Metformin alleviates hyperglycemia-induced endothelial impairment by downregulating autophagy via the Hedgehog pathway.
Studies regarding macroautophagic/autophagic regulation in endothelial cells (ECs) under diabetic conditions are very limited. Clinical evidence establishes an endothelial protective effect of metformin, but the underlying mechanisms remain unclear. We aimed to investigate whether metformin exerts its protective role against hyperglycemia-induced endothelial impairment through the autophagy machinery. db/db mice were treated with intravitreal metformin injections. Human umbilical vein endothelial cells (HUVECs) were cultured either in normal glucose (NG, 5.5 mM) or high glucose (HG, 33 mM) medium in the presence or absence of metformin for 72 h. We observed an obvious inhibition of hyperglycemia-triggered autophagosome synthesis in both the diabetic retinal vasculature and cultured HUVECs by metformin, along with restoration of hyperglycemia-impaired Hedgehog (Hh) pathway activity. Specifically, deletion of ATG7 in retinal vascular ECs of db/db mice and cultured HUVECs indicated a detrimental role of autophagy in hyperglycemia-induced endothelial dysfunction. Pretreatment with GANT61, a Hh pathway inhibitor, abolished the metformin-mediated downregulation of autophagy and endothelial protective action. Furthermore, GLI-family (transcription factors of the Hh pathway) knockdown in HUVECs and retinal vasculature revealed that downregulation of hyperglycemia-activated autophagy by the metformin-mediated Hh pathway activation was GLI1 dependent. Mechanistically, GLI1 knockdown-triggered autophagy was related to upregulation of BNIP3, which subsequently disrupted the association of BECN1/Beclin 1 and BCL2. The role of BNIP3 in BECN1 dissociation from BCL2 was further confirmed by BNIP3 overexpression or BNIP3 RNAi. Taken together, the endothelial protective effect of metformin under hyperglycemia conditions could be partly attributed to its role in downregulating autophagy via Hh pathway activation. Abbreviations: 3-MA = 3-methyladenine; 8×GLI BS-FL = 8×GLI-binding site firefly luciferase; AAV = adeno-associated virus; AAV-Cdh5-sh-Atg7 = AAV vectors carrying shRNA against murine Atg7 under control of murine Cdh5 promoter; AAV-Cdh5-sh-Gli1 = AAV vectors carrying shRNA against murine Gli1 under control of murine Cdh5 promoter; AAV-Cdh5-Gli1 = AAV vectors carrying murine Gli1 cDNA under the control of murine Cdh5 core promoter; ACAC = acetyl-CoA carboxylase; Ad-BNIP3 = adenoviruses harboring human BNIP3`; Ad-GLI1 = adenoviruses harboring human GLI1; Ad-sh-ATG7 = adenoviruses harboring shRNA against human ATG7; Ad-sh-BNIP3 = adenoviruses harboring shRNA against human BNIP3; Ad-sh-GLI = adenoviruses harboring shRNA against human GLI; AGEs = advanced glycation end products; ATG = autophagy-related; atg7flox/flox mice = mice bearing an Atg7flox allele, in which exon 14 of the Atg7 gene is flanked by 2 loxP sites; BafA1 = bafilomycin A1; BECN1 = beclin 1; CDH5/VE-cadherin = cadherin 5; CASP3 = caspase 3; CASP8 = caspase 8; CASP9 = caspase 9; ECs = endothelial cells; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; GCL = ganglion cell layer; GFP-LC3B = green fluorescent protein labelled LC3B; HG = high glucose; Hh = Hedgehog; HHIP = hedgehog interacting protein; HUVECs = human umbilical vein endothelial cells; IB4 = isolectin B4; INL = inner nuclear layer; i.p. = intraperitoneal; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MAN = mannitol; MET = metformin; NG = normal glucose; ONL = outer nuclear layer; p-ACAC = phosphorylated acetyl-CoA carboxylase; PECAM1/CD31= platelet/endothelial cell adhesion molecule 1; PRKAA1/2 = protein kinase AMP-activated catalytic subunits alpha 1/2; p-PRKAA1/2 = phosphorylated PRKAA1/2; PTCH1 = patched 1; RAPA = rapamycin; RL = Renilla luciferase; SHH = sonic hedgehog; shRNA = short hairpin RNA; sh-PRKAA1/2 = short hairpin RNA against human PRKAA1/2; scrambled shRNA = the scrambled short hairpin RNA serves as a negative control for the target-specific short hairpin RNA, which has the same nucleotide composition as the input sequence and has no match with any mRNA of the selected organism database; SMO = smoothened, frizzled class receptor; sqRT-PCR = semi-quantitative RT-PCR; TEK/Tie2 = TEK receptor tyrosine kinase; Tek-Cre (+) mice = a mouse strain expressing Cre recombinase under the control of the promoter/enhancer of Tek, in a pan-endothelial fashion; TUNEL = terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling.


Rotator cuff: evaluation with fat-suppressed MR arthrography.
Thirty-seven shoulders with rotator cuff diagnoses proved at arthrography, arthroscopy, or open surgery were examined prospectively with magnetic resonance (MR) arthrography. T1-weighted MR images were obtained with and without fat suppression after intraarticular injection of gadopentetate dimeglumine. Without fat suppression, overall accuracy was 84%. False-positive full-thickness tears were diagnosed in three patients who were proved to have partial tears. False-negative normal tendons were diagnosed in two patients who had partial tears. The corresponding sensitivity and specificity were 90% and 75%, respectively. With the aid of fat-suppressed imaging, full-thickness and partial cuff tears were identified with 100% sensitivity and specificity. Fat-suppressed images also showed intratendinous contrast material imbibition in three torn cuffs with frayed, friable tendon margins. Fat suppression in MR arthrography is valuable in the differentiation of partial from full-thickness cuff tears and in the detection of small partial tears of the inferior tendon surface.


Tools for decision-making in older cancer patients. Role of the comprehensive geriatric assessment.
Approximately 60% of cancer incidence and 70% of cancer mortality occurs in individuals older than 65 years. The optimal approach to cancer therapy in older adults is often unclear. Historically, advanced age has been an exclusion criterion in clinical cancer trials, and older adults have been consistently underrepresented. As a result, there is a lack of information about treatment efficacy and tolerability in this population. Comprehensive Geriatric Assessment (CGA) is one of the most useful tools for the oncologist to make decisions related to older patients diagnosed with cancer. This tool has proved to be very useful to detect many deficits, tolerance to chemotherapy and survival in such patients. In this review, we analyze the role of CGA in decision making in geriatric oncology.


