The MALVA (MAntova LongeVA) study: an investigation on people 98 years of age and over in a province of Northern Italy.
The MALVA (MAntova LongeVA) study aims at investigating the socio-demographic, clinical and genetic characteristics of all subjects over 98 years of age residing in the province of Mantova (Northern Italy). In this paper we present the study protocol and the main demographic results. Absolute number, prevalence ratio and female/male ratio of the subjects aged 98+ and of the centenarians in the Mantova province (370,645 inhabitants at 31st December 1997) were checked at the baseline of the study (31st March 1998) as well as in the two years preceding and following the study. A total of 117 subjects aged 98+ (including 39 centenarians) were traced at 31st March 1998; the prevalence ratio was 31.6 per 100000 (12.1 for centenarians), and the female/male ratio was 6.3 (6.5 for centenarians). The distribution of the oldest old according to places of birth and residence was non-homogeneous across the provincial territory. Seventy-seven subjects (66% of the identified subjects) were enrolled in the study and administered a protocol including an interview about socio-economic conditions, lifetime habits and pathological and pharmacological case histories, as well as medical examination, performance-based tests and blood sample collection. Data on the socio-demographic characteristics and the health status of very old people in the province of Mantova are discussed and compared to findings from previous studies on Italian centenarians.


The effect of Polbax extract on lipofuscin accumulation in cultured neonatal rat cardiac myocytes.
Polbax, a water-soluble extract of fresh pollen grains and pistils, was tested for its ability to influence the accumulation of lipofuscin (age pigment) in cultured neonatal rat cardiac myocytes. Exposure for 3 weeks to Polbax at concentrations of 0.1, 1.0 or 10 mg/L decreased lipofuscin accumulation morphometrically assayed using laser scanning microscopy images (green excitation light) of formaldehyde-fixed cells, by 24%, 41% or 43%, respectively. Based on the knowledge that oxidative stress and iron-catalysed peroxidation play an important role in lipofuscinogenesis, we suggest that Polbax may slow lipofuscin formation due to antioxidant activities, perhaps involving intralysosomal dismutation of superoxide produced by autophagocytosed mitochondria and/or iron-chelation.


Improvement of Medication Guidance Sheet for Total Body Irradiation/Cyclophosphamide Followed by Allogeneic Hematopoietic Stem Cell Transplantation Based on Real Monitoring Data.
Adverse events (AEs) must be managed during cancer therapy. We had previously developed a medication guidance sheet (MGS) to monitor AEs after conditioning therapy with allogeneic hematopoietic stem cell transplantation (HSCT). However, it remains unclear whether this sheet can accurately predict the type, onset, and duration of AEs in clinical practice. In this study, we evaluated the clinical utility of the original MGS in patients receiving total body irradiation (TBI) and cyclophosphamide (CY). Fifty-eight patients who underwent TBI/CY were included. The types, onsets, and durations of AEs observed during real monitoring were compared with those listed in the original MGS. A total of 361 subjective AE symptoms were observed, all of which were predictive, as listed in the MGS. However, the durations of several AEs were longer than expected. Thus, the prediction accuracy for all AEs was 67.0%. The accuracy rate was the lowest for anorexia (6.7%), followed by diarrhea (42.6%), and nausea/vomiting (55.6%). Acute graft versus host disease (GVHD) most likely caused the prolongation of AEs. Subsequently, the original MGS was revised to account for the possible occurrence of acute GVHD. When monitoring AEs in patients receiving a TBI/CY conditioning regimen for HSCT, the involvement of acute GVHD-associated AEs should be considered. In this respect, the present modified MGS is particularly useful for rapid and accurate monitoring of AEs.


The answer is 17 years, what is the question: understanding time lags in translational research.
This study aimed to review the literature describing and quantifying time lags in the health research translation process. Papers were included in the review if they quantified time lags in the development of health interventions. The study identified 23 papers. Few were comparable as different studies use different measures, of different things, at different time points. We concluded that the current state of knowledge of time lags is of limited use to those responsible for R&D and knowledge transfer who face difficulties in knowing what they should or can do to reduce time lags. This effectively 'blindfolds' investment decisions and risks wasting effort. The study concludes that understanding lags first requires agreeing models, definitions and measures, which can be applied in practice. A second task would be to develop a process by which to gather these data.


Pharmacokinetics of culture-directed antibiotics for the treatment of peritonitis in automated peritoneal dialysis: A systematic narrative review.
The objectives of this study were to provide a summary of the pharmacokinetic data of some intraperitoneal (IP) antibiotics that could be used for both empirical and culture-directed therapy, as per the ISPD recommendations, and examine factors to consider when using IP antibiotics for the management of automated peritoneal dialysis (APD)-associated peritonitis. A literature search of PubMed, EMBASE, Scopus, MEDLINE and Google Scholar for articles published between 1998 and 2020 was conducted. To be eligible, articles had to describe the use of antibiotics via the IP route in adult patients ≥18 years old on APD in the context of pharmacokinetic studies or case reports/series. Articles describing the use of IP antibiotics that had been recently reviewed (cefazolin, vancomycin, gentamicin and ceftazidime) or administered for non-APD-associated peritonitis were excluded. A total of 1119 articles were identified, of which 983 abstracts were screened. Seventy-three full-text articles were assessed for eligibility. Eight records were included in the final study. Three reports had pharmacokinetic data in patients on APD without peritonitis. Each of cefepime 15 mg/kg IP, meropenem 0.5 g IP and fosfomycin 4 g IP given in single doses achieved drug plasma concentrations above the minimum inhibitory concentration for treating the susceptible organisms. The remaining five records were case series or reports in patients on APD with peritonitis. While pharmacokinetic data support intermittent cefepime 15 mg/kg IP daily, only meropenem 0.5 g IP and fosfomycin 4 g IP are likely to be effective if given in APD exchanges with dwell times of 15 h. Higher doses may be required in APD with shorter dwell times. Information on therapeutic efficacy was derived from case reports/series in individual patients and without therapeutic drug monitoring. Until more pharmacokinetic data are available on these antibiotics, it would be prudent to shift patients who develop peritonitis on APD to continuous ambulatory peritoneal dialysis, where pharmacokinetic information is more readily available.


Planning security architecture for health survey data storage and access.
Sensitive data from health research surveys need to be protected from loss, damage or unwanted release, especially when data include personally identifying information, protected health information or other private material. Researchers and practitioners must ensure privacy and confidentiality in the architecture of data systems and in access to the data. Internal and external risks may be deliberate or accidental, involving unintended loss, modification or exposure. To prevent risk while allowing access requires balancing concerns against providing an environment that does not impede work. The authors' purpose in this paper is to draw attention to basic data security needs for health survey data from the perspective of both the health researcher/practitioner and infrastructure/programming staff to ensure that data are securely and adequately protected. We describe risk classifications and how they affect system architecture, drawing on recent experience with systems for storage of and access to electronic health survey data.


Association of light-to-moderate alcohol drinking in pregnancy with preterm birth and birth weight: elucidating bias by pooling data from nine European cohorts.
Women who drink light-to-moderately during pregnancy have been observed to have lower risk of unfavourable pregnancy outcomes than abstainers. This has been suggested to be a result of bias. In a pooled sample, including 193 747 live-born singletons from nine European cohorts, we examined the associations between light-to-moderate drinking and preterm birth, birth weight, and small-for-gestational age in term born children (term SGA). To address potential sources of bias, we compared the associations from the total sample with a sub-sample restricted to first-time pregnant women who conceived within six months of trying, and examined whether the associations varied across calendar time. In the total sample, drinking up to around six drinks per week as compared to abstaining was associated with lower risk of preterm birth, whereas no significant associations were found for birth weight or term SGA. Drinking six or more drinks per week was associated with lower birth weight and higher risk of term SGA, but no increased risk of preterm birth. The analyses restricted to women without reproductive experience revealed similar results. Before 2000 approximately half of pregnant women drank alcohol. This decreased to 39% in 2000-2004, and 14% in 2005-2011. Before 2000, every additional drink was associated with reduced mean birth weight, whereas in 2005-2011, the mean birth weight increased with increasing intake. The period-specific associations between low-to-moderate drinking and birth weight, which also were observed for term SGA, are indicative of bias. It is impossible to distinguish if the bias is attributable to unmeasured confounding, which change over time or cohort heterogeneity.


Macroscopic stiffening of embryonic tissues via microtubules, RhoGEF and the assembly of contractile bundles of actomyosin.
During morphogenesis, forces generated by cells are coordinated and channeled by the viscoelastic properties of the embryo. Microtubules and F-actin are considered to be two of the most important structural elements within living cells accounting for both force production and mechanical stiffness. In this paper, we investigate the contribution of microtubules to the stiffness of converging and extending dorsal tissues in Xenopus laevis embryos using cell biological, biophysical and embryological techniques. Surprisingly, we discovered that depolymerizing microtubules stiffens embryonic tissues by three- to fourfold. We attribute tissue stiffening to Xlfc, a previously identified RhoGEF, which binds microtubules and regulates the actomyosin cytoskeleton. Combining drug treatments and Xlfc activation and knockdown lead us to the conclusion that mechanical properties of tissues such as viscoelasticity can be regulated through RhoGTPase pathways and rule out a direct contribution of microtubules to tissue stiffness in the frog embryo. We can rescue nocodazole-induced stiffening with drugs that reduce actomyosin contractility and can partially rescue morphogenetic defects that affect stiffened embryos. We support these conclusions with a multi-scale analysis of cytoskeletal dynamics, tissue-scale traction and measurements of tissue stiffness to separate the role of microtubules from RhoGEF activation. These findings suggest a re-evaluation of the effects of nocodazole and increased focus on the role of Rho family GTPases as regulators of the mechanical properties of cells and their mechanical interactions with surrounding tissues.


Benthic Diatom Communities in an Alpine River Impacted by Waste Water Treatment Effluents as Revealed Using DNA Metabarcoding.
Freshwater ecosystems are continuously affected by anthropogenic pressure. One of the main sources of contamination comes from wastewater treatment plant (WWTP) effluents that contain wide range of micro- and macropollutants. Chemical composition, toxicity levels and impact of treated effluents (TEs) on the recipient aquatic ecosystems may strongly differ depending on the wastewater origin. Compared to urban TEs, hospital ones may contain more active pharmaceutical substances. Benthic diatoms are relevant ecological indicators because of their high species and ecological diversity and rapid response to human pressure. They are routinely used for water quality monitoring. However, there is a knowledge gap on diatom communities' development and behavior in treated wastewater in relation to prevailing micro- and macropollutants. In this study, we aim to (1) investigate the response of diatom communities to urban and hospital TEs, and (2) evaluate TEs effect on communities in the recipient river. Environmental biofilms were colonized in TEs and the recipient river up- and downstream from the WWTP output to study benthic diatoms using DNA metabarcoding combined with high-throughput sequencing (HTS). In parallel, concentrations of nutrients, pharmaceuticals and seasonal conditions were recorded. Diatom metabarcoding showed that benthic communities differed strongly in their diversity and structure depending on the habitat. TE sites were generally dominated by few genera with polysaprobic preferences belonging to the motile guild, while river sites favored diverse communities from oligotrophic and oligosaprobic groups. Seasonal changes were visible to lower extent. To categorize parameters important for diatom changes we performed redundancy analysis which suggested that communities within TE sites were associated to higher concentrations of beta-blockers and non-steroidal anti-inflammatory drugs in urban effluents vs. antibiotics and orthophosphate in hospital effluents. Furthermore, indicator species analysis showed that 27% of OTUs detected in river downstream communities were indicator for urban or hospital TE sites and were absent in the river upstream. Finally, biological diatom index (BDI) calculated to evaluate the ecological status of the recipient river suggested water quality decrease linked to the release of TEs. Thus, in-depth assessment of diatom community composition using DNA metabarcoding is proposed as a promising technique to highlight the disturbing effect of pollutants in Alpine rivers.


Streptomyces hoynatensis sp. nov., isolated from deep marine sediment.
A novel actinobacterium, strain S1412(T), was isolated from a deep sediment sample, collected from the southern Black Sea coast of Turkey, and was examined using a polyphasic approach. The organism had chemical and morphological features typical of the genus Streptomyces. The cell wall of the novel strain contained ll-diaminopimelic acid. Whole-cell hydrolysates contained galactose, glucose and traces of xylose. The polar lipid profile of S1412(T) consisted of the predominant compound diphosphatidylglycerol, moderate amounts of phosphatidylethanolamine and phosphatidylinositol, and minor amounts of phosphatidylglycerol. Strain S1412(T) exhibited an unusual quinone system, with the predominant compounds MK-10(H8), MK-9(H8) and MK-10(H6) and small amounts of MK-9(H6) and MK-10(H4). Major fatty acids were iso-C16 : 0, iso-C16 : 1 H and anteiso-C17:0. The 16S rRNA gene sequence similarities for strain S1412(T) with respect to the most closely related type strains of species of the genus Streptomyces were less than 97.0%. Phenotypic data clearly distinguished the isolate from its closest relatives, Streptomyces specialis GW 41-1564(T), Streptomyces mayteni YIM 60475(T), Streptomyces hainanensis YIM 47672(T), Streptomyces avicenniae MCCC1A01535(T) and Streptomyces sedi YIM 65188(T). Based on chemotaxonomic, phenotypic and genotypic characteristics, strain S1412(T) is considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces hoynatensis sp. nov. is proposed. The type strain is S1412(T) ( = KCTC 29097(T) = DSM 42069(T)).


Cell differentiation and infectivity of Leishmania mexicana are inhibited in a strain resistant to an ABC-transporter blocker.
We analysed whether markers of cell differentiation and infectivity differed when compared to the parental sensitive strain [NR(Gs)] in an in vitro selected Leishmania strain [NR(Gr)] resistant to Glibenclamide, an ATP-binding-cassette (ABC)-transporter blocker. The data show that the cell body area was larger in NR(Gr) compared to NR(Gs) and that functional characters associated with an infective metacyclic phenotype, such as resistance to the lytic effect of the alternative complement pathway and expression of the Meta-1 protein, were reduced. The infectivity of NR(Gr) to J774.1 macrophages was also significantly reduced. These results suggest that resistance in Leishmania against Glibenclamide, a general blocker of P-glycoproteins, could produce functional modifications that may be relevant for Leishmania differentiation, infectivity and survival.


[Effect of ciliary muscle electrical stimulation on ocular hydrodynamics and visual function in patients with glaucoma].
A course of transscleral electrostimulation of the ciliary muscle (10 sessions) using ESOF-1 device was administered to 20 patients (23 eyes) with bilateral primary open-angle glaucoma. A lens with 4 electrodes was placed on the eyeball in the ciliary body projection. Rectangular bipolar pulses up to 15 msec long were generated in the pack mode with current amplitude up to 10 mA for 3 to 7 min. Control group consisted of 17 "paired" eyes. After electrostimulation the accommodation volume increased by 54%, relative accommodation reserve by 34%, coefficient of discharge by 42%, and vision acuity by 0.1 to 0.4 diopters in 6 out of 7 eyes in which vision was lower than 1.0 diopter; intraocular pressure was 16% decreased and the number of absolute and relative scotomas in the central visual field (Humphry, 24-2) dropped by 40%. Improvement of the visual functions and hydrodynamic parameters of the eye was gradual, reaching the maximum by the end of the follow-up (6 months). In control eyes no positive changes were observed. The results indicate a positive effect of electrostimulation of the ciliary body and posterior ocular structures on intraocular fluid circulation and visual functions.


Experience of families in accessing government-led support for children with disabilities in Bangladesh.
The purpose of the study was to understand the experiences of families in accessing government support (i.e., disability allowances and rehabilitation services) for their children with disabilities (CWDs) in Bangladesh. We employed a qualitative descriptive method of study and interviewed 27 family members of CWDs. A thematic analysis was applied to analyze data using the following access dimensions to organize themes: availability, accommodation, accessibility, affordability, acceptability, and awareness. Participants shared both positive and negative experiences across the access dimensions in accessing government support. Participants appreciated the government's effort in providing support to CWDs. In particular, disability allowances and coordinated rehabilitation services at one-stop were important for families. Further, positive attitudes, such as respect and support from providers, were reported by many families. However, a majority of participants reported a long wait time to get the disability allowance for CWDs. Participants also reported that a shortage of rehabilitation professionals in the public sector was a major concern. Finally, inaccessible infrastructure (e.g., facilities and transportation) and stigma were barriers for many participants of the study. The results suggest that the government's commitment "on paper" is yet to meet the needs of its intended beneficiaries "in practice". There is a need for policy intervention to address barriers faced by families within the context of current access pathways.Implications for rehabilitationShortage of rehabilitation services and limited availability of disability allowances [negatively] affect family member's access to government-led support for their CWDs in Bangladesh.The government has increased services for people with disability significantly but there is a need for it to ensure the availability of all forms of rehabilitation and increase the quota for disability allowances to meet the needs of families.It is imperative to improve mechanisms of monitoring the commitment of enacting tangible results from policies in order to ensure equitable distribution of disability allowance and rehabilitation services.


Expression of cell cycle related proteins--proliferating cell nuclear antigen (PCNA) and statin--during adaptation and de-adaptation of EUE cells to a hypertonic medium.
EUE cells adapted to grow for long times in a hypertonic medium have a longer cell cycle than those growing in isotonic medium. To elucidate whether this lengthening involves specific cycle phases to differing extents, the expression of two cycle-related protein, PCNA and statin, was studied by dual parameter flow cytometry of indirect immunofluorescence protein labelling and DNA content. In isotonic medium, most cells, in all the cycle phases, were PCNA positive; in contrast, PCNA negative cells and statin positive cells were very few in number and only fell in the G0/1 range of DNA contents. In hypertonic medium, the frequency of PCNA positive cells was lower, and that of statin positive cells higher, than in isotonic medium, particularly in the G0/1 range of DNA contents: this suggests that a G0 block occurs under long-term hypertonic stress. Consistently, dual parameter flow cytometric measurement of BrdUrd immunofluorescence labelling and DNA content showed that fewer cells entered S phase in hypertonic medium and their progression through the S phase was slower; evidence was also found for the occurrence of a G2 block. These kinetics changes were fully reversible in isotonic medium, thus indicating the adaptive nature of the EUE response to hypertonicity.


Hantavirus disease (nephropathia epidemica) in Belgium: effects of tree seed production and climate.
Recently, human cases of nephropathia epidemica (NE) due to Puumala virus infection in Europe have increased. Following the hypothesis that high reservoir host abundance induces higher transmission rates to humans, explanations for this altered epidemiology must be sought in factors that cause bank vole (Myodes glareolus) abundance peaks. In Western Europe, these abundance peaks are often related to high tree seed production, which is supposedly triggered by specific weather conditions. We evaluated the relationship between tree seed production, climate and NE incidence in Belgium and show that NE epidemics are indeed preceded by abundant tree seed production. Moreover, a direct link between climate and NE incidence is found. High summer and autumn temperatures, 2 years and 1 year respectively before NE occurrence, relate to high NE incidence. This enables early forecasting of NE outbreaks. Since future climate change scenarios predict higher temperatures in Europe, we should regard Puumala virus as an increasing health threat.


Drug delivery systems based on pharmaceutically active ionic liquids and biocompatible poly(lactic acid).
Poly(l-lactic acid) (PLLA) membranes containing pharmaceutically active ionic liquids (API-ILs) have been prepared by using a simple film casting from solvent evaporation method. Several sets of membranes were prepared from two different ionic liquids namely 1-methyl-3-butyl-imidazolium ibuprofenate (C4MImIbu) and lidocainium ibuprofenate (LidIbu) with different API-IL contents. Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Wide-Angle and Small-Angle X-ray Scattering (WAXS and SAXS) revealed the strong influence of both the IL nature and content on the morphology and the crystallinity of the resulting PLLA. At 20 weight%, LidIbu was shown to act as a plasticizer for PLLA and homogeneous membranes were obtained. In contrast, at the same IL content, phase separation occurred using C4MImIbu, resulting in the formation of porous PLLA. An increase of LidIbu content to 50 weight% results also in phase separation. 1H and 1H-13C CP-MAS NMR measurements evidenced the influence of different morphologies and crystallinities on IL mobility. C4MImIbu was found to be highly mobile whereas the mobility of LidIbu was content dependent. At low percent, low mobility was observed while at higher content, two populations with respectively high and low mobility were observed. These PLLA-IL membranes were further tested as drug delivery systems. In accordance with the morphology and mobility obtained, we demonstrated that release kinetics from PLLA membranes can be tuned by the nature and the content of API-ILs. Sustainable release kinetics were obtained with API-IL acting as a plasticizer while the fastest release was obtained with API-IL acting as a porogenic agent.


Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer.
This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR-135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. These findings indicated that miR-135a promotes cell apoptosis and inhibits cell proliferation, migration, invasion and tumor angiogenesis by targeting IGF-1 gene through the IGF-1/PI3K/Akt signaling pathway in NSCLC.


[Vitreous cyst and retinitis pigmentosa: case report].
Vitreous cyst is a rare condition of the posterior segment of the eye. It can occur in eyes with coexistent ocular diseases or in eyes that are otherwise normal. This study reports a case of vitreous cyst in a patient with retinitis pigmentosa and presents its clinical and ultrasonographic features.


Efficient retrovirus-mediated transfer of cell-cycle control genes to transformed cells.
The use of gene therapy continues to be a promising, yet elusive, alternative for the treatment of cancer. The origins of cancer must be well understood so that the therapeutic gene can be chosen with the highest chance of successful tumor regression. The gene delivery system must be tailored for optimum transfer of the therapeutic gene to the target tissue. In order to accomplish this, we study models of G1 cell-cycle control in both normal and transformed cells in order to understand the reasons for uncontrolled cellular proliferation. We then use this information to choose the gene to be delivered to the cells. We have chosen to study p16, p21, p53 and pRb gene transfer using the pCL-retrovirus. Described here are some general concepts and specific results of our work that indicate continued hope for the development of genetically based cancer treatments.


A Novel Treatment of Opioid Cravings With an Effect Size of .73 for Unilateral Transcranial Photobiomodulation Over Sham.
Opioid use disorders (OUDs) are an epidemic causing catastrophic consequences to individuals, families, and society despite treatments including psychotherapy, substitution therapy or receptor blockers, and psychoeducation. We have developed a novel treatment that combines unilateral transcranial photobiomodulation (t-PBM) to the hemisphere with a more positive valence by Dual Brain Psychology (DBP). We used a randomized, double blind, placebo-controlled protocol in which 22 patients with significant opioid cravings and a history of recent or current OUD attended three 1-h weekly sessions. After baseline measures of opioid craving and other psychometrics, subjects received two unilateral t-PBM applications (810 nm CW LED, 250 mW/cm2, 60 J/cm2, 4 min) or a sham (foil-covered LED) at F3 or F4. Prior to any treatment we used two tests to determine which hemisphere was more associated with a negative outlook and cravings and treated that side before the more positive hemisphere. Primary outcome measure was an opioid craving scale (OCS). Secondary outcomes were weekly Hamilton Depression (HDRS) and Anxiety (HARS) Rating Scales prior to treatments and at follow-up. Immediately after treatment the OCS improved significantly for both the sham and active treatments, but one week later the active treatment showed a 51.0% (SD 33.7) decrease in OCS while a week after the sham treatments there was a decrease of only 15.8% (SD 35.0) (by Wilcoxon Sign Rank Test, p = 0.004) and by a mixed model it was p = 0.0071. The effect size for the differences between active and sham was 0.73. For the active treatment from before and after treatment the effect size was 1.51 and for the sham, 0.45. The HDRS improved from a baseline of 15.1 to 8.8 (SD 10.3) a week after the active treatment and to 13.3 (SD 12.9) after the sham (p = 0.0071). HARS improved from 14.7 to 8.0 (SD 13.2) after the active treatments and to 14.3 (SD 16.0) after the sham, p = 0.08. Active treatment of the positive hemisphere after the negative hemisphere significantly improved the OCS, but there was no significant difference after the sham treatment. One patient complained of 2 h of abdominal bloating and dropped out; no other adverse effects were observed. Unilateral t-PBM to the hemisphere with a more positive hemispheric emotional valence was an effective and safe treatment for opioid cravings as well as for depression and anxiety. Our results also lend support to the underlying premises of DBP.


New oral anticoagulants for thromboprophylaxis after elective total hip and knee arthroplasty.
Anticoagulant drugs reduce the risk of venous thromboembolic events after total hip and knee arthroplasty. However, the use of current drugs, such as low molecular weight heparins, is hampered by their subcutaneous route of administration. The use of vitamin K antagonists is hampered by the requirement for routine coagulation monitoring and dose titration to provide effective anticoagulation without an increased risk of bleeding and numerous food and drug interactions. Clearly, there is a need for new oral, fixed-dose anticoagulant drugs that do not require coagulation monitoring, while demonstrating similar or better efficacy and safety profiles when compared with current agents.


Treatment of humeral shaft delayed unions and nonunions with humeral locked nails.
To report experience with use of humeral locked nails in treating humeral delayed unions and nonunions. The following techniques yielded encouragingly good results: static locking, short-to-long segment nailing, bone grafting, fracture compression, and minimal surgical trauma. A total of 41 consecutive patients with 13 delayed unions and 28 nonunions were treated with humeral locked nails. Delay from trauma to surgery averaged 4.2 months for delayed union and 15.5 months for nonunion. The average age of patients was 50.2 years; average follow-up time was 23.2 months. There were 7 proximal-third fractures, 21 middle-third fractures, and 13 distal-third fractures. The antegrade approach was used for 13 fractures and retrograde for 28. Open nailing was performed in 39 fractures and closed nailing in 2. If the fracture motion was still present after nail insertion, axial compression of the fracture site was specially applied. Bone grafting was performed in the fractures with open nailing. Thirty-four fractures were nailed with 8-mm nails, and 7 fractures were nailed with 7-mm nails. With a single operation, all but two patients achieved osseous union in, on average, 5.6 months. One of these two patients eventually gained union after another surgery with fracture compression along the original nail and concurrent bone grafting. The second patient, undergoing hemodialysis for chronic renal failure, had persistent nonunion. At follow-up, for patients with antegrade nailing, all but four patients had less than 20 degrees limitation of shoulder abduction. For patients with retrograde nailing, all but two had less than 10 degrees limitation of elbow motion. Only the patient with persistent nonunion had continual pain and significant impairment of arm function. Humeral locked nailing seems to be effective for humeral delayed unions or nonunions. It may be an acceptable alternative for fractures unsuited for plate fixation, such as those with comminution, osteoporosis, or a severely adhered radial nerve.


Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons.
In the developing vertebrate nervous system, both neural crest and sensory neurons form at the boundary between non-neural ectoderm and the neural plate. From an in situ hybridization based expression analysis screen, we have identified a novel zebrafish mutation, narrowminded (nrd), which reduces the number of early neural crest cells and eliminates Rohon-Beard (RB) sensory neurons. Mosaic analysis has shown that the mutation acts cell autonomously suggesting that nrd is involved in either the reception or interpretation of signals at the lateral neural plate boundary. Characterization of the mutant phenotype indicates that nrd is required for a primary wave of neural crest cell formation during which progenitors generate both RB sensory neurons and neural crest cells. Moreover, the early deficit in neural crest cells in nrd homozygotes is compensated later in development. Thus, we propose that a later wave can compensate for the loss of early neural crest cells but, interestingly, not the RB sensory neurons. We discuss the implications of these findings for the possibility that RB sensory neurons and neural crest cells share a common evolutionary origin.


CpG oligodeoxynucleotide-loaded PAMAM dendrimer-coated magnetic nanoparticles promote apoptosis in breast cancer cells.
One major application of nanotechnology in cancer treatment involves designing nanoparticles to deliver drugs, oligonucleotides, and genes to cancer cells. Nanoparticles should be engineered so that they could target and destroy tumor cells with minimal damage to healthy tissues. This research aims to develop an appropriate and efficient nanocarrier, having the ability of interacting with and delivering CpG-oligodeoxynucleotides (CpG-ODNs) to tumor cells. CpG-ODNs activate Toll-like receptor 9 (TLR9), which can generate a signal cascade for cell death. In our study, we utilized three-layer magnetic nanoparticles composed of a Fe3O4 magnetic core, an aminosilane (APTS) interlayer and a cationic poly(amidoamine) (PAMAM) dendrimer. This will be a novel targeted delivery system to enhance the accumulation of CpG-ODN molecules in tumor cells. The validation of CpG-ODN binding to DcMNPs was performed using agarose gel electrophoresis, UV-spectrophotometer, XPS analyses. Cytotoxicity of conjugates was assessed in MDA-MB231 and SKBR3 cancer cells based on cell viability by XTT assay and flow cytometric analysis. Our results indicated that the synthesized DcMNPs having high positive charges on their surface could attach to CpG-ODN molecules via electrostatic means. These nanoparticles with the average sizes of 40±10nm bind to CpG-ODN molecules efficiently and induce cell death in MDA-MB231 and SKBR3 tumor cells and could be considered a suitable targeted delivery system for CpG-ODN in biomedical applications. The magnetic core of these nanoparticles represents a promising option for selective drug targeting as they can be concentrated and held in position by means of an external magnetic field.


Increased delayed type hypersensitivity in rats subjected to unilateral mononeuropathy is mediated by neurokinin-1 receptors.
An animal model or peripheral mononeuropathy was utilized in the present study to investigate the potential role of substance P (SP) in modifying immune responses associated with chronic pain conditions. Animals subjected to unilateral sciatic ligation and sham-operated animals were sensitized with keyhole limpet hemocyanin (KLH) and subsequently challenged in the ipsilateral or contralateral hind paw to produce a delayed-type hypersensitivity (DTH) response. Subcutaneous microdialysis and radioimmunoassay were used to measure interstitial fluid SP levels in the challenged tissue prior to and following immune challenge in control and neuropathic animals. Following immune challenge, there was a significant increase in the concentration of SP in tissue dialysate samples from the challenged paw of both sham-operated and neuropathic animals. However, tissue SP levels in neuropathic animals were more than two-fold higher than those obtained from sham-operated controls following challenge. SP concentration remained elevated for 2.5 h following immune challenge in neuropathic animals compared to 90 min in sham-operated animals. Compared with controls, neuropathic animals also exhibited an increased DTH response that was reversed, in a dose-related fashion, by the non-peptide NK-1 receptor blocker L-703,606. The same antagonist had no effect in sham-operated animals. These data suggest that the increased DTH response in animals subjected to unilateral mononeuropathy involves SP and NK-1 receptors present in the challenged tissue.


miR-15b suppression of Bcl-2 contributes to cerebral ischemic injury and is reversed by sevoflurane preconditioning.
Ischemic neuroprotection afforded by sevoflurane preconditioning has been previously demonstrated, yet the underlying mechanism is poorly understood and likely affects a wide range of cellular activities. Several individual microRNAs have been implicated in both the pathogenesis of cerebral ischemia and cellular survival, and are capable of affecting a range of target mRNA. Conceivably, sevoflurane preconditioning may lead to alterations in ischemia-induced microRNA expression that may subsequently exert neuroprotective effects. We first examined the microRNA expression profile following transient cerebral ischemia in rats and the impact of sevoflurane preconditioning. Microarray analysis revealed that 3 microRNAs were up-regulated (>2.0 fold) and 9 were down-regulated (< 0.5 fold) following middle cerebral artery occlusion (MCAO) compared to sham controls. In particular, miR-15b was expressed at significantly high levels after MCAO. Preconditioning with sevoflurane significantly attenuated the upregulation of miR-15b at 72h after reperfusion. Bcl-2, an anti-apoptotic gene involved in the pathogenesis of cerebral ischemia, has been identified as a direct target of miR-15b. Consistent with the observed downregulation of miR-15b in sevoflurane-preconditioned brain, postischemic Bcl-2 expression was significantly increased by sevoflurane preconditioning. We identified the 3'-UTR of Bcl-2 as the target for miR-15b. Molecular inhibition of miR-15b was capable of mimicking the neuroprotective effect of sevoflurane preconditioning, suggesting that the suppression of miR-15b due to sevoflurane contributes to its ischemic neuroprotection. Thus, sevoflurane preconditioning may exert its anti-apoptotic effects by reducing the elevated expression of miR-15b following ischemic injury, allowing its target proteins, including Bcl-2, to be translated and expressed at the protein level.


Acute haemodynamic effects of nifedipine at rest and during maximal exercise in patients with chronic cor pulmonale.
The pulmonary hypertension of cor pulmonale can be reversed by sustained correction of hypoxia but continuous oxygen treatment poses problems in clinical practice. Alternative methods of relieving pulmonary vasoconstriction have therefore been explored. Eight patients with chronic cor pulmonale (five of them men) were studied to measure the haemodynamic effects of the calcium antagonist nifedipine, both at rest and on maximal, symptom limited exercise. The mean duration of exercise was unchanged by nifedipine (7.8 (SD 3.3) compared with 7.3(3.1) min). Cardiac output rose from 5.2(1.5) l min-1 to 8.6(3.3) 1 min-1 on exercise. Nifedipine increased resting cardiac output by 26%, but did not influence maximal exercise output. It did not significantly alter resting mean pulmonary artery pressure but reduced the level during exercise from 67(15) to 52(11) mm Hg. Nifedipine lowered resting pulmonary vascular resistance (PVR) by 32% and exercise PVR by 28%. It reduced supine mean systemic arterial pressure by 17%, standing pressure by 22%, and pressure at the maximal exercise level by 20%. Nifedipine lowered supine systemic vascular resistance (SVR) by 35%, standing SVR by 28%, and exercise SVR by 20%. Haemodynamic changes were achieved without adverse symptoms, alteration in arterial PO2, or impairment of calculated oxygen delivery. Nifedipine therefore reduced both pulmonary and systemic vasomotor tone at rest and during exercise. It did not alter exercise tolerance, which is probably limited by underlying respiratory disease. It seems possible therefore that nifedipine could delay the development of cor pulmonale, although this hypothesis remains to be tested.


OX40/OX40L costimulation affects induction of Foxp3+ regulatory T cells in part by expanding memory T cells in vivo.
OX40 is a member of the TNFR superfamily and has potent T cell costimulatory activities. OX40 also inhibits the induction of Foxp3(+) regulatory T cells (Tregs) from T effector cells, but the precise mechanism of such inhibition remains unknown. In the present study, we found that CD4(+) T effector cells from OX40 ligand-transgenic (OX40Ltg) mice are highly resistant to TGF-beta mediated induction of Foxp3(+) Tregs, whereas wild-type B6 and OX40 knockout CD4(+) T effector cells can be readily converted to Foxp3(+) T cells. We also found that CD4(+) T effector cells from OX40Ltg mice are heterogeneous and contain a large population of CD44(high)CD62L(-) memory T cells. Analysis of purified OX40Ltg naive and memory CD4(+) T effector cells showed that memory CD4(+) T cells not only resist the induction of Foxp3(+) T cells but also actively suppress the conversion of naive CD4(+) T effector cells to Foxp3(+) Tregs. This suppression is mediated by the production of IFN-gamma by memory T cells but not by cell-cell contact and also involves the induction of T-bet. Importantly, memory CD4(+) T cells have a broad impact on the induction of Foxp3(+) Tregs regardless of their origins and Ag specificities. Our data suggest that one of the mechanisms by which OX40 inhibits the induction of Foxp3(+) Tregs is by inducing memory T cells in vivo. This finding may have important clinical implications in tolerance induction to transplanted tissues.


Clinical perceptions of the risk of vertebral artery dissection after cervical manipulation: the effect of referral bias.
The growing recognition of cervical manipulation as a treatment of neck pain and cervicogenic headaches has lead to increased interest in potential complications that may result from this treatment approach. Recent surveys have reported that many neurologists will encounter cases of vertebral artery dissection that occur at various times after cervical manipulation, whereas most practitioners of spinal manipulation are of the opinion that these events are extremely rare. We asked the question whether these differences in perception could be explained in part by referral or selection bias. To assess the effect of referral bias on the differences in perceived incidence of vertebral artery dissection after cervical manipulation between neurologists and chiropractors in Canada. This study was a retrospective review of cases where neurological symptoms consistent with cerebrovascular ischemia were reported by chiropractors in Canada. An analysis of data from a chiropractic malpractice insurance carrier (Canadian Chiropractic Protective Association [CCPA]) and results of a survey of chiropractors was performed to determine the likelihood that a vertebral artery dissection after cervical manipulation would be reported to practicing chiropractors. This was compared with the likelihood that a neurologist would be made aware of such a complication. For the 10-year period 1988 to 1997, there were 23 cases of vertebral artery dissection after cervical manipulation reported to the CCPA that represents 85% of practicing chiropractors in Canada. Based on the survey, an estimated 134,466,765 cervical manipulations were performed during this 10-year period. This gave a calculated rate of vertebral artery dissection after manipulation of 1:5,846,381 cervical manipulations. Based on the number of practicing chiropractors and neurologists during the period of this study, 1 of every 48 chiropractors and one of every two neurologists would have been made aware of a vascular complication from cervical manipulation that was reported to the CCPA during their practice lifetime. The perceived risk after cervical manipulation by chiropractors and neurologists is related to the probability that a practitioner will be made aware of such an incident. The difference in the number of chiropractors (approximately 3,840 in 1997) and neurologists (approximately 4,000 in 1997) in active practice and the fact that each patient who has a stroke after manipulation will likely be seen by only one chiropractor but by three or more neurologists partly explains the difference in experience and the perception of risk of these two professions. This selection or referral bias is important in shaping the clinical opinions of the various disciplines and distorts discussion on the true incidence of these complications of cervical manipulation. The nature of this study, however, describes the likelihood that a clinician will be made aware of such an event and cannot be interpreted as describing the actual risk of stroke after manipulation.


Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies.
Brain cells are metabolically flexible because they can derive energy from both glucose and ketone bodies (acetoacetate and beta-hydroxybutyrate). Metabolic control theory applies principles of bioenergetics and genome flexibility to the management of complex phenotypic traits. Epilepsy is a complex brain disorder involving excessive, synchronous, abnormal electrical firing patterns of neurons. We propose that many epilepsies with varied etiologies may ultimately involve disruptions of brain energy homeostasis and are potentially manageable through principles of metabolic control theory. This control involves moderate shifts in the availability of brain energy metabolites (glucose and ketone bodies) that alter energy metabolism through glycolysis and the tricarboxylic acid cycle, respectively. These shifts produce adjustments in gene-linked metabolic networks that manage or control the seizure disorder despite the continued presence of the inherited or acquired factors responsible for the epilepsy. This hypothesis is supported by information on the management of seizures with diets including fasting, the ketogenic diet and caloric restriction. A better understanding of the compensatory genetic and neurochemical networks of brain energy metabolism may produce novel antiepileptic therapies that are more effective and biologically friendly than those currently available.


Analysis of inherited genetic variations at the UGT1 locus in the French-Canadian population.
The UDP-glucuronosyltransferase UGT1 locus is composed of nine exon 1s, each flanked by a unique promoter region, and common exons (2, 3, 4, and the alternatively spliced exons 5a and 5b). Here, we characterized the genetic architecture of the UGT1 gene in a Caucasian sample. Overall, 98 variations in regulatory domains, exons and exon-intron boundaries were genotyped in 254 unrelated subjects, including 12 unreported UGT1 polymorphisms. We determined allele frequencies, computed pairwise linkage disequilibrium (LD), and inferred haplotypes; this thorough analysis yielding a limited number of common UGT1 haplotypes. Moreover, only 17 haplotype tagging single nucleotide polymorphisms (htSNPs) are required to capture most of the allelic diversity of the locus. Four haplotype blocks were inferred: Block 9/6 (UGT1A9, UGT1A7 and UGT1A6), Block 4 (UGT1A4), Block 3/1 (UGT1A3 and UGT1A1), and Block C (3'UTR). A high level of linkage exists between Blocks 9/6 and 3/1, while the 3'UTR SNPs are genetically isolated. The most common haplotype (16.5%) presents multiple deleterious alleles, mainly 1A1*28, 1A3*2, 1A6*2, and 1A7*4. More interestingly, we reveal the co-occurrences of multiple deleterious variations, some of which could be associated with interindividual differences in glucuronidation. Comparison with the HapMap data set demonstrated differences in haplotypic diversity between ethnic samples, but similarity between Caucasian cohorts, as observed previously. This report provides relevant data for further pharmacogenomic studies.


Human liver fatty acid binding protein cDNA and amino acid sequence. Functional and evolutionary implications.
Human liver fatty acid binding protein (L-FABP) cDNA clones were identified in a liver cDNA library. The two longest clones were completely sequenced. The nucleotide sequence predicts a protein of 127 amino acid residues. Identity of the clones was confirmed by limited amino acid sequence analysis of purified human L-FABP peptides and Edman degradation of radiolabeled in vitro translated FABP. Statistical analysis of the amino acid and mRNA sequences of human L-FABP, rat L-FABP, rat intestinal (I-) FABP, and mouse 422 protein indicates that the human and rat L-FABPs are highly homologous and that L-FABP and I-FABP diverged a long time ago (approximately 650-690 million years ago), although they are more closely related to each other than either of them is to 422 protein. Secondary structure predictions from the primary sequence of human and rat L-FABP reveal a region (residues 12-30) that might be the putative fatty acid binding domain of the two L-FABPs. Knowledge of the primary amino acid sequence of L-FABP and possible functional domains will be pivotal in further defining and understanding the mechanism of ligand binding and transfer by this protein.


[Cerebrovascular pathology in nonspecific aortoarteritis].
Thirty patients with nonspecific aortoarteritis (NAA) associated with occlusive lesions of the main arteries of the head verified by aortography, ultrasonography of the aorta, volumetric sphygmography and REG were under observation. Young women predominated among the patients. The identification of the early form of cerebrovascular insufficiency associated with NAA is important for delimiting indications for surgical treatment.


Dietary fats promote inflammation in Wistar rats as well as induce proliferation, invasion of SKOV3 ovarian cancer cells.
The role of high fat diet (HFD) in ovarian cancer and its underlying mechanisms are poorly known. In current investigation, we investigated inflammatory and oncogenic effect of dietary fats in female Wistar rats and ovarian cancer cell line (SKOV3). The ELISA kits were used for adipokines and inflammatory factors analyses in sera collected from rats fed with high fat diet (SR-HFD). Cell growth, proliferation, apoptosis, migration, and invasion were measured in SKOV3 cells treated with the SR-HFD and FA mix. IL6, IL1β, TNFα, NF-kβ, and p53 expression were measured in cells incubated with the mentioned treatments. Leptin and inflammatory factors increased, while adiponectin decreased in SR-HFD. Moreover, FA mix significantly induced proliferation, migration, and invasion, promoted the expression of inflammatory factors and NF-κB and inhibited apoptosis markers in SKOV3 cells. Taken together, our findings revealed that diet might be a crucial factor in ovarian cancer progression through altering the inflammatory factors. PRACTICAL APPLICATIONS: The HFD-mediated obesity promotes cancer progression in various tissues. This study highlights the progression of inflammation in female Wistar rats and the growth of ovarian cancer cells by dietary fats. Thus, dietary factors can be considered as key factors for the prevention of ovarian cancer.


Establishment of A Protocol for In Vitro Culture of Cardiogenic Mesodermal Cells Derived from Human Embryonic Stem Cells.
Cardiovascular progenitor cells (CPCs) are introduced as one of the promising cell sources for preclinical studies and regenerative medicine. One of the earliest type of CPCs is cardiogenic mesoderm cells (CMCs), which have the capability to generate all types of cardiac lineage derivatives. In order to benefit from CMCs, development of an efficient culture strategy is required. We aim to explore an optimized culture condition that uses human embryonic stem cell (hESC)-derived CMCs. In this experimental study, hESCs were expanded and induced toward cardiac lineage in a suspension culture. Mesoderm posterior 1-positive (MESP1+) CMCs were subjected to four different culture conditions: i. Suspension culture of CMC spheroids, ii. Adherent culture of CMC spheroids, iii. Adherent culture of single CMCs using gelatin, and iv. Adherent culture of single CMCs using Matrigel. Although, we observed no substantial changes in the percentage of MESP1+ cells in different culture conditions, there were significantly higher viability and total cell numbers in CMCs cultured on Matrigel (condition iv) compared to the other groups. CMCs cultivated on Matrigel maintained their progenitor cell signature, which included the tendency for cardiogenic differentiation. These results showed the efficacy of an adherent culture on Matrigel for hESC-derived CMCs, which would facilitate their use for future applications.


Congenital absence of salivary glands in Down syndrome.
Children with Down syndrome have different saliva composition compared to normal children. The presence or absence of the salivary glands has not been previously reported. To examine the presence or absence of the salivary glands in children with Down syndrome. 15 children with Down syndrome underwent an ultrasound examination of the salivary glands. The control group consisted of 31 healthy children. The areas of the parotid and submandibular glands on both sides were scanned in an attempt to demonstrate all four glands. The result was reported as 'present' or 'absent'. In four children out of 15 with Down syndrome, one or more salivary glands were absent (26.7%), while in the controls all salivary glands were present. The difference between the groups was statistically significant (p=0.008). There was no significant difference between the groups regarding age and sex. At least one salivary gland is undetected by ultrasound in some children with Down syndrome.


Stakeholder-Engaged Measure Development for Pediatric Obstructive Sleep-Disordered Breathing: The Obstructive Sleep-Disordered Breathing and Adenotonsillectomy Knowledge Scale for Parents.
Parental decision making about adenotonsillectomy (AT) for obstructive sleep-disordered breathing (oSDB) is associated with decisional conflict that may be alleviated with improved knowledge about symptoms and treatments. To develop a measure of parental knowledge about oSDB and AT. A sequential design was used for scale development. A prototype measure containing 9 oSDB and AT themes and 85 items was administered in survey format via an online platform. Participants included 19 clinician experts (otolaryngologists and pediatricians) and 13 laymen (parents of children who snore or do not snore, and other adults). Quantitative and qualitative responses were used to modify the measure and create the knowledge scale. Content validity of the scale was established through expert feedback and evaluation. Criterion validity was established with t test comparisons of experts with laymen. Reliability of the responses was assessed with Cronbach α testing. An 85-item prototype measure and 39-item modified measure were evaluated for consensus/approval and psychometric integrity. Of 45 potential participants, 32 individuals (71%) responded to the prototype scale. Respondents included 19 clinician experts (59%) (otolaryngologists and pediatricians) and 13 laymen (41%) (parents of children who snore [n = 8] or do not snore [n = 2] and other adults [n = 3]); demographic data were not collected. Content analysis and qualitative feedback were largely rated positively: 27 respondents (84%) stated that the measure was a good evaluation of knowledge, 30 respondents (94%) commented that the items were clear, and 31 individuals (97%) approved of its organization, although there were several suggestions for rewording and/or addition of response options. Experts identified themes most important for assessing oSDB (symptoms) and AT (experiences: risks and benefits) knowledge. These qualitative comments were used to modify the scale, and items were eliminated if more than 2 were reported as misleading or less than 85% of clinicians provided correct responses. Five themes (oSDB symptoms, treatment options, AT risks, anesthesia, and AT benefits) and 39 items composed the final scale. Experts scored higher than laymen on the oSDB and AT Knowledge Scale for Parents overall (17 [94%] vs 12 [67%]; Cohen d = 1.96; 95% CI, 1.05-2.86) and within all themes, including experiences of children with oSDB (19 [88%] vs 13 [62%]; Cohen d = 1.53; 95% CI, 0.71-2.32), treatment options (19 [97%] vs 12 [68%]; Cohen d = 1.74; 95% CI, 0.88-2.57), AT risks (17 [97%] vs 12 [59%]; Cohen d = 1.94; 95% CI, 1.03-2.83), anesthesia (17 [97%] vs 12 [79%]; Cohen d = 1.09; 95% CI, 0.29-1.88), and AT benefits (17 [95%] vs 12 [67%]; Cohen d = 1.28; 95% CI, 0.46-2.09), demonstrating criterion validity. All responses demonstrated high reliability (Cronbach α = 0.94). The oSDB and AT Knowledge Scale for Parents is psychometrically sound for use in the assessment of parental knowledge.


Occupational skin disease in Singapore: epidemiology & causative agents.
Of 557 patients with occupational dermatoses seen at the Middle Road Hospital, Singapore, 55.7% (310) were irritant contact dermatitis, 38.6% (215) were allergic contact dermatitis and 5.7% (32) were non contact dermatitis. More than half of the patients were below 30 years old and most were from the construction (29.5%), metal/engineering (20.6%), electrical/electronic (16.4%), transport (5.5%) and food catering (3.8%) industries. Common occupational irritants included coolants, oils, cement, solvents, detergents and soldering flux. Chromates in cement was the most common occupational allergen. Other occupational allergens included rubber chemicals from rubber apparels. Thiurammix followed by carba-mix, and PPD-mix were common rubber allergens. Resins including epoxy, acrylate and paratertiary butyl phenol resins and other metals (nickel and cobalt) were less common occupational allergens. 5 workers had contact urticaria to proteinaceous food. Non dermatitic occupational dermatoses included fibreglass dermatoses, miliaria and oil folliculitis.


Entangling strings of neutral atoms in 1D atomic pipeline structures.
We study a string of neutral atoms with nearest neighbor interaction in a 1D beam splitter configuration, where the longitudinal motion is controlled by a moving optical lattice potential. The dynamics of the atoms crossing the beam splitter maps to a 1D spin model with controllable time dependent parameters, which allows the creation of maximally entangled states of atoms by crossing a quantum phase transition. Furthermore, we show that this system realizes protected quantum memory, and we discuss the implementation of one- and two-qubit gates in this setup.


Efficiency of placental transfer of vaccine-elicited antibodies relative to prenatal Tdap vaccination status.
Administration of vaccines during pregnancy provides maternal protection against infectious diseases. This protection is extended to their infants during the first months of life, as pathogen-specific antibodies formed in response to maternal vaccination are transferred across the placenta to the fetus. Notably, Tdap (tetanus-diphtheria-acellular pertussis) vaccination booster is routinely administered to pregnant women both to prevent neonatal tetanus and to ensure that infants have protective levels of pertussis antibodies until they are able to establish their own vaccine-induced levels. Whether infant protection through maternal immunization is merely due to an increase in maternal antibody levels or whether maternal immunization enhances the transfer of vaccine-specific antibodies is unclear. Moreover, the potential impact of prenatal vaccinations on the transplacental transfer of other antibodies, such as antibodies raised as a result of infections or other vaccines administered prior to pregnancy, has not been studied. The goal of this study was to define the impact of maternal vaccination on IgG transplacental transfer efficiency. We analyzed antigen-specific antibody populations and IgG subclass distribution in maternal and cord blood samples from 58 mother-infant pairs. All women received the seasonal inactivated influenza vaccine during pregnancy and 25 women received the Tdap vaccine during the second or third trimester of gestation. Prenatal Tdap vaccination did not impact the efficiency of IgG transplacental transfer; however, it was associated with higher maternal and infant vaccine-elicited Tdap-specific antibody levels, and with a higher proportion of infants with protective levels of antibodies, especially against diphtheria. There was also no difference in the IgG transplacental transfer rate of antibodies against non-Tdap vaccines between the two groups of women. Our results confirm previous reports demonstrating the benefits of prenatal Tdap immunization and indicate that this strategy does not impede the transplacental transfer of other antibodies that are also important for infant protection.


Entanglement of Purification in Many Body Systems and Symmetry Breaking.
We study the entanglement of purification (EOP), a measure of total correlation between two subsystems A and B, for free scalar field theory on a lattice and the transverse-field Ising model by numerical methods. In both of these models, we find that the EOP becomes a nonmonotonic function of the distance between A and B when the total number of lattice sites is small. When it is large, the EOP becomes monotonic and shows a plateaulike behavior. Moreover, we also show that the original reflection symmetry which exchanges A and B can get broken in optimally purified systems. We provide an interpretation of our results in terms of the interplay between classical and quantum correlations.


Understanding Basic Temporal Relations in Primary School Pupils with Hearing Impairments.
Time can be observed as a subjective, as well as an objective phenomenon which is a component of our life, and due to its communicational needs, it is standardized by temporal signs and symbols. The aim of this study was to determine the understanding of basic temporal relations of pupils with hearing impairments. We assumed that the knowledge of basic time relations is a precondition for the acquisition of knowledge that is connected with the understanding of the syllabus in regular school programs. Three groups of pupils have been examined: pupils with hearing impairments who attend the primary school of SUVAG Polyclinic under special condition, integrated hearing impaired pupils with minor additional difficulties who attend regular primary schools in Zagreb with a prolonged expert procedure and pupils of the control group. The subjects have been examined with a measuring instrument constructed by the expert team of the Polyclinic Suvag. Twenty nine subjects have been questioned, chronologically aged between 10 and 12.


To Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors.
The generation of immunological memory is a hallmark of adaptive immunity by which the immune system "remembers" a previous encounter with an antigen expressed by pathogens, tumors, or normal tissues; and, upon secondary encounters, mounts faster and more effective recall responses. The establishment of T cell memory is influenced by both cell-intrinsic and cell-extrinsic factors, including genetic, epigenetic and environmental triggers. Our current knowledge of the mechanisms involved in memory T cell differentiation has instructed new opportunities to engineer T cells with enhanced anti-tumor activity. The development of adoptive T cell therapy has emerged as a powerful approach to cure a subset of patients with advanced cancers. Efficacy of this approach often requires long-term persistence of transferred T cell products, which can vary according to their origin and manufacturing conditions. Host preconditioning and post-transfer supporting strategies have shown to promote their engraftment and survival by limiting the competition with a hostile tumor microenvironment and between pre-existing immune cell subsets. Although in the general view pre-existing memory can confer a selective advantage to adoptive T cell therapy, here we propose that also "bad memories"-in the form of antigen-experienced T cell subsets-co-evolve with consequences on newly transferred lymphocytes. In this review, we will first provide an overview of selected features of memory T cell subsets and, then, discuss their putative implications for adoptive T cell therapy.


Two dosages of imipramine in hospitalized endogenous and neurotic depressives.
Fifty-one newly hospitalized depressed patients participated in a double-blind comparison of two dosage levels of imipramine hydrochloride (150 mg vs 300 mg daily). Although some patients were suffering from neurotic depressions, they, together with the endogenous depressives, were a severely depressed group who required hospitalization. Improvement occurred with both dosage regimens, although a greater and more consistent improvement was noted in the 300-mg group than in the 150-mg group. There were a few differences between the response of the endogenous and that of the neurotic depressives, as assessed by the physician and self=rating scales. However, endogenous depressives who received 150 mg were overrepresented in the treatment failure group. A comparison of the response of deluded and nondeluded depressives indicated that the deluded patients responded less well than the nondeluded depressives, although half of the delusional group did respond to the treatment.


Nutraceuticals in diabetes and metabolic syndrome.
Metabolic syndrome represents a clustering of risk factors related to an elevated risk of cardiovascular disease and type 2 diabetes. Occurrence of both metabolic syndrome and diabetes and their vascular complications share several pathogenetic features including subclinical, low-grade inflammation, altered oxidative/antioxidant status, and persistent platelet activation. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, weight control and drugs, epidemiological data are witnessing the growing trend of the problem, reflecting both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Several nutraceuticals used in clinical practice have been shown to target the pathogenesis of diabetes mellitus, metabolic syndrome and their complications and to favorably modulate a number of biochemical and clinical endpoints. These compounds include antioxidant vitamins, such as vitamins C and E, flavonoids, vitamin D, conjugated linoleic acid, omega-3 fatty acids, minerals such as chromium and magnesium, alpha-lipoic acid, phytoestrogens, and dietary fibers. Several areas of concern exist regarding the use of dietary supplements and nutraceuticals in this setting, including product standardization, definition of optimal dosing regimen, potential side effects, drug interactions, and need for evidence-based indications.


Highly Accurate and Robust Absolute Quantification of Target Proteins in Formalin-Fixed Paraffin-Embedded (FFPE) Tissues by LC-MS.
Accurate, absolute liquid chromatography-mass spectrometry (LC-MS)-based quantification of target proteins in formalin-fixed paraffin-embedded (FFPE) tissues would greatly expand sample availability for pharmaceutical/clinical investigations but remains challenging owing to the following issues: (i) efficient/quantitative recovery of target signature peptides from FFPE tissues is essential but an optimal procedure for targeted, absolute quantification is lacking; (ii) most FFPE samples are long-term-stored; severe immunohistochemistry (IHC) signal losses of target proteins during storage were widely reported, while the effect of storage on LC-MS-based methods was unknown; and (iii) the proper strategy to prepare calibration/quality-control samples to ensure accurate targeted protein analysis in FFPE tissues remained elusive. Using targeted quantification of monoclonal antibody (mAb), antigen, and 40 tissue markers in FFPE tissues as a model system, we extensively investigate those issues and develope an LC-MS-based strategy enabling accurate and precise targeted protein quantification in FFPE samples. First, we demonstrated a surfactant cocktail-based procedure (f-SEPOD), providing high/reproducible recovery of target signature peptides from FFPE tissues. Second, a heat-accelerated degradation study within a roughly estimated 5 year storage period recapitulated the loss of protein IHC signals while LC-MS signals of all targets remained constant. This indicates that the storage of FFPE tissues mainly causes decreased immunoreactivity but unlikely chemical degradation of proteins, which strongly suggests that the storage of FFPE tissues does not cause significant quantitative bias for LC-MS-based methods. Third, while a conventional spike-and-extract approach for calibration caused substantial negative biases, a novel approach, using FFPE-treated calibration standards, enabled accurate and precise quantification. With the pipeline, we conducted the first-ever pharmacokinetics measurement of mAb and its target in FFPE tissues, where time courses by FFPE vs fresh tissues showed excellent correlation.


Construction and validation of the Intragroup Marginalization Inventory.
This study reports the development and validation of the Intragroup Marginalization Inventory (IMI). The IMI consists of three scales that assess the extent to which an individual perceives interpersonal distancing from family, friends, and ethnic group community members. Intragroup marginalization is defined as the interpersonal distancing that occurs when an acculturating individual is believed to exhibit behaviors, values, and beliefs that are outside the heritage culture's group norms. Intragroup marginalization is based on social identity theory that asserts that groups maintain their identity by the distinctive behaviors of its members. When an acculturating individual displays behaviors or attitudes that differ from the heritage culture group's norms, the group may respond to the threat with social alienation of the transgressor. The results support the IMI's validity via a) content validity in the development of the items, b) construct validity in the selection of the factors based upon an exploratory factor analysis, c) the replicability of the factors based upon a confirmatory factor analysis, and d) discriminant validity through examining the relationship of the factors with other established measures.


[On the chronic toxicity of labetalol (AH-5158); a combined alpha-and beta-adrenoceptor-blocking agent (author's transl)].
Chronic toxicity and recovery tests of labetalol hydrochloride, alpha-and beta-adrenoceptor blocking agent, were carried out using male and female Wistar strain rats. The drug was orally administered at 50, 100 or 200 mg/kg/day for 9 months. In all the drug-treated groups, increase in salivation was observed from immediately after to 15 minutes after dosing through treatment period. Suppression of body weight gain was observed in male rats in the 200 mg/kg/day group. Food comsumption tended to be higher in all the drug-treated groups than in the control group. Similar trend was seen also in water comsumption, and increase in urine volume was noted in the groups treated with 100 and 200 mg/kg/day. In the serum biochemical examination, dose-dependent elevation in potassium level was noted in all drug-treated groups, but the values were within the range of physiological variation. In the 100 and 200 mg/kg/day groups, an increase was observed in the absolute heart weight and in its relative weight against body weight. Major abnormalities found in histopathological findings were; swelling of parenchymatous cells in liver and kidney, swelling of fibers and swelling or proliferation of interstitial cells in cardiac and skeletal muscles, and congestion in spleen. No notable abnormality was found in any examination item in the recovery test.


Efficiency and Stability of Step-To Gait in Slow Walking.
As humans, we constantly change our movement strategies to adapt to changes in physical functions and the external environment. We have to walk very slowly in situations with a high risk of falling, such as walking on slippery ice, carrying an overflowing cup of water, or muscle weakness owing to aging or motor deficit. However, previous studies have shown that a normal gait pattern at low speeds results in reduced efficiency and stability in comparison with those at a normal speed. Another possible strategy is to change the gait pattern from normal to step-to gait, in which the other foot is aligned with the first swing foot. However, the efficiency and stability of the step-to gait pattern at low speeds have not been investigated yet. Therefore, in this study, we compared the efficiency and stability of the normal and step-to gait patterns at intermediate, low, and very low speeds. Eleven healthy participants were asked to walk with a normal gait and step-to gait on a treadmill at five different speeds (i.e., 10, 20, 30, 40, and 60 m/min), ranging from very low to normal walking speed. The efficiency parameters (percent recovery and walk ratio) and stability parameters (center of mass lateral displacement) were analyzed from the motion capture data and then compared for the two gait patterns. The results suggested that step-to gait had a more efficient gait pattern at very low speeds of 10-30 m/min, with a larger percent recovery, and was more stable at 10-60 m/min in comparison with a normal gait. However, the efficiency of the normal gait was better than that of the step-to gait pattern at 60 m/min. Therefore, step-to gait is effective in improving gait efficiency and stability when faced with situations that force us to walk slowly or hinder quick walking because of muscle weakness owing to aging or motor deficit along with a high risk of falling.


Changes in the contents and profiles of selected phenolics, soyasapogenols, tocopherols, and amino acids during soybean-rice mixture cooking: Electric rice cooker vs electric pressure rice cooker.
This study investigated the changes in the contents and profiles of 35 phenolics (including 12 isoflavones), four tocopherols, two soyasapogenols and 20 amino acids when soybean and rice were cooked together (soybean-rice mixture) using either an electric rice cooker (ERC) or an electric pressure rice cooker (EPRC). The contents of the 35 selected phenolics in soybean decreased by 12% and 8% upon cooking by ERC and EPRC, respectively, and their profiles were different from that prior to cooking (P<0.05). Total tocopherol content of soybeans decreased by 7% after cooking in an ERC, but increased by 3% in soybeans cooked by EPRC. Total soyasapogenol content in soybeans cooked by ERC and EPRC decreased by 15% and 6%, respectively. Lastly, the total amino acid content of soybeans increased by 41% and 10% after cooking by ERC and EPRC, respectively. This study extends our knowledge about the effects of heat and pressure on the contents and profiles of bioactive compounds during soybean-rice mixture cooking. These results may be useful for improving the quality of bioactive compounds in soybean and rice depending on cooking conditions.


Glyphosate and a glyphosate-based herbicide affect bumblebee gut microbiota.
Pollinator decline is one of the gravest challenges facing the world today, and the overuse of pesticides may be among its causes. Here, we studied whether glyphosate, the world's most widely used pesticide, affects the bumblebee gut microbiota. We exposed the bumblebee diet to glyphosate and a glyphosate-based herbicide and quantified the microbiota community shifts using 16S rRNA gene sequencing. Furthermore, we estimated the potential sensitivity of bee gut microbes to glyphosate based on previously reported presence of target enzyme. Glyphosate increased, whereas the glyphosate-based herbicide decreased gut microbiota diversity, indicating that negative effects are attributable to co-formulants. Both glyphosate and the glyphosate-based herbicide treatments significantly decreased the relative abundance of potentially glyphosate-sensitive bacterial species Snodgrasella alvi. However, the relative abundance of potentially glyphosate-sensitive Candidatus Schmidhempelia genera increased in bumblebees treated with glyphosate. Overall, 50% of the bacterial genera detected in the bee gut microbiota were classified as potentially resistant to glyphosate, while 36% were classified as sensitive. Healthy core microbiota have been shown to protect bees from parasite infections, change metabolism, and decrease mortality. Thus, the heavy use of glyphosate-based herbicides may have implications on bees and ecosystems.


Changes of the acoustic startle reflex in rats with radiation-induced hippocampal lesion.
The main question of the study was: to what extent does a neonatal radiation-induced hippocampal lesion lead to emotional changes in adulthood? Acoustic startle response (ASR) was studied in two groups of adult rats. The rats from the first group (14 animals) were exposed to neonatal x-ray irradiation. Their ASR were compared with those from the 10 intact rats that formed a control group. The ASR was tested during two sessions with different illumination of the acoustic chamber. During the first session the rats were tested in the darkness while during the second test the acoustic chamber was illuminated with a 15 W bulb. Irradiation resulted in a significant reduction of granule cells of the hippocampus (about 55%). The lesion resulted in emotional and behavioral changes evidenced by modification of the ASR. The irradiated rats exhibited a significantly increased amplitude of the startle response. In contrast to the light condition, the darkness context caused a decline of the ASR amplitude in the control group and failed to elicit significant changes in the lesioned animals. The results support the hypothesis that hippocampal lesions disrupt motor inhibition.


An Introduction to Qualitative Health Research.
Within the context of evidence-informed decision making, health care professionals are critical consumers of research evidence. Clinician scientists, including nurse researchers, play a central role in producing this research evidence to inform and improve health practice, education, and policy. Health research is commonly conducted within one of three different paradigms: quantitative, qualitative or mixed methods. Each research approach is underpinned with unique philosophic assumptions, methods, and rhetoric. The evidence produced within each paradigm is necessary to provide health care decision-makers with information about the complex, and intrinsically diverse, human experiences of health and illness. Qualitative health research has been defined as a discipline, which has its roots in qualitative research and yet is unique in its focus, methods, and rules. The focus of qualitative health research is to describe, explore, and explain the health-illness continuum and issues specific to health services or policy contexts. Research designs unique to conducting qualitative health research include qualitative description, interpretive description, focused ethnography, and case study. Each qualitative health research design helps to logically and pragmatically determine the appropriate methods to use to: 1) define a purposeful sample; 2) identify appropriate strategies for data collection; 3) rigorously apply analytic techniques to the gathered data; and 4) present valid findings. In health, qualitative studies are often an integral component of program evaluations to identify and describe contextual factors related to individuals, teams, organizations or social structures that inhibit or facilitate the successful adoption, implementation and delivery of an intervention or program. Findings from qualitative studies can also inform the development of theoretically and contextually relevant assessment tools that can be used in practice.


Metabolism of benzo[a]pyrene in cell suspension cultures of parsley (Petroselinum hortense, Hoffm.) and soybean (Glycine max L.).
Cell suspension cultures of parsley and soybean were incubated for 38 h with (14)C-labeled benzo[a]pyrene; autoclaved cultures were used as controls. Metabolites were isolated by a sequential extraction procedure and further studied by chromatography or by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The soluble metabolites amounted to 1-2.2% in the case of parsley cells, and 19-28% in the case of soybean cells. These metabolites varied in polarity, some being soluble in organic solvent or aqueous buffer while other metabolite fractions were soluble only in hot aqueous sodium dodecylsulphate. In addition, a significant amount of an insoluble metabolite fraction was isolated from the culture fluid as well as the cellular material of soybean suspension cultures.


[Cryopreservation of ovarian tissue; now is the time for ethical considerations].
The development of ovarian tissue cryopreservation will expand the range of clinical applications in reproductive medicine. This emerging technology may have beneficial opportunities for patients, particularly in oncology, as well as for the process of oocyte donation. However, it will also lead to new moral problems requiring critical reflection concerning the criteria for tissue banking and future clinical applications. Because cryopreservation of ovarian tissue nowadays is the focus of experimental research, technology assessment is currently appropriate, anticipating introduction into clinical practice. Specific guidelines, developed by the medical profession in cooperation with ethicists and lawyers can contribute to prudent clinical use.


Phenology-dependent cold exposure and thermal performance of Ostrinia nubilalis ecotypes.
Understanding adaptation involves establishing connections between selective agents and beneficial population responses. However, relatively little attention has been paid to seasonal adaptation, in part, because it requires complex and integrative knowledge about seasonally fluctuating environmental factors, the effects of variable phenology on exposure to those factors, and evidence for temporal specialization. In the European corn borer moth, Ostrinia nubilalis, sympatric pheromone strains exploit the same host plant (Zea mays) but may genetically differ in phenology and be reproductively "isolated by time." Z strain populations in eastern North America have been shown to have a prolonged larval diapause and produce one annual mating flight (July), whereas E strain populations complete an earlier (June) and a later (August) mating flight by shortening diapause duration. Here, we find evidence consistent with seasonal "adaptation by time" between these ecotypes. We use 12 years of field observation of adult seasonal abundance to estimate phenology of ecotype life cycles and to quantify life-stage specific climatic conditions. We find that the observed reduction of diapause duration in the E strain leads their non-diapausing, active life stages to experience a ~ 4 °C colder environment compared to the equivalent life stages in the Z strain. For a representative pair of populations under controlled laboratory conditions, we compare life-stage specific cold tolerance and find non-diapausing, active life stages in the E strain have as much as a 60% greater capacity to survive rapid cold shock. Enhanced cold hardiness appears unrelated to life-stage specific changes in the temperature at which tissues freeze. Our results suggest that isolation by time and adaptation by time may both contribute to population divergence, and they argue for expanded study in this species of allochronic populations in nature experiencing the full spectrum of seasonal environments. Cyclical selective pressures are inherent properties of seasonal habitats. Diverse fluctuating selective agents across each year (temperature, predation, competition, precipitation, etc.) may therefore be underappreciated drivers of biological diversity.


Contextual priming: where people vote affects how they vote.
American voters are assigned to vote at a particular polling location (e.g., a church, school, etc.). We show these assigned polling locations can influence how people vote. Analysis of a recent general election demonstrates that people who were assigned to vote in schools were more likely to support a school funding initiative. This effect persisted even when controlling for voters' political views, demographics, and unobservable characteristics of individuals living near schools. A follow-up experiment using random assignment suggests that priming underlies these effects, and that they can occur outside of conscious awareness. These findings underscore the subtle power of situational context to shape important real-world decisions.


4-Mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 2. Computational and experimental approach of the radical scavenging mechanism.
The radical-scavenging mechanism of fourteen 4-mercaptoimidazoles, derived from the natural family of ovothiols, was studied via a QSAR approach, cyclic voltammetry, ESR and NMR spectroscopy. A significant correlation was found between the DPPH scavenging abilities of test compounds and thermodynamic parameters like overall ease of disulphide formation. The production of a disulphide compound via thiyl radical formation is proposed. Upon DPPH scavenging, hydrogen abstraction from thiols yields transient short-lived thiyl radicals, which were characterised by ESR and rapidly dimerise to form a disulphide compound. Cyclic voltammetry showed that the best DPPH scavengers exhibit low oxidation potentials for their oxidation to disulphides.


Ethics and Medical Aid in Dying: Physicians' Perspectives on Disclosure, Presence, and Eligibility.
Medical aid in dying (MAiD), despite being legal in many jurisdictions, remains controversial ethically. Existing surveys of physicians' perceptions of MAiD tend to focus on the legal or moral permissibility of MAiD in general. Using a novel sampling strategy, we surveyed physicians likely to have engaged in MAiD-related activities in Colorado to assess their attitudes toward contemporary ethical issues in MAiD.


Effects of long-term moderate food restriction on growth, serum factors, lipogenic enzymes and adipocyte glucose metabolism in lean and obese Zucker rats.
The effects of long-term moderate food restriction were assessed in lean and obese male Zucker rats. A 30% reduction in food intake from 5 to 68 wk of age resulted in parallel lowering of body weight in both lean and obese rats compared to their respective ad libitum-fed control groups. In lean rats, epididymal and retroperitoneal fat pad weights and cell size were lowered by food restriction. In obese rats there was an effect of food restriction on growth of the epididymal pad but not the retroperitoneal pad. Hyperinsulinemia, hyperlipidemia and elevated serum albumin levels, as well as higher activity of lipogenic enzymes, were also not affected by food restriction in the obese rat. In a second experiment, long-term food restriction resulted in greater glucose conversion to CO2 in response to insulin in adipocytes from lean rats but not obese rats compared to their respective control groups. These results indicate that food restriction throughout the first year of life in the obese Zucker rat does not alter the development of hyperplastic obesity and insulin resistance.


Ungulate saliva inhibits a grass-endophyte mutualism.
Fungal endophytes modify plant-herbivore interactions by producing toxic alkaloids that deter herbivory. However, studies have neglected the direct effects herbivores may have on endophytes. Antifungal properties and signalling effectors in herbivore saliva suggest that evolutionary pressures may select for animals that mitigate the effects of endophyte-produced alkaloids. Here, we tested whether saliva of moose (Alces alces) and European reindeer (Rangifer tarandus) reduced hyphal elongation and production of ergot alkaloids by the foliar endophyte Epichloë festucae associated with the globally distributed red fescue Festuca rubra. Both moose and reindeer saliva reduced the growth of isolated endophyte hyphae when compared with a treatment of distilled water. Induction of the highly toxic alkaloid ergovaline was also inhibited in plants from the core of F. rubra's distribution when treated with moose saliva following simulated grazing. In genotypes from the southern limit of the species' distribution, ergovaline was constitutively expressed, as predicted where growth is environmentally limited. Our results now present the first evidence, to our knowledge, that ungulate saliva can combat plant defences produced by a grass-endophyte mutualism.


Evaluation of the diagnostic power of thermography in breast cancer using Bayesian network classifiers.
Breast cancer is one of the leading causes of death among women worldwide. There are a number of techniques used for diagnosing this disease: mammography, ultrasound, and biopsy, among others. Each of these has well-known advantages and disadvantages. A relatively new method, based on the temperature a tumor may produce, has recently been explored: thermography. In this paper, we will evaluate the diagnostic power of thermography in breast cancer using Bayesian network classifiers. We will show how the information provided by the thermal image can be used in order to characterize patients suspected of having cancer. Our main contribution is the proposal of a score, based on the aforementioned information, that could help distinguish sick patients from healthy ones. Our main results suggest the potential of this technique in such a goal but also show its main limitations that have to be overcome to consider it as an effective diagnosis complementary tool.


Treatment of FLT3-ITD acute myeloid leukemia.
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.


Re-thinking stroke rehabilitation: the Corbin and Strauss chronic illness trajectory framework.
Re-thinking stroke rehabilitation: the Corbin and Strauss chronic illness trajectory framework The dramatic effects of a stroke can have far-reaching implications for patients and carers. Effective recovery involves a considerable array of coping strategies that facilitate and promote engagement in the social world. Their development is a long-term process that requires considerable effort, motivation and enterprise on the part of patients and their families. Traditional approaches to the provision of stroke rehabilitation services, however, appear to be underpinned by frameworks that are short-term in outlook. As a consequence, nursing interventions often focus on the progression of the patient through the care system, rather than on facilitating future recovery. Much of the work of stroke recovery is consequently done by patients and their families at home, with little provision of ongoing professional help and advice. This paper explores the application of the Corbin and Strauss Chronic Illness Trajectory Framework for stroke. In particular, the major concepts of the framework are applied to a vignette derived from a longitudinal study of patients' experiences of recovery. The trajectory framework is shown to be a useful structure that has the potential to enhance the appropriateness of nursing interventions for stroke patients. However, the validity of the framework can only be established through its application and evaluation in clinical practice. The purpose of this paper is to contribute to a debate that encourages consideration of the framework's utility for nurses to enhance the stroke rehabilitation experience.


Factors affecting use of magnesium sulphate for pre-eclampsia or eclampsia: a qualitative evidence synthesis.
Hypertensive disorders account for 14% of global maternal deaths. Magnesium sulphate (MgSO4 ) is recommended for prevention and treatment of pre-eclampsia/eclampsia. However, MgSO4 remains underused, particularly in low- and middle-income countries (LMICs). This qualitative evidence synthesis explores perceptions and experiences of healthcare providers, administrators and policy-makers regarding factors affecting use of MgSO4 to prevent or treat pre-eclampsia/eclampsia. We searched MEDLINE, EMBASE, Emcare, CINAHL, Global Health and Global Index Medicus, and grey literature for studies published between January 1995 and June 2021. Primary qualitative and mixed-methods studies on factors affecting use of MgSO4 in healthcare settings, from the perspectives of healthcare providers, administrators and policy-makers, were eligible for inclusion. We applied a thematic synthesis approach to analysis, using COM-B behaviour change theory to map factors affecting appropriate use of MgSO4 . We included 22 studies, predominantly from LMICs. Key themes included provider competence and confidence administering MgSO4 (attitudes and beliefs, complexities of administering, knowledge and experience), capability of health systems to ensure MgSO4 availability at point of use (availability, resourcing and pathways to care) and knowledge translation (dissemination of research and recommendations). Within each COM-B domain, we mapped facilitators and barriers to physical and psychological capability, physical and social opportunity, and how the interplay between these domains influences motivation. These findings can inform policy and guideline development and improve implementation of MgSO4 in clinical care. Such action is needed to ensure this life-saving treatment is widely available and appropriately used. Global qualitative review identifies factors affecting underutilisation of MgSO4 for pre-eclampsia and eclampsia.