IU hCG, both administered two times per week. Spermatogenesis was restored in five of the seven patients. During treatment one patient achieved spontaneous pregnancy with his wife, and spermatozoa recovered from the other four patients were frozen for future use in intracytoplasmic sperm injection.


Eomesodermin-expressing T-helper cells are essential for chronic neuroinflammation.
Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4(+) T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes(+) CD4(+) T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes(+) CD4(+) T cells.


Pressure pain mapping of the wrist extensors after repeated eccentric exercise at high intensity.
The purpose of this study was to investigate adaptation mechanisms after 2 test rounds consisting of eccentric exercise using pressure pain imaging of the wrist extensors. Pressure pain thresholds (PPTs) were assessed over 12 points forming a 3 × 4 matrix over the dominant elbow in 12 participants. From the PPT assessments, pressure pain maps were computed. Delayed onset muscle soreness was induced in an initial test round of high-intensity eccentric exercise. The second test round performed 7 days later aimed at resulting in adaptation. The PPTs were assessed before, immediately after, and 24 hours after the 2 test rounds of eccentric exercise. For the first test round, the mean PPT was significantly lower 24 hours after exercise compared with before exercise (389.5 ± 64.1 vs. 500.5 ± 66.4 kPa, respectively; p = 0.02). For the second test round, the PPT was similar before and 24 hours after (447.7 ± 51.3 vs. 458.0 ± 73.1 kPa, respectively; p = 1.0). This study demonstrated adaptive effects of the wrist extensors monitored by pain imaging technique in healthy untrained humans. A lack of hyperalgesia, i.e., no decrease in PPT underlined adaptation after the second test round of eccentric exercise performed 7 days after the initial test round. The present findings showed for the first time that repeated eccentric exercise performed twice over 2 weeks protects the wrist extensor muscles from developing exacerbated pressure pain sensitivity. Thus, the addition of eccentric components to training regimens should be considered to induce protective adaptation.


An expanded developmental line for negation: rejection, refusal, denial.
Freud's 1925 paper on negation provides the foundation for exploring an expanded developmental line of negation. Incorporating evidence from child language studies and explanations from the philosophy of language, this paper describes three types of negation that emerge in a developmental sequence: rejection, refusal, and denial. Clinical examples illustrate each type of negation, demonstrating how it might appear in clinical interactions. Along the way, confusions in terminology (due partly to translation problems) and questions for developmental theory are discussed. An expanded developmental line of negation provides additional interpretive perspectives on the forms of defense that Freud was addressing in "Negation" (1925) and subsequent papers (1927, 1940a,b).


Communication resources of managers and business professionals.
To analyze the communication resources reported by managers in the business environment and compare the resources used to those reported by business professionals. 82 professionals volunteered to participate in the research, divided into 50 managers (MP) and 32 business professionals (BP) from industry section in Caxias do Sul and the surrounding region (Brazil). A questionnaire with 4 topics was used: personal data, self-assessment of communicative behavior, self-assessment of communicative resources, and selection of positive and negative resources influencing communication. Regarding communicative behavior, both groups reported normal voice but with significant differences regarding the use of softness in communication, 25% of MP and only 4% of BP. Both groups selected the following main positive resources: knowledge of subject, use of proper vocabulary, and objectivity. The negative resources were, similarly, the lack of subject domain, criticism or prejudgment, and improper vocabulary. Finally, analyzing the degree of influence of each communicative resource, the MP highlighted tone of voice as an important positive resource, while the BP pointed the subject domain. Still, the monotonous voice for MP and nervousness for BP were indicated as the main negative influences. Managers value more communicative resources connected to communicative attitude, such as tone of voice and expression, while business professionals worry about demonstrating security and technical understanding of the subject.


[Identification of a protein interacting with apoptin from human leucocyte cDNA library by using yeast two-hybrid screening].
To screen the protein interacting with apoptin from human leucocyte cDNA library by using yeast two-hybrid system, four clones interacting with apoptin were identified. One of them was homologous with Nmi (N-Myc interaction protein). Cell co-immunoprecipitation showed that apoptin could bind to Nmi in mammalian cells. Apoptin mutants T1, T2 and T3 lacked the C-terminal 11 AA,33-46 AA and both,respectively. Apoptin mutants T2 and T3 failed to interact with Nmi, suggesting that its 33-46 AA was pivotal for the interaction. Apoptin mutant T1 still interacted with Nmi, suggesting that its C-terminal 11 AA was not essential for the interaction.


Safety and feasibility of short course pre-operative radiation therapy followed by surgical excision for canine solid tumours.
Surgical resection of solid tumours, especially in early stages of disease, remains a cornerstone of cancer treatment in dogs and cats. There are numerous publications that show a strong association between local tumour control and outcome. To achieve local control in some cases radiation therapy and surgery are combined, with radiation therapy being delivered in the neoadjuvant or adjuvant setting. The objective of the study was to report acute toxicity and surgical site complication data in dogs that received a short-course pre-operative (SCPO) radiation therapy protocol, followed by surgical excision for various solid tumours. Medical records were reviewed, and data was analysed retrospectively. Dogs were included if a dermal or subcutaneous solid tumour was treated with SCPO radiation therapy and then was resected on the last day of radiation or 2-3 weeks later. A total of 34 dogs with 35 primary tumours were included. Acute radiation toxicity was diagnosed in 14 sites (40%). VRTOG scores were grade 1 in 50%, grade 2 in 43%, and grade 3 in 7%. Surgical site complications were identified in 17% of dogs with an overall surgical site infection rate of 11%. According to the Clavien-Dindo classification, two dogs required medical intervention (grade 2), 1 dog required surgical intervention under general anaesthesia (grade 3b), and 1 dog died as a result of complications (grade 5). Logistic regression analysis found that anatomic site was significantly associated with complications, where tumours located on the extremity was protective (P = .02; OR 0.06).


Epidemiology of dermatophytoses in children living in northeast France: a 5-year study.
Dermatologic fungal infections are thought to occur less frequently in children than in adults. This study, performed over a 5-year period, emphasizes the interregional variability of dermatophytes that cause skin and cutaneous apprendageal diseases in children. In northeast France, two-thirds of dermatophytoses are due to zoophilic fungi, while they are most commonly caused by anthropophilic agents in the Paris region and in other countries. The clinical features of pediatric dermatophytoses vary with the age of the child: tinea capitis and tinea corporis are far more frequent before the age of 12 years. After the age of 12, even if these are still quite frequent, tinea pedis and onychomycosis become more common.


Dictionary Learning: A Novel Approach to Detecting Binary Black Holes in the Presence of Galactic Noise with LISA.
The noise produced by the inspiral of millions of white dwarf binaries in the Milky Way may pose a threat to one of the main goals of the space-based LISA mission: the detection of massive black hole binary mergers. We present a novel study for reconstruction of merger waveforms in the presence of Galactic confusion noise using dictionary learning. We discuss the limitations of untangling signals from binaries with total mass from 10^{2} M_{⊙} to 10^{4} M_{⊙}. Our method proves extremely successful for binaries with total mass greater than ∼3×10^{3} M_{⊙} up to redshift 3 in conservative scenarios, and up to redshift 7.5 in optimistic scenarios. In addition, consistently good waveform reconstruction of merger events is found if the signal-to-noise ratio is approximately 5 or greater.


Is spaceflight-induced immune dysfunction linked to systemic changes in metabolism?
The Space Shuttle Atlantis launched on its final mission (STS-135) on July 8, 2011. After just under 13 days, the shuttle landed safely at Kennedy Space Center (KSC) for the last time. Female C57BL/6J mice flew as part of the Commercial Biomedical Testing Module-3 (CBTM-3) payload. Ground controls were maintained at the KSC facility. Subsets of these mice were made available to investigators as part of NASA's Bio-specimen Sharing Program (BSP). Our group characterized cell phenotype distributions and phagocytic function in the spleen, catecholamine and corticosterone levels in the adrenal glands, and transcriptomics/metabolomics in the liver. Despite decreases in most splenic leukocyte subsets, there were increases in reactive oxygen species (ROS)-related activity. Although there were increases noted in corticosterone levels in both the adrenals and liver, there were no significant changes in catecholamine levels. Furthermore, functional analysis of gene expression and metabolomic profiles suggest that the functional changes are not due to oxidative or psychological stress. Despite changes in gene expression patterns indicative of increases in phagocytic activity (e.g. endocytosis and formation of peroxisomes), there was no corresponding increase in genes related to ROS metabolism. In contrast, there were increases in expression profiles related to fatty acid oxidation with decreases in glycolysis-related profiles. Given the clear link between immune function and metabolism in many ground-based diseases, we propose a similar link may be involved in spaceflight-induced decrements in immune and metabolic function.


Brief alteration of NMDA or GABAA receptor-mediated neurotransmission has long term effects on the developing cerebral cortex.
Neurotransmitter signaling is essential for physiologic brain development. Sedative and anticonvulsant agents that reduce neuronal excitability via antagonism at N-methyl-D-aspartate receptors (NMDARs) and/or agonism at gamma-aminobutyric acid subtype A receptors (GABA(A)Rs) are applied frequently in obstetric and pediatric medicine. We demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABA(A)R agonist phenobarbital not only has acute but also long term effects on the cerebral cortex. Changes of the cerebral cortex proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6 suggest that a suppression of synaptic neurotransmission during brain development dysregulates proteins associated with apoptosis, oxidative stress, inflammation, cell proliferation, and neuronal circuit formation. These effects appear to be age-dependent as most protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Previously performed histological evaluations of the brains revealed widespread apoptosis and decreased cell proliferation following such a drug treatment in infancy and are thus consistent with brain protein changes reported in this study. Our results point toward several pathways modulated by a reduction of neuronal excitability that might interfere with critical developmental events and thus affirm concerns about the impact of NMDAR- and/or GABA(A)R-modulating drugs on human brain development.


Dynamics of nitrogen retention at two feeding levels in gestating parity 2 and 3 sows.
Parity-2 ( = 39) and -3 ( = 28; same sows from parity-2 sows) Yorkshire sows were used to measure whole body protein deposition (Pd) during gestation (maternal and pregnancy-associated) at 2 feeding levels to test the hypothesis that the pattern of whole body and maternal Pd during gestation does not differ when feeding either 15% above or 15% below estimated ME requirements, both exceeding AA requirements. Initial BW and backfat (BF) at d 26 ± 0.3 of gestation were 195.4 ± 5.2 kg and 15.1 ± 0.5 mm, and 223.1 ± 5.3 kg and 16.0 ± 0.6 mm for parity-2 and -3, respectively. Sows were assigned to 1 of 2 feeding levels (high and low; 15% above and 15% below estimated ME requirements, respectively) of the same diet (3.30 Mcal ME/kg, 17.8% CP, 0.82% SID Lys) from d 31 to 110 of each gestation cycle. Five N balances were conducted throughout each gestation starting at d 36, 51, 65, 85, and 106 ± 0.5 during 4-d periods. Pregnancy-associated Pd was model-derived for each sow and N balance period using the gestating sow model, based on actual litter size (including stillborn) and mean piglet birth weight. Maternal Pd was calculated as the difference between whole body and pregnancy-associated Pd. Whole body Pd and maternal Pd were greater ( 0.002) for sows on the high feeding level. Whole body Pd increased ( 0.001) with day of gestation and maternal Pd did not differ with day of gestation. Whole body and maternal Pd were greater ( ≤ 0.004) for parity-3 sows from d 51 to 54 and 85 to 88 of gestation only. Estimated efficiency of Lys retention for whole body Pd was not different between the 2 feeding levels, greater ( 0.016) for parity-3 sows, and increased quadratically ( 0.027) with day of gestation. During lactation (21.3 ± 0.3 d), there was no effect on sow ADFI and minimal effect on litter performance due to gestation feeding level or parity. Sows on the high feeding level had greater ( 0.009) BW and BF loss during lactation and these parameters were not affected by parity. Feeding 15% above estimated ME requirements during gestation resulted in consistently greater whole body and maternal. Whole body and maternal Pd were particularly greater for parity-3 sows from d 51 to 54 and 85 to 88 of gestation. The pattern of maternal Pd, regardless of feeding level, was not affected by day of gestation and is in contrast to , where maternal Pd is expected to be greater in early gestation.


Microplate hybridization for Borna disease virus RNA in human peripheral blood mononuclear cells.
We developed a simple and sensitive microplate hybridization procedure with which to identify Borna disease virus cDNA in amplified products from human peripheral blood mononuclear cells. The mean values for the positive PCR products were significant compared with those for any of the negative products, indicating that this method can be applied to rapidly diagnose a large number of clinical specimens.


Knowledge of supplemental folic acid during pregnancy.
To identify the use of folic acid during pregnancy, as well as the new mothers´ knowledge about folic acid. Quantitative, descriptive exploratory, and prospective study. A total of 198 mothers were interviewed in the pediatric outpatient service of Hospital de Base Sao José do Rio Preto, Brazil. They have taken their children for neonatal screening and formally consented to participating in the study. The research project was approved by the Research Ethics Committee (350,287). A specific instrument was used for data collection. The data were entered into an appropriate spreadsheet and later statistically analyzed. Pearson´s chi-squared test, p <0.15, was used. On average, the interviewed mothers were 25 years old and received less than two minimum wages. Most had prenatal in the first quartile and a mean of seven appointments, starting the use of folic acid from the 7th to the 9th week of gestational age. However, when asked about the importance of folic acid and its action, almost the majority was not able to answer. Although daily acid supplementation is recommended in prenatal care, this study found that consumption is inadequate, contributing to the increased risk of fetal malformation. Healthcare professionals, especially nurses, should develop educational activities for women about the use of folic acid in the pre-gestation period and in the first pregnancy trimester.


Ultrastructure of ovarian follicles in in vitro perfused rabbit ovaries: response to human chorionic gonadotropin and comparison with in vivo observations.
Ovulation may be achieved and studied in an isolated perfused rabbit ovary upon inclusion of human chorionic gonadotropin (hCG) in the perfusion fluid. The ultrastructural features of the rabbit ovarian follicle prior to ovulation in vitro were compared with those in vivo. The perifollicular vasculature was also examined in in vitro perfused rabbit ovaries during the preovulatory interval. Granulosa cells of the preovulatory follicle share many ultrastructural features in vivo and in vitro; however, only small amounts of smooth endoplasmic reticulum (sER) were observed in granulosa cells in vitro after hCG. Ovulation after hCG in the in vitro preparation tends to occur earlier (6 hours) than in vivo (12 hours). Thus, there may be insufficient time and/or gonadotropin exposure to permit full functional development of granulosa cells, as reflected by reduced amounts of sER. Degradation of collagen fibrils was less prominent in the theca externa and tunica albuginea in vitro than in in vivo. Perifollicular capillaries became dilated after hCG, but interendothelial gaps were not observed. Disappearance of surface epithelium in the apex of follicles was similar in vitro and in vivo.


Regional three-dimensional deformation of human Achilles tendon during conditioning.
Our understanding of in vivo Achilles tendon (AT) conditioning is limited to two-dimensional ultrasound measures of longitudinal deformation of the whole tendon. This study investigated the regional three-dimensional (3D) deformation of the AT during conditioning. Eighteen ATs were scanned using 3D freehand ultrasound during 10 successive 25 s submaximal (50%) voluntary isometric plantarflexion contractions. Longitudinal strain was assessed for the whole AT, aponeurosis, and free AT and transverse strain was assessed for the proximal-, mid-, and distal-portions of the free AT. Longitudinal conditioning of the whole AT was primarily driven by creep response of the free AT and transverse conditioning was greatest for the mid-portion of the free AT. Whole and free AT longitudinal strain increased up to the third contraction and were accompanied by a corresponding reduction in free AT cross-sectional area (CSA) strain in proximal-, mid-, and distal-portions. No significant changes in aponeurosis strain or tendon volume were detected between contractions. These findings suggest that conditioning alters free AT shape, with increased tendon length attained at the expense of reduction in free AT CSA. Although AT experiences different amounts of strain in different regions, the number of contractions required to reach steady-state strain during conditioning is uniform throughout the tendon.


Interpreting microarray data: towards the complete bioinformatics toolkit for cancer.
Functional genomics has been applied in the study of human malignancies since the inception of this field nearly a decade ago. Microarray analysis has been specifically used in an attempt to re-classify carcinomas at the molecular level, to aid in diagnosis/prognosis and to predict how various types of tumour respond to different therapeutic agents. Bioinformatics is now at the forefront of the post-genomics era and is providing a number of tools with which to mine the large datasets produced by genome-wide analysis. Of particular importance is the emergence of techniques that give the ability to reveal the transcription regulatory networks that are active in the cell in response to environmental stimuli or disease states. Deciphering the transcription networks that function in malignant cells not only will provide the knowledge to understand how carcinomas progress, but would also allow the construction of useful therapeutic tools for their effective treatment. In this review the recent advances that have been made in functional genomics that allow microarray data to be more fully interpreted and reveal the transcription networks that have gone awry in transformed cells are described.


Conditional cash transfer schemes in Nigeria: potential gains for maternal and child health service uptake in a national pilot programme.
This paper describes use of a Conditional Cash Transfer (CCT) programme to encourage use of critical MNCH services among rural women in Nigeria. The CCT programme was first implemented as a pilot in 37 primary health care facilities (PHCs), in nine Nigerian states. The programme entitles women using these facilities up to N5,000 (approximately US$30) if they attend antenatal care (ANC), skilled delivery, and postnatal care. There are 88 other PHCs from these nine states included in this study, which implemented a standard package of supply upgrades without the CCT. Data on monthly service uptake throughout the continuum of care was collected at 124 facilities during quarterly monitoring visits. An interrupted time series using segmented linear regression was applied to estimate separately the effects of the CCT programme and supply package on service uptake. From April 2013-March 2014, 20,133 women enrolled in the CCT. Sixty-four percent of beneficiaries returned at least once after registration, and 80% of women delivering with skilled attendance returned after delivery. The CCT intervention is associated with a statistically significant increase in the monthly number of women attending four or more ANC visits (increase of 15.12 visits per 100,000 catchment population, p < 0.01; 95% confidence interval 7.38 to 22.85), despite a negative level effect immediately after the intervention began (-45.53/100,000 catchment population; p < 0.05; 95% CI -82.71 to -8.36). A statistically significant increase was also observed in the monthly number of women receiving two or more Tetanus toxoid doses during pregnancy (21.65/100,000 catchment population; p < 0.01; 95% CI 9.23 to 34.08). Changes for other outcomes with the CCT intervention (number of women attending first ANC visit; number of deliveries with skilled attendance; number of neonates receiving OPV at birth) were not found to be statistically significant. The results show that the CCT intervention is capable of significant effects on service uptake, although results for several outcomes of interest were inconclusive. Key lessons learnt from the pilot phase of implementation include a need to track beneficiary retention throughout the continuum of care as closely as possible, and avert loss to follow-up.


Physicians' satisfaction with clinical laboratory services at public hospitals in Ethiopia: A national survey.
Physician is a central figure in the client list of clinical laboratory. Monitoring physicians' satisfaction with laboratory service is an important indicator of the quality management system and required by international laboratory standards. However, there is no national data on physician satisfaction with laboratory services in Ethiopia. Therefore, the aim of this national survey was to assess satisfaction level of physicians with laboratory services at public hospitals in Ethiopia. Institutional based cross-sectional study design was employed from November 1-30/2017. A total of 327 physicians were randomly selected from 60 public hospitals from all regions of Ethiopia. Data was collected using pre-tested self-administered questionnaire and analyzed with SPSS version 23 software. Logistic regression model was fitted to identify predictors of physician satisfaction with laboratory services. A p-value of less than 0.05 was taken as statistically significant. Overall, 55% of physicians were satisfied with the clinical laboratory services. More than half of the physicians were satisfied with the existing laboratory request form (69%), legibility and completeness of laboratory report (61%), notification of new test (78%) and test interruption (70%). On the other hand, many physicians were dissatisfied with the absence of laboratory hand book (87.5%), the existing test menu (68%), lab-physician interface (62%), availability of referral and/or back up service (62%), notification of Turn Around Time (TAT) (54%), timely notification of panic result (55%), long TAT (33.1%), provision of urgent service (67%), and timely advisory service (57%). Most of the physicians perceived that consistent quality of service was not delivered at all working shifts (71%). At 5% level of significance, we did not find enough evidence to conclude that sex, age, marital status, education level, and experience were statistically associated with physician satisfaction (p-values > 0.05). This national survey revealed nearly half of the physicians were unsatisfied with laboratory service at public hospitals in Ethiopia, which mainly related to lack of adequate test menu, laboratory hand book, on time notification of panic result, provision of urgent service, timely advisory service, delivery of quality services in all working shifts and weak lab-physician interface. Therefore, hospital management should address the gaps and improve the needs of physicians for better patient health care. In addition, laboratories should evaluate and monitor physician satisfaction level at regular interval.


Microbial iron management mechanisms in extremely acidic environments: comparative genomics evidence for diversity and versatility.
Iron is an essential nutrient but can be toxic at high intracellular concentrations and organisms have evolved tightly regulated mechanisms for iron uptake and homeostasis. Information on iron management mechanisms is available for organisms living at circumneutral pH. However, very little is known about how acidophilic bacteria, especially those used for industrial copper bioleaching, cope with environmental iron loads that can be 1018 times the concentration found in pH neutral environments. This study was motivated by the need to fill this lacuna in knowledge. An understanding of how microorganisms thrive in acidic ecosystems with high iron loads requires a comprehensive investigation of the strategies to acquire iron and to coordinate this acquisition with utilization, storage and oxidation of iron through metal responsive regulation. In silico prediction of iron management genes and Fur regulation was carried out for three Acidithiobacilli: Acidithiobacillus ferrooxidans (iron and sulfur oxidizer) A. thiooxidans and A. caldus (sulfur oxidizers) that can live between pH 1 and pH 5 and for three strict iron oxidizers of the Leptospirillum genus that live at pH 1 or below. Acidithiobacilli have predicted FeoB-like Fe(II) and Nramp-like Fe(II)-Mn(II) transporters. They also have 14 different TonB dependent ferri-siderophore transporters of diverse siderophore affinity, although they do not produce classical siderophores. Instead they have predicted novel mechanisms for dicitrate synthesis and possibly also for phosphate-chelation mediated iron uptake. It is hypothesized that the unexpectedly large number and diversity of Fe(III)-uptake systems confers versatility to this group of acidophiles, especially in higher pH environments (pH 4-5) where soluble iron may not be abundant. In contrast, Leptospirilla have only a FtrI-Fet3P-like permease and three TonB dependent ferri-dicitrate siderophore systems. This paucity of iron uptake systems could reflect their obligatory occupation of extremely low pH environments where high concentrations of soluble iron may always be available and were oxidized sulfur species might not compromise iron speciation dynamics. Presence of bacterioferritin in the Acidithiobacilli, polyphosphate accumulation functions and variants of FieF-like diffusion facilitators in both Acidithiobacilli and Leptospirilla, indicate that they may remove or store iron under conditions of variable availability. In addition, the Fe(II)-oxidizing capacity of both A. ferrooxidans and Leptospirilla could itself be a way to evade iron stress imposed by readily available Fe(II) ions at low pH. Fur regulatory sites have been predicted for a number of gene clusters including iron related and non-iron related functions in both the Acidithiobacilli and Leptospirilla, laying the foundation for the future discovery of iron regulated and iron-phosphate coordinated regulatory control circuits. In silico analyses of the genomes of acidophilic bacteria are beginning to tease apart the mechanisms that mediate iron uptake and homeostasis in low pH environments. Initial models pinpoint significant differences in abundance and diversity of iron management mechanisms between Leptospirilla and Acidithiobacilli, and begin to reveal how these two groups respond to iron cycling and iron fluctuations in naturally acidic environments and in industrial operations. Niche partitions and ecological successions between acidophilic microorganisms may be partially explained by these observed differences. Models derived from these analyses pave the way for improved hypothesis testing and well directed experimental investigation. In addition, aspects of these models should challenge investigators to evaluate alternative iron management strategies in non-acidophilic model organisms.


Treatment gap and help-seeking for postpartum depression in a rural African setting.
Postpartum depression (PPD) affects more than one in ten women and is associated with adverse consequences for mother, child and family. Integrating mental health care into maternal health care platforms is proposed as a means of improving access to effective care and reducing the 'treatment gap' in low- and middle-income countries. This study aimed to determine the proportion of women with PPD who sought help form a health facility and the associated factors. A community based, cross-sectional survey was conducted in southern Ethiopia. A total of 3147 women who were between one and 12 months postpartum were screened for depressive symptoms in their home using a culturally validated version of the Patient Health Questionnaire (PHQ-9). Women scoring five or more (indicating potential depressive disorder) (n = 385) were interviewed regarding help-seeking behavior. Multiple logistic regression was used to identify factors associated independently with help-seeking from health services. Only 4.2 % of women (n = 16) with high PPD symptoms had obtained mental health care and only 12.7 % of women (n = 49) had been in contact with any health service since the onset of their symptoms. In the multivariable analysis, urban residence, adjusted odds ratio (aOR): 4.39 (95 % confidence interval (CI) 1.23, 15.68); strong social support, aOR: 2.44 (95 % CI 1.30, 4.56); perceived physical cause, aOR: 6.61 (95 % CI 1.76, 24.80); perceived higher severity aOR: 2.28 (95 % CI 1.41, 5.47); perceived need for treatment aOR: 1.46 (95 % CI 1.57, 18.99); PHQ score, aOR: 1.14 (95 % CI 1.04, 1.25); and disability, aOR: 1.06 (95 % CI 1.01, 1.15) were associated significantly with help-seeking from health services. More than half of the women with high levels of PPD symptoms (n = 231; 60.0 %) attributed their symptoms to a psychosocial cause and 269 (69.9 %) perceived a need for treatment. Equal proportions endorsed biomedical treatment and traditional or religious healing as the appropriate intervention. In the absence of an accessible maternal mental health service the treatment gap was very high. There is a need to create public awareness about PPD, its causes and consequences, and the need for help seeking. However, symptom attributions and help-seeking preferences indicate potential acceptability of interventions located in maternal health care services within primary care.


Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients?
Removing the primary tumor is indispensable for eliminating the major pool of metastasizing cells, but the surgical procedure itself is suspected of promoting metastases. This adverse effect is attributed to several mechanisms acting in synergy, including mechanical release of tumor cells, enhanced angiogenesis, secretion of growth factors, and immunosuppression. Here we provide new insights into mechanisms of postoperative immunosuppression and assess the assumptions underlying the hypothesis that, by suppressing cell-mediated immunity (CMI), surgery may render the patient vulnerable to metastases that otherwise could have been controlled. An extensive review of relevant articles in English identified by using the MEDLINE database and cross-referencing. Current literature suggests that (1) CMI can control minimal residual disease, especially if surgery is performed early; (2) major surgery transiently but markedly suppresses CMI through multiple mechanisms now better understood; (3) surgical stress promotes experimental metastasis through immunosuppression, but the clinical evidence remains indirect because of ethical limitations. Minimizing postoperative immunosuppression seems feasible, may limit recurrence, and should be introduced into the broader array of considerations when planning oncological surgeries. In the short run, physicians could try to avoid immunosuppressive anesthetic approaches, inadvertent hypothermia, excessive blood transfusions, and untended postoperative pain. When feasible, minimally invasive surgery should be considered. In the long run, clinical trials should evaluate prophylactic measures, including perioperative immunostimulation and several antagonists to cytokines and hormones specified herein.


[The Effect of a Movie-Based Nursing Intervention Program on Rehabilitation Motivation and Depression in Stroke Patients].
The aim of this study was to develop and measure the effect of a movie-based-nursing intervention program designed to enhance motivation for rehabilitation and reduce depression levels in stroke patients. The study used a quasi-experimental, nonequivalent control group and a pretest-posttest design. The 60 research subjects were assigned to the experimental (n=30) or control group (n=30). The moviebased nursing intervention program was provided for the experimental group during 60-minute sessions held once per week for 10 weeks. The program consisted of patient education to strengthen motivation for rehabilitation and reduce depression, watching movies to identify role models, and group discussion to facilitate therapeutic interaction. After 10 weeks of participation in the movie-based nursing intervention program, the experimental group's rehabilitation motivation score was significantly higher, F=1161.54 (within groups df=49, between groups df=1), p<.001, relative to that observed in the control group. In addition, the experimental group's depression score was significantly lower relative to that observed in the control group, F=258.97 (within groups df=49, between groups df=1), p<.001. The movie-based nursing intervention program could be used for stroke patients experiencing psychological difficulties including reduced motivation for rehabilitation and increased depression during the rehabilitation process.


[Drug therapy of bronchial asthma and chronic obstructive pulmonary disease: data of evidence-based medicine and real clinical practice].
The study was designed to estimate quantitative and qualitative characteristics of drug consumption for therapy of bronchial asthma and chronic obstructive pulmonary disease in outpatient and inpatient facilities. The frequency and intensity of the use of selected drugs are considered in terms of their conformity to principles of evidence-based medicine. Analysis of prescriptions revealed different degree of awareness of district physicians and other specialists about rational drug therapy. The drawbacks of the treatment of bronchial asthma and chronic obstructive pulmonary disease are first and foremost attributable to poor compliance with the existing standards and inefficient use of medications. It was shown that each outpatient and inpatient facility has its own policy of fund allocation for pharmacotherapy. The results of the study can be useful for rational organization of the treatment of patients with bronchial asthma and chronic obstructive pulmonary disease and for optimization of medical aid provision with a view to saving healthcare resources.


Reconstruction of electron spectra using singular component decomposition.
Reconstruction of electron spectra of medical accelerators from measured depth dose distributions is an attractive tool for commissioning of a Monte Carlo treatment planning system. However, the reconstruction method is an inverse radiation transport problem which is poorly conditioned, in the sense it may become unstable due to small perturbations in the input data. Predicting the sharp (delta-like) peak in the electron spectrum provides an additional challenge for the numerical reconstruction technique. To improve efficiency and robustness of the reconstruction technique, we developed an algorithm based on a separation of the electron spectrum into singular and regular components. We approximate the singular peak of the spectrum by a narrow weighted Gaussian function. The parameters of this Gaussian function are sought using only the fall-off and toe regions of the depth-dose curve. Analytical representation of the spectral peak by a Gaussian has benefit since only one weight and the mean and variance must be derived from the depth-dose curve instead of multiple spectra weights. The regular part of the spectrum is reconstructed from the residual depth-dose distribution using a variational method combined with a regularization technique to avoid the nonphysical oscillations. The effectiveness of the method is demonstrated by comparing predictions to "benchmark" spectra and depth-dose distributions from Monte Carlo simulation of medical accelerators.


A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells.
Expression of neuropeptide calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancers (PCs) and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. Specific, cell-permeable inhibitors of protein kinase A abolish CTR-stimulated invasion of PC cells. Since PKA is ubiquitously distributed in cells, the present study examined the mechanism(s) by which CTR-stimulated PKA activity is regulated in time and space. CT reduced cell adhesion but increased invasion of PC cells. Both these actions were abolished by st-Ht31 inhibitory peptide suggesting the involvement of an A-kinase anchoring protein (AKAP) in CT action. Next, we identified the AKAP associated with CT action by the subtraction of potential AKAP candidates using siRNAs. Knock-down of membrane-associated AKAP2, but not other AKAPs, abolished CT-stimulated invasion. Stable knock-down of AKAP2 in PC3-CTR cells remarkably decreased their cell proliferation, invasion, clonogenicity and ability to form orthotopic tumors and distant metastases in nude mice. Re-expression of AKAP2-wt restored these characteristics. Primary PC specimens displayed remarkable upregulation of CTR/AKAP2 expression as compared to benign prostates. Metastatic cancers displayed significantly higher CTR/AKAP2 expression than localized cancers. These results for the first time demonstrate that AKAP2 is expressed in human prostates, its expression is elevated in metastatic prostate cancer, and the knock-down of its expression remarkably decreased tumorigenicity and metastatic ability of prostate cancer cells. AKAP2 may serve as a critical component of CTR-mediated oncogenic actions.