DJ-1 in Ocular Diseases: A Review.
Protein deglycase DJ-1 (Parkinson disease protein 7) is a 20 kDa protein encoded by PARK7 gene. It is also known as a redox-sensitive chaperone and sensor that protect cells against oxidative stress-induced cell death in many human diseases. Though increasing evidence implicates that DJ-1 may also participate in ocular diseases, the overview of DJ-1 in ocular diseases remains elusive. In this review, we discuss the role as well as the underlying molecular mechanisms of DJ-1 in ocular diseases, including Fuchs endothelial corneal dystrophy (FECD), age-related macular degeneration (AMD), cataracts, and ocular neurodegenerative diseases, highlighting that DJ-1 may serve as a very striking therapeutic target for ocular diseases.


The maturase HydF enables [FeFe] hydrogenase assembly via transient, cofactor-dependent interactions.
[FeFe] hydrogenases have attracted extensive attention in the field of renewable energy research because of their remarkable efficiency for H2 gas production. H2 formation is catalyzed by a biologically unique hexanuclear iron cofactor denoted the H-cluster. The assembly of this cofactor requires a dedicated maturation machinery including HydF, a multidomain [4Fe4S] cluster protein with GTPase activity. HydF is responsible for harboring and delivering a precatalyst to the apo-hydrogenase, but the details of this process are not well understood. Here, we utilize gas-phase electrophoretic macromolecule analysis to show that a HydF dimer forms a transient interaction complex with the hydrogenase and that the formation of this complex depends on the cofactor content on HydF. Moreover, Fourier transform infrared, electron paramagnetic resonance, and UV-visible spectroscopy studies of mutants of HydF show that the isolated iron-sulfur cluster domain retains the capacity for binding the precatalyst in a reversible fashion and is capable of activating apo-hydrogenase in in vitro assays. These results demonstrate the central role of the iron-sulfur cluster domain of HydF in the final stages of H-cluster assembly, i.e. in binding and delivering the precatalyst.


Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus.
Vaccines against influenza viruses with pandemic potential, including H5N1, are under development. Because of a lack of preexisting immunity to these viruses, adjuvants (immune potentiators or enhancers) are needed to improve immune responses, to conserve scarce vaccine, and for cross-protection against strains that have drifted evolutionarily from the original. Aluminum-based adjuvants do not improve vaccine immunogenicity for influenza subunit vaccines, whereas oil-in-water adjuvants are effective, especially with H5N1-inactivated vaccines. We used whole-genome-fragment phage display libraries followed by surface plasmon resonance (SPR) technologies to elucidate the effect of different adjuvants on the antibody repertoire against H5N1 vaccine in humans. The oil-in-water adjuvant MF59 induced epitope spreading from HA2 to HA1 in hemagglutinin (HA) and neuraminidase relative to unadjuvanted or aluminum-adjuvanted vaccines. Moreover, we observed an increase by a factor of 20 in the frequency of HA1-to-HA2-specific phage clones in sera after MF59-adjuvanted vaccine administration and a factor of 2 to 3 increase in the avidity of antibodies binding to properly folded HA1(28-319), as measured by SPR. The adjuvant-dependent increase in binding to conformational HA1 epitopes correlated with broadening of cross-clade neutralization and predicted improved in vivo protection. Thus, MF59 adjuvant improves the immune response to a H5N1 vaccine by inducing qualitative and quantitative expansion of the antibody repertoires with protective potential.


Effect of a monoclonal anti-large granular lymphocyte antibody on the human NK activity.
A monoclonal hybridoma antibody of IgGIa subclass was produced by fusing NS-1 myeloma cells with spleen cells of a mouse immunized with human LGL cells. This hybridoma antibody, termed NK-8, was reactive by indirect immunofluorescence with 33% of peripheral blood LGL cells and 70% of LGL forming conjugates with K-562 cells. Monocytes, granulocytes, and other lymphocytes were nonreactive. In iodinated protein A binding assays NK-8 was nonreactive with all kinds of leukemia and lymphoma lines tested and showed activity only against LGL cells. NK-8 inhibited the LGL-mediated cytotoxicity against K-562 cells by 50 to 60% without complement and inhibited the K-562 induced interferon production from the LGL population. However, the spontaneous cytotoxicity against human skin fibroblasts was augmented if the effector cells were pretreated with NK-8.


A prospective cohort study of maternal and neonatal morbidity in relation to use of episiotomy at operative vaginal delivery.
To evaluate the maternal and neonatal morbidity of operative vaginal delivery in relation to the use of episiotomy. Prospective cohort study. Two urban maternity units in Scotland and England. All nonrandomised nulliparous women delivered by forceps or vacuum during the recruitment period of a clinical trial evaluating the use of episiotomy at operative vaginal delivery. Use of episiotomy was compared to no episiotomy for all operative vaginal deliveries with sub-group analyses for forceps or vacuum deliveries. The primary outcome was anal sphincter tearing (third or fourth degree). Secondary outcomes included postpartum haemorrhage, neonatal trauma and pelvic floor symptoms up until 10 days postpartum. A total of 1360 women were included in the study, of whom 294 (21.6%) did not receive an episiotomy. Vacuum delivery was associated with less use of episiotomy than forceps (56.1 versus 89.4%, OR 0.15, 95% CI 0.11-0.20). Anal sphincter tear rates were not statistically different with use of episiotomy compared with no episiotomy (9.9 versus 7.1%, adjusted OR 1.11, 95% CI 0.66-1.87). Episiotomy use was associated with higher rates of postpartum haemorrhage (28.5 versus 18.4%, adjusted OR 1.72, 95% CI 1.21-2.45), need for moderate or strong analgesia (90.5 versus 67.6%, adjusted OR 3.70, 95% CI 2.60-5.27), perineal infection (5.1 versus 1.4%, adjusted OR 4.04, 95% CI 1.44-11.37) and neonatal trauma (38.1 versus 22.0%, adjusted OR 1.65, 95% CI 1.20-2.27). Use of episiotomy did not reduce the risk of shoulder dystocia (3.5 versus 1.7%, adjusted OR 1.42, 95% CI 0.53-3.85). The use of episiotomy did not reduce or greatly increase anal sphincter tears and was associated with greater maternal and neonatal morbidity. This may reflect the complexity of deliveries. The role of episiotomy at operative vaginal delivery should be evaluated in a randomised controlled trial.


IFN-β mediates suppression of IL-12p40 in human dendritic cells following infection with virulent Francisella tularensis.
Active suppression of inflammation is a strategy used by many viral and bacterial pathogens, including virulent strains of the bacterium Francisella tularensis, to enable colonization and infection in susceptible hosts. In this study, we demonstrated that virulent F. tularensis strain SchuS4 selectively inhibits production of IL-12p40 in primary human cells via induction of IFN-β. In contrast to the attenuated live vaccine strain, infection of human dendritic cells with virulent SchuS4 failed to induce production of many cytokines associated with inflammation (e.g., TNF-α and IL-12p40). Furthermore, SchuS4 actively suppressed secretion of these cytokines. Assessment of changes in the expression of host genes associated with suppression of inflammatory responses revealed that SchuS4, but not live vaccine strain, induced IFN-β following infection of human dendritic cells. Phagocytosis of SchuS4 and endosomal acidification were required for induction of IFN-β. Further, using a defined mutant of SchuS4, we demonstrated that the presence of bacteria in the cytosol was required, but not sufficient, for induction of IFN-β. Surprisingly, unlike previous reports, induction of IFN-β by F. tularensis was not required for activation of the inflammasome, was not associated with exacerbation of inflammatory responses, and did not control SchuS4 replication when added exogenously. Rather, IFN-β selectively suppressed the ability of SchuS4-infected dendritic cells to produce IL-12p40. Together, these data demonstrated a novel mechanism by which virulent bacteria, in contrast to attenuated strains, modulate human cells to cause disease.


MicroRNA 221 expression in theca and granulosa cells: hormonal regulation and function.
Small noncoding RNA molecules (miRNA) regulate protein levels in a post-transcriptional manner by partial base pairing to the 3'-UTR of target genes thus mediating degradation or translational repression. Previous studies indicate that numerous miRNA regulate the biosynthesis of intraovarian hormones, and emerging evidence indicates that one of these, miRNA-221 (MIR221), may be a modulator of ovarian function. However, the hormonal control of ovarian MIR221 is not known. The objectives of this study were to investigate the developmental and hormonal regulation of MIR221 expression in granulosa (GC) and theca cell (TC) and its possible role in regulating follicular function. Bovine ovaries were collected from a local abattoir and GC and TC were obtained from small (<6 mm) and large (≥8 mm) follicles. In Exp. 1, GCs of small follicles had 9.7-fold greater (P < 0.001) levels of MIR221 than those of large follicles, and TCs of large follicles had 3.7-fold greater (P < 0.001) levels of MIR221 than those of small follicles. In large follicles, abundance of MIR221 was 66.6-fold greater (P < 0.001) in TCs than in GCs. In small follicles, MIR221 abundance did not differ (P = 0.14) between GC and TCs. In vitro Exp. 2, 3, and 4 revealed that treatment of bovine TCs with various steroids, phytoestrogens, IGF1, forskolin, and dibutyryl cyclic adenosine monophosphate had no effect (P > 0.35) on MIR221 expression, whereas treatment with fibroblast growth factor 9 (FGF9) and FGF2 increased (P < 0.001) TC MIR221 abundance 1.7- to 2.5-fold. In Exp. 5, FGF9 increased (P < 0.05) GC MIR221 abundance by 1.7- and 2.0-fold in small and large follicles, respectively. The role of MIR221 in GC steroidogenesis was investigated in Exp. 6 and it was found that transfection with a MIR221 mimic reduced (P < 0.01) GC estradiol and progesterone production induced by FSH and IGF1, whereas transfection with MIR221 inhibitor had little or no effect. We conclude that thecal MIR221 expression is increased by FGF9 and increased MIR221 may act to inhibit GC steroidogenesis in cattle.


Multimodal chronic pain rehabilitation program: its effect on immune function, depression, and health behaviors.
This pilot study examined the effects of a multimodal pain rehabilitation program on the immune function, self-reported pain, depression levels, and health behaviors of patients with chronic back pain. It also estimated the relationships between self-reported pain levels, immune function, depression, and health behaviors. Data were collected at week 1 (baseline) and at week 4 (last week of treatment program) on a convenience sample of 23 patients. In general, the patients' mean T lymphocyte proliferation levels showed a decline from baseline to week 4, while natural killer cell activity showed a slight increase in cell lysis. None of the findings were statistically significant. Failure to detect significant differences may be attributed to a small effect size due to the relatively small sample size. The depression levels dropped significantly during the treatment program (p = .001). Reported levels of pain and health behaviors did not significantly change. More research is needed to determine treatment effects on immune function as well as relationships between pain levels, immune function, depression, and health behaviors in this patient population.


Conserved, yet disruption-prone, gut microbiomes in neotropical bumblebees.
Bumblebees are important pollinators in natural ecosystems and agriculture, but many species are declining. Temperate-zone bumblebees have host-specific and beneficial gut microbiomes, which may have a role in mediating the effects of stressors. However, there is almost no published information on the gut microbiomes of tropical bumblebees. As temperate and tropical bumblebees encounter different floral resources and environmental conditions, their microbiomes could differ. Here, we characterized the gut microbiomes of four neotropical Bombus species and, for comparison, co-occurring solitary bees (genus Thygater). We collected wild-foraging bees from multiple sites in central Colombia and used 16S rRNA gene sequencing to characterize their gut microbiomes. DNA barcoding and morphology were used to identify bumblebee species. We found that the microbiomes of neotropical bumblebees cluster with those of closely related temperate-zone species, in agreement with a model of bumblebee-symbiont codiversification. There was no evidence of geographic differences in microbiome composition between neotropical and temperate-zone bumblebees. These results suggest that the microbiome was conserved during bumblebee dispersal from North America, despite major shifts in ecology and life history. As previously observed in temperate-zone species, some neotropical bumblebees have highly disrupted microbiomes, in which conserved gut bacterial symbionts are replaced by environmental microbes. In these individuals, the gut microbial profile is more like that of solitary bees than of conspecifics. The gut parasites Nosema and Crithidia are also prevalent and associated with microbiome disruption. Our findings provide insights into the biogeography of bee microbiomes and a foundation for studying bee-microbe-stressor interactions in the neotropics. IMPORTANCE Social bees are an important model for the ecology and evolution of gut microbiomes. These bees harbor ancient, specific, and beneficial gut microbiomes and are crucial pollinators. However, most of the research has concentrated on managed honeybees and bumblebees in the temperate zone. Here we used 16S rRNA gene sequencing to characterize gut microbiomes in wild neotropical bumblebee communities from Colombia. We also analyzed drivers of microbiome structure across our data and previously published data from temperate bumblebees. Our results show that lineages of neotropical bumblebees not only retained their ancient gut bacterial symbionts during dispersal from North America but also are prone to major disruption, a shift that is strongly associated with parasite infection. Finally, we also found that microbiomes are much more strongly structured by host phylogeny than by geography, despite the very different environmental conditions and plant communities in the two regions.


Assessment of global histone acetylation in pediatric and adolescent obesity: Correlations with SIRT1 expression and metabolic-inflammatory profiles.
Epigenetic modifications, particularly histone acetylation-deacetylation and its related enzymes, such as sirtuin 1 (SIRT1) deacetylase, may have substantial roles in the pathogenesis of obesity and its associated health issues. This study aimed to evaluate global histone acetylation status and SIRT1 gene expression in children and adolescents with obesity and their association with metabolic and anthropometric parameters. This study included 60 children and adolescents, 30 with obesity and 30 normal-weight. The evaluation consisted of the analysis of global histone acetylation levels and the expression of the SIRT1 gene in peripheral blood mononuclear cells, by specific antibody and real-time PCR, respectively. Additionally, insulin, fasting plasma glucose, lipid profile and tumor necrosis factor α (TNF-α) levels were measured. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Metabolic syndrome was determined based on the diagnostic criteria established by IDF. Individuals with obesity, particularly those with insulin resistance, had significantly higher histone acetylation levels compared to control group. Histone acetylation was positively correlated with obesity indices, TNF-α, insulin, and HOMA-IR. Additionally, a significant decrease in SIRT1 gene expression was found among obese individuals, which was negatively correlated with the histone acetylation level. Furthermore, SIRT1 expression levels showed a negative correlation with various anthropometric and metabolic parameters. Histone acetylation was enhanced in children and adolescents with obesity, potentially resulting from down-regulation of SIRT1, and could play a role in the obesity-associated metabolic abnormalities and insulin resistance. Targeting global histone acetylation modulation might be considered as an epigenetic approach for early obesity management.


Spin-flip induced magnetoresistance in positionally disordered organic solids.
A model for magnetoresistance in positionally disordered organic materials is presented and solved using percolation theory. The model describes the effects of spin dynamics on hopping transport by considering changes in the effective density of hopping sites, a key quantity determining the properties of percolative transport. Faster spin-flip transitions open up "spin-blocked" pathways to become viable conduction channels and hence produce magnetoresistance. Features of this percolative magnetoresistance can be found analytically in several regimes, and agree with previous measurements, including the sensitive dependence of the magnetic-field dependence of the magnetoresistance on the ratio of the carrier hopping time to the hyperfine-induced carrier spin precession time. Studies of magnetoresistance in known systems with controllable positional disorder would provide an additional stringent test of this theory.


Utilization of Stop-flow Micro-tubing Reactors for the Development of Organic Transformations.
A new reaction screening technology for organic synthesis was recently demonstrated by combining elements from both continuous micro-flow and conventional batch reactors, coined stop-flow micro-tubing (SFMT) reactors. In SFMT, chemical reactions that require high pressure can be screened in parallel through a safer and convenient way. Cross-contamination, which is a common problem in reaction screening for continuous flow reactors, is avoided in SFMT. Moreover, the commercially available light-permeable micro-tubing can be incorporated into SFMT, serving as an excellent choice for light-mediated reactions due to a more effective uniform light exposure, compared to batch reactors. Overall, the SFMT reactor system is similar to continuous flow reactors and more superior than batch reactors for reactions that incorporate gas reagents and/or require light-illumination, which enables a simple but highly efficient reaction screening system. Furthermore, any successfully developed reaction in the SFMT reactor system can be conveniently translated to continuous-flow synthesis for large scale production.


Triangulation and Parent-Adolescent Relationships: Implications for Adolescent Dating Competence and Abuse.
This study focuses on family predictors of conflict behavior in adolescent dating relationships, drawing on family systems and socialization perspectives. Mother-adolescent, father-adolescent, and triadic relationships each was examined as predictors of adolescent dating outcomes that hold importance for developmental and prevention science (positive conflict resolution, verbal abuse, and physical abuse). We conducted a longitudinal analysis using a 6-month longitudinal design with 236 ethnically diverse high school students. Findings indicate that triangulation into parental conflicts was related to increases in positive conflict resolution and with increases in verbally abusive behavior with dating partners over time. Parent-adolescent closeness and conflict each was related to positive conflict resolution and verbal abuse, but these associations were only found for boys.


Selective Targeting of Integrin αvβ8 by a Highly Active Cyclic Peptide.
Integrins play important roles in physiological and pathophysiological processes. Among the RGD-recognizing integrin subtypes, the αvβ8 receptor is emerging as an attractive target because of its involvement in various illnesses, such as autoimmune diseases, viral infections, and cancer. However, its functions have, so far, not been investigated in living subjects mainly because of the lack of a selective αvβ8 ligand. Here, we report the design and potential medical applications of a cyclic octapeptide as the first highly selective small-molecule ligand for αvβ8. Remarkably, this compound displays low nanomolar αvβ8 binding affinity and a strong discriminating power of at least 2 orders of magnitude versus other RGD-recognizing integrins. Peptide functionalization with fluorescent or radioactive labels enables the selective imaging of αvβ8-positive cells and tissues. This new probe will pave the way for detailed characterization of the distinct (patho)physiological role of this relatively unexplored integrin, providing a basis to fully exploit the potential of αvβ8 as a target for molecular diagnostics and personalized therapy regimens.


Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases.
This is an update to the review published in the Cochrane Library (2012, Issue 4).It is estimated that 20% to 40% of people with cancer will develop brain metastases during the course of their illness. The burden of brain metastases impacts quality and length of survival. To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) given alone or in combination with other therapies to adults with newly diagnosed multiple brain metastases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase to May 2017 and the National Cancer Institute Physicians Data Query for ongoing trials. We included phase III randomised controlled trials (RCTs) comparing WBRT versus other treatments for adults with newly diagnosed multiple brain metastases. Two review authors independently assessed trial quality and abstracted information in accordance with Cochrane methods. We added 10 RCTs to this updated review. The review now includes 54 published trials (45 fully published reports, four abstracts, and five subsets of data from previously published RCTs) involving 11,898 participants.Lower biological WBRT doses versus controlThe hazard ratio (HR) for overall survival (OS) with lower biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 1.21 (95% confidence interval (CI) 1.04 to 1.40; P = 0.01; moderate-certainty evidence) in favour of control. The HR for neurological function improvement (NFI) was 1.74 (95% CI 1.06 to 2.84; P = 0.03; moderate-certainty evidence) in favour of control fractionation.Higher biological WBRT doses versus controlThe HR for OS with higher biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 0.97 (95% CI 0.83 to 1.12; P = 0.65; moderate-certainty evidence). The HR for NFI was 1.14 (95% CI 0.92 to 1.42; P = 0.23; moderate-certainty evidence).WBRT and radiosensitisersThe addition of radiosensitisers to WBRT did not confer additional benefit for OS (HR 1.05, 95% CI 0.99 to 1.12; P = 0.12; moderate-certainty evidence) or for brain tumour response rates (odds ratio (OR) 0.84, 95% CI 0.63 to 1.11; P = 0.22; high-certainty evidence).Radiosurgery and WBRT versus WBRT aloneThe HR for OS with use of WBRT and radiosurgery boost as compared with WBRT alone for selected participants was 0.61 (95% CI 0.27 to 1.39; P = 0.24; moderate-certainty evidence). For overall brain control at one year, the HR was 0.39 (95% CI 0.25 to 0.60; P < 0.0001; high-certainty evidence) favouring the WBRT and radiosurgery boost group.Radiosurgery alone versus radiosurgery and WBRTThe HR for local brain control was 2.73 (95% CI 1.87 to 3.99; P < 0.00001; high-certainty evidence)favouring the addition of WBRT to radiosurgery. The HR for distant brain control was 2.34 (95% CI 1.73 to 3.18; P < 0.00001; high-certainty evidence) favouring WBRT and radiosurgery. The HR for OS was 1.00 (95% CI 0.80 to 1.25; P = 0.99; moderate-certainty evidence). Two trials reported worse neurocognitive outcomes and one trial reported worse quality of life outcomes when WBRT was added to radiosurgery.We could not pool data from trials related to chemotherapy, optimal supportive care (OSC), molecular targeted agents, neurocognitive protective agents, and hippocampal sparing WBRT. However, one trial reported no differences in quality-adjusted life-years for selected participants with brain metastases from non-small-cell lung cancer randomised to OSC and WBRT versus OSC alone. None of the trials with altered higher biological WBRT dose-fractionation schemes reported benefit for OS, NFI, or symptom control compared with standard care. However, OS and NFI were worse for lower biological WBRT dose-fractionation schemes than for standard dose schedules.The addition of WBRT to radiosurgery improved local and distant brain control in selected people with brain metastases, but data show worse neurocognitive outcomes and no differences in OS.Selected people with multiple brain metastases from non-small-cell lung cancer may show no difference in OS when OSC is given and WBRT is omitted.Use of radiosensitisers, chemotherapy, or molecular targeted agents in conjunction with WBRT remains experimental.Further trials are needed to evaluate the use of neurocognitive protective agents and hippocampal sparing with WBRT. As well, future trials should examine homogeneous participants with brain metastases with focus on prognostic features and molecular markers.


Hemidiaphragmatic Paralysis Post Stroke Leading to Hypercapneic Respiratory Failure.
Unilateral diaphragmatic paralysis is a rare complication after stroke. We report a case of right-sided hemidiaphragmatic paralysis after stroke in a 51-year-old man who presented with shortness of breath and orthopnea. Chest X-ray (CXR) revealed an elevated right-sided hemidiaphragm. The weakened diaphragmatic contraction from paralyzed right hemidiaphragm resulted in persistent atelectasis of the right lung base and inadequate alveolar ventilation leading to the development of right basal pneumonia with hypercapneic respiratory failure. However, the patient had a remarkable improvement with the appropriate institution of non-invasive ventilation and medical management with intravenous antibiotics.


Masking generates contiguous segments of metal-coated and bare DNA for scanning tunneling microscope imaging.
To date, no microscopic methods are available to confirm scanning tunneling microscope (STM) images of DNA. The difficulties encountered in repeating these images may be attributed to inadequate distribution of molecules on the substrate, poor adhesion to the substrate, or the low conductivity of the molecules. However, these factors are difficult to assess in an STM experiment where they may act simultaneously. A method to isolate these factors involves partly masking the deposited molecules before coating them with a conductive film to produce adjacent segments of coated and bare DNA after the mask is removed. The coated DNA segments are conductive and mechanically stable to allow easy identification of DNA by the STM. Furthermore, the path of a molecule can be traced from a coated to an uncoated region to test STM imaging of bare DNA. Masked preparations of DNA deposited on platinum/carbon-coated mica and highly oriented pyrolytic graphite were examined with a tunneling current 1000 times lower than the usual nanoamps. The tip apparently displaces molecules adsorbed to graphite to preclude imaging whereas more stably bound DNA on platinum/carbon-coated mica appears in reversed contrast.


[The treatment of psychopathologic disorders associated with tardive dyskinesias].
Tardive dyskinesia, an extrapyramidal syndrome consisting of involuntary hyperkinetic movements, is a serious side effect induced by the administration, usually on a long-term basis, of neuroleptic therapy mostly for psychotic disorders. Therefore, psychopathologic disturbances, florid or residual may coexist with the appearance and persistence of tardive dyskinesia. Thus, the exact nature of the psychopathology observed with the presence of tardive dyskinesia and its origin is difficult to delineate and to assess. Indeed, the psychopathological findings observed can possibly originate from the initial psychiatric disorder itself from the intrinsic effect of the neuroleptic medication on psychic processes, may be specifically related to tardive dyskinesia, or be the result of all these factors. Cognitive, thymic or psychotic disturbances have been closely associated with tardive dyskinesia, but their systematic studies is still scarce. Based on these findings, some tentative therapeutic considerations will be outlined, keeping in mind that exact nature and origin of these disturbances still remains to be elucidated, that no really specific and generally effective treatment of tardive dyskinesia has been found.


Development of a real-time RT-PCR and Reverse Line probe Hybridisation assay for the routine detection and genotyping of Noroviruses in Ireland.
Noroviruses are the most common cause of non-bacterial gastroenteritis. Improved detection methods have seen a large increase in the number of human NoV genotypes in the last ten years. The objective of this study was to develop a fast method to detect, quantify and genotype positive NoV samples from Irish hospitals. A real-time RT-PCR assay and a Reverse Line Blot Hybridisation assay were developed based on the ORF1-ORF2 region. The sensitivity and reactivity of the two assays used was validated using a reference stool panel containing 14 NoV genotypes. The assays were then used to investigate two outbreaks of gastroenteritis in two Irish hospitals. 56 samples were screened for NoV using a real-time RT-PCR assay and 26 samples were found to be positive. Genotyping of these positive samples found that all positives belonged to the GII/4 variant of NoV. The combination of the Real-time assay and the reverse line blot hybridisation assay provided a fast and accurate method to investigate a NoV associated outbreak. It was concluded that the predominant genotype circulating in these Irish hospitals was GII/4 which has been associated with the majority of NoV outbreaks worldwide. The assays developed in this study are useful tools for investigating NoV infection.


Impact of Arginine Nutrition and Metabolism during Pregnancy on Offspring Outcomes.
By serving as a precursor for the synthesis of nitric oxide, polyamines, and other molecules with biological importance, arginine plays a key role in pregnancy and fetal development. Arginine supplementation is a potential therapy for treating many human diseases. An impaired arginine metabolic pathway during gestation might produce long-term morphological or functional changes in the offspring, namely, developmental programming to increase vulnerability to developing a variety of non-communicable diseases (NCDs) in later life. In contrast, reprogramming is a strategy that shifts therapeutic interventions from adulthood to early-life, in order to reverse the programming processes, which might counterbalance the rising epidemic of NCDs. This review presented the role of arginine synthesis and metabolism in pregnancy. We also provided evidence for the links between an impaired arginine metabolic pathway and the pathogenesis of compromised pregnancy and fetal programming. This was followed by reprogramming strategies targeting the arginine metabolic pathway, to prevent the developmental programming of NCDs. Despite emerging evidence from experimental studies showing that targeting the arginine metabolic pathway has promise as a reprogramming strategy in pregnancy to prevent NCDs in the offspring, these results need further clinical application.


Redefinition of Denisiella Folsom Mills, 1938 (Collembola: Sminthurididae) with description of three new species from Brazil.
A new diagnosis of Denisiella is provided, based on the revision of most descriptions, including three new species from Brazil. New Brazilian taxa share the presence of 6 + 6 eyes, 4 + 4 serrate spine-like on tibiotarsi III and the polycarinate setae on tibiotarsi II but differ from each other by the shape and size of the sensilla of the tibiotarsi I. Denisiella rhizophorae sp. nov. has the combination of sensilla on tibiotarsi I of rhagidial type and C2 blunt on antennal segment III. Only D. betschi sp. nov. has barbulate spines on head and D. caatingae sp. nov. is the only which males present nasal organ. They are illustrated with drawings and scanning electron microscope photographs. Three different shapes of sensilla in the tibiotarsi I were observed and were compared with other species.


Rubella in Iceland.
Rubella has been a notifiable disease in Iceland since 1888. In this century rubella epidemics of increasing size have occurred at intervals of 5-10 years. The disease has spread throughout the country. About 75% of the patients were below 15 years of age at the time of the last two epidemics. Females account for 51-61 per cent of the reported cases. In this first study of the sero-epidemiology of rubella in Iceland, epidemiological data and blood samples were collected from 1464 women from 13 locations. The group of 1464 women was further divided into 12 age-groups (range 5-49 years), so as to make correlations with the last six epidemics. The immunity status was determined by measuring HI-antibodies in serum. 67.8 percent of the sera were positive (HI-titre greater than 20). 81.1 per cent of women of child-bearing age (16-42 ys.) were seropositive. Two of the age-groups have gone through only one epidemic '63-'64. Children who were then 1-3 ys. old have an immunity ratio of 46.1 per cent, this ratio being 73.3 per cent in the case of children who had attained school age. The immunity ratio is slightly lower among subjects from rural districts than among those from urban districts. Most of the women have caught the disease at the time of the first or second epidemic to occur in their lifetime. 11.6 per cent of persons giving a positive history were seronegative, 52.1 per cent of seropositive subjects gave a positive history. According to population statistics and the serological results it is estimated that appr. 1 out of 7 cases was reported in the epidemic '63-'64.


Solubility of alkali metal halides in the ionic liquid [C4C1im][OTf].
The solubilities of the metal halides LiF, LiCl, LiBr, LiI, NaF, NaCl, NaBr, NaI, KF, KCl, KBr, KI, RbCl, CsCl, CsI, were measured at temperatures ranging from 298.15 to 378.15 K in the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([C4C1im][OTf]). Li(+), Na(+) and K(+) salts with anions matching the ionic liquid have also been investigated to determine how well these cations dissolve in [C4C1im][OTf]. This study compares the influence of metal cation and halide anion on the solubility of salts within this ionic liquid. The highest solubility found was for iodide salts, and the lowest solubility for the three fluoride salts. There is no outstanding difference in the solubility of salts with matching anions in comparison to halide salts. The experimental data were correlated employing several phase equilibria models, including ideal mixtures, van't Hoff, the λh (Buchowski) equation, the modified Apelblat equation, and the non-random two-liquid model (NRTL). It was found that the van't Hoff model gave the best correlation results. On the basis of the experimental data the thermodynamic dissolution parameters (ΔH, ΔS, and ΔG) were determined for the studied systems together with computed gas phase metathesis parameters. Dissolution depends on the energy difference between enthalpies of fusion and dissolution of the solute salt. This demonstrates that overcoming the lattice energy of the solid matrix is the key to the solubility of inorganic salts in ionic liquids.


The hedgehog pathway in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hh pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.


Complete pathway for protein disulfide bond formation encoded by poxviruses.
We show that three cytoplasmic thiol oxidoreductases encoded by vaccinia virus comprise a complete pathway for formation of disulfide bonds in intracellular virion membrane proteins. The pathway was defined by analyzing conditional lethal mutants and effects of cysteine to serine substitutions and by trapping disulfide-bonded heterodimer intermediates for each consecutive step. The upstream component, E10R, belongs to the ERV1/ALR family of FAD-containing sulfhydryl oxidases that use oxygen as the electron acceptor. The second component, A2.5L, is a small alpha-helical protein with a CxxxC motif that forms a stable disulfide-linked heterodimer with E10R and a transient disulfide-linked complex with the third component, G4L. The latter is a thioredoxin-like protein that directly oxidizes thiols of L1R, a structural component of the virion membrane with three stable disulfide bonds, and of the related protein F9L. These five proteins are conserved in all poxviruses, suggesting that the pathway is an ancestral mechanism for direct thiol-disulfide interchanges between proteins even in an unfavorable reducing environment.


Research on Anxiety of Learning Chinese as a Second or Foreign Language in and Outside Mainland China: A Systematic Review of the Literature 1999-2020.
This paper reviews research on anxiety of learning Chinese as a second or foreign language (CSL/CFL) in and outside mainland China. This review involves 52 Chinese language articles identified in leading journals from the Chinese National Knowledge Infrastructure (CNKI) database () and 42 English language articles from the Web of Science and ERIC database published during the period of 1999 to 2020. By adopting bibliometric analysis and content analysis, this study compares the topical issues and methodological approaches of research on CSL/CFL learning anxiety published in leading Chinese and international journals. The review found that, compared with mainland Chinese scholars, international researchers examined a broader range of topical issues from multidimensional perspectives. While most Chinese empirical studies are dominated by the quantitative approach, qualitative methods such as classroom observations and in-depth interviews were also widely adopted by international researchers. The analysis also revealed that although Chinese scholars had drawn on well-established theories and concepts originating from foreign language anxiety (FLA) research, their role in CSL/CFL anxiety research is limited and peripheral. Consequently, we conclude this review with recommendations that encourage mainland Chinese researchers to be well informed by the updated theoretical perspective and methodological approaches such as the utilization of social network analysis and the integration of Information Communications Technology in language education.


Electrostatic contribution of serine phosphorylation to the Drosophila SLBP--histone mRNA complex.
Unlike all other metazoan mRNAs, mRNAs encoding the replication-dependent histones are not polyadenylated but end in a unique 26 nucleotide stem-loop structure. The protein that binds the 3' end of histone mRNA, the stem-loop binding protein (SLBP), is essential for histone pre-mRNA processing, mRNA translation, and mRNA degradation. Using biochemical, biophysical, and nuclear magnetic resonance (NMR) experiments, we report the first structural insight into the mechanism of SLBP-RNA recognition. In the absence of RNA, phosphorylated and unphosphorylated forms of the RNA binding and processing domain (RPD) of Drosophila SLBP (dSLBP) possess helical secondary structure but no well-defined tertiary fold. Drosophila SLBP is phosphorylated at four out of five potential serine or threonine sites in the sequence DTAKDSNSDSDSD at the extreme C-terminus, and phosphorylation at these sites is necessary for histone pre-mRNA processing. Here, we provide NMR evidence for serine phosphorylation of the C-terminus using (31)P direct-detect experiments and show that both serine phosphorylation and RNA binding are necessary for proper folding of the RPD. The electrostatic effect of protein phosphorylation can be partially mimicked by a mutant form of SLBP wherein four C-terminal serines are replaced with glutamic acids. Hence, both RNA binding and protein phosphorylation are necessary for stabilization of the SLBP RPD.


Investigation of Public Perception of Brain Death Using the Internet.
Brain death is a difficult concept for the public to comprehend, resulting in a reliance on alternative resources for clarity. This study aims to understand the public's perception of brain death via analysis of information on the Internet, determine the accuracy of that information, and understand how its perception affects the physician-patient relationship. We conducted a prospective cross-sectional study to evaluate information available to the public about brain death. The top 10 Google websites were analyzed for language complexity and accuracy in describing brain death. The top 10 YouTube videos were examined for content and the comments qualitatively analyzed for themes. Inaccuracies describing brain death inconsistent with national guidelines were prevalent amongst 4 of 10 Google websites, 6 of 10 YouTube videos, and 80% of YouTube comments. On average, Google websites were written at a 12th grade level and 90% mentioned organ donation. Videos were frequently emotional (78%); 33% included negative comments toward physicians, of which 50% mentioned organ donation. All videos included clarification comments questioning the differences between brain death, death, coma, and persistent vegetative states. The study revealed a significant amount of inaccurate information about brain death, affecting the public's understanding of the concept of brain death and resulting in negative emotions specifically toward physicians, and the link between brain death and organ donation. The medical community can improve understanding through consistent, simplified language, dissociating brain death from organ donation, and recognizing the emotions tied to discussions of brain death.


White Matter Dementia: Origin, Development, Progress, and Prospects.
The term white matter dementia (WMD) was introduced in 1988 to highlight the role of white matter in the development of dementia. As the concept has been refined with new insights into the structure and function of normal and abnormal white matter, research has expanded to consider normal cognition, network connectivity, novel treatment ideas, and the etiopathogenesis of neurodegenerative dementia. Emerging data are also identifying new opportunities for dementia prevention by avoidance of acquired vascular and traumatic white matter insults. The idea of WMD promises to continue as a useful construct informing the study of dementia and the understanding of brain-behavior relationships.


Lineup composition, suspect position, and the sequential lineup advantage.
N. M. Steblay, J. Dysart, S. Fulero, and R. C. L. Lindsay (2001) argued that sequential lineups reduce the likelihood of mistaken eyewitness identification. Experiment 1 replicated the design of R. C. L. Lindsay and G. L. Wells (1985), the first study to show the sequential lineup advantage. However, the innocent suspect was chosen at a lower rate in the simultaneous lineup, and no sequential lineup advantage was found. This led the authors to hypothesize that protection from a sequential lineup might emerge only when an innocent suspect stands out from the other lineup members. In Experiment 2, participants viewed a simultaneous or sequential lineup with either the guilty suspect or 1 of 3 innocent suspects. Lineup fairness was varied to influence the degree to which a suspect stood out. A sequential lineup advantage was found only for the unfair lineups. Additional analyses of suspect position in the sequential lineups showed an increase in the diagnosticity of suspect identifications as the suspect was placed later in the sequential lineup. These results suggest that the sequential lineup advantage is dependent on lineup composition and suspect position.


Psychometric properties of the Dermatology Life Quality Index (DLQI) in 900 Italian patients with psoriasis.
The Dermatology Life Quality Index (DLQI) is one of the most frequently used questionnaires to evaluate the impact of dermatological diseases on patients' lives. This study aimed to assess the reliability and validity of the instrument and to test its unidimensionality in a large sample of patients with psoriasis (n=976) hospitalized at IDI-IRCCS, Rome, Italy. Nine hundred patients completed the DLQI, the Psoriasis Disability Index (PDI) and the Skindex-29 (response rate 92%). The internal consistency of the DLQI was high (Cronbach's alpha=0.83). Evidence of convergent validity was provided by high (r=0.64-0.81) correlations between the DLQI, the PDI, and the functioning and emotions scales of Skindex-29. Exploratory factor analysis indicated the presence of four different principal common factors. Confirmatory factor analysis showed a clear second-order factor structure, with a homogeneous second-order factor underlying the four primary-surface factors. This study confirms that the DLQI is a reliable and valid instrument to assess patient-perceived impact of skin disease. Also, it supports the unidimensionality of the DLQI and hence corroborates the common practice of using the total score.


Influence of water content on Raman spectroscopy characterization of skin sample.
We report that the Raman spectrum obtained from porcine skin varies significantly with the change of skin water content. At different water contents from 40 to 55 wt.%, the Raman spectra results using confocal Raman spectroscopy show that the spectral variation of porcine skin is highly affected by skin water content. Experimental data are consistent with the Monte Carlo calculation and it is proved that the intensity of the Raman spectrum depends on the angle distribution and collection efficiency of backscattered light from the sample surface for a varied water content. It is suggested that water content for a given skin sample should be controlled carefully to minimize errors and deviations in the Raman peak analyses.


Stable Heterometallic Cluster Ions based on Werner's Hexol.
Large aqueous ions are interesting because they are useful in materials science (for example to generate thin films) but also because they serve as molecular models for the oxide-aqueous mineral interface where spectroscopy is difficult. Here we show that new clusters of the type M[(μ-OH)2 Co(NH3 )4 ]3 (NO3 )6 (M=Al, Ga) can be synthesized using Werner's century-old cluster as a substitutable framework. We substituted Group 13 metals into the hexol Co[(μ-OH)2 Co(NH3 )4 ]36+ ion to make diamagnetic heterometallic ions. The solid-state structure of the hexol-type derivatives were determined by single-crystal XRD and NMR spectroscopy and confirmed that the solid-state structure persists in solution after dissolution into either D2 O or [D6 ]DMSO. Other compositions besides these diamagnetic ions can undoubtedly be made using a similar approach, which considerably expands the number of stable aqueous heteronuclear ions.


Metabolism, plasma transport and biliary excretion of radioactive vitamin A and its metabolites as a function of liver reserves of vitamin A in the rat.
Groups of 7-12 weanling Sprague-Dawley male rats were fed graded daily doses of vitamin A (5-176 micrograms retinol) for 7 or 12 weeks. Final mean liver concentrations of vitamin A, which ranged from 0.4 to 331 micrograms retinol per gram, depended both on the daily dose given and on the length of the feeding period. The mean serum retinol concentration was 24 micrograms/dl at the lowest liver vitamin A concentration, approached a plateau of 40 micrograms/dl at a liver concentration of 5-10 micrograms/g, and then very slowly increased with higher levels of vitamin A in the liver. Seven days after the oral administration of a standard dose (4.6 microCi) of 11,12-[3H2]retinyl acetate, during which period rats were fed the customary vitamin A-containing diet, bile was collected via bile duct cannulae for 1-4 hours, and then the livers and serum were extracted and analyzed. The key relationships defined were: 1) that the mean ratio of specific activities of retinol in serum to that in liver was 0.65 +/- 0.05 (SEM) (range: 0.46-0.81) at daily retinol intakes of 8-176 micrograms/day, 2) that the ratio did not vary systematically with vitamin A intake or liver reserves and 3) that the mean excretion rate of vitamin A metabolites in the bile was invariant at 0.28 microgram retinol metabolites per milliliter of bile up to a liver vitamin A concentration of 32 micrograms retinol per gram, but then increased rapidly by eightfold to a maximal rate of 2.4 micrograms retinol metabolites per milliliter of bile at a liver vitamin A value of 140 micrograms retinol per gram.(ABSTRACT TRUNCATED AT 250 WORDS)


The functional role of calcineurin in hypertrophy, regeneration, and disorders of skeletal muscle.
Skeletal muscle uses calcium as a second messenger to respond and adapt to environmental stimuli. Elevations in intracellular calcium levels activate calcineurin, a serine/threonine phosphatase, resulting in the expression of a set of genes involved in the maintenance, growth, and remodeling of skeletal muscle. In this review, we discuss the effects of calcineurin activity on hypertrophy, regeneration, and disorders of skeletal muscle. Calcineurin is a potent regulator of muscle remodeling, enhancing the differentiation through upregulation of myogenin or MEF2A and downregulation of the Id1 family and myostatin. Foxo may also be a downstream candidate for a calcineurin signaling molecule during muscle regeneration. The strategy of controlling the amount of calcineurin may be effective for the treatment of muscular disorders such as DMD, UCMD, and LGMD. Activation of calcineurin produces muscular hypertrophy of the slow-twitch soleus muscle but not fast-twitch muscles.


High refractive index Fresnel lens on a fiber fabricated by nanoimprint lithography for immersion applications.
In this Letter, we present a Fresnel lens fabricated on the end of an optical fiber. The lens is fabricated using nanoimprint lithography of a functional high refractive index material, which is suitable for mass production. The main advantage of the presented Fresnel lens compared to a conventional fiber lens is its high refractive index (n=1.68), which enables efficient light focusing even inside other media, such as water or an adhesive. Measurement of the lens performance in an immersion liquid (n=1.51) shows a near diffraction limited focal spot of 810 nm in diameter at the 1/e2 intensity level for a wavelength of 660 nm. Applications of such fiber lenses include integrated optics, optical trapping, and fiber probes.


A Case of Acute Generalized Exanthematous Pustulosis Induced by Ceftriaxone.
Acute generalized exanthematous pustulosis (AGEP) is a rare and severe skin disorder induced in more than 90% of cases by an adverse drug reaction. This condition is defined by an acute growth of numerous, pin-head-sized, non-follicular pustules on a background of edematous erythema that starts on the face or in the armpits and groin. It is accompanied by fever and increased inflammatory markers. We present a case of a 39-year-old male, admitted to the internal medicine department due to Streptococcus pneumoniae meningitis treated with ceftriaxone, who developed erythema covered with small sterile pustules in the face, neck, and axilla four days after antibiotic treatment. The clinical and pathological correlations confirmed the diagnosis, and the dermatosis resolved after discontinuing the drug and systemic corticosteroid treatment. Early recognition of this drug-induced dermatosis is crucial for adequate treatment.


Effect of fruit intake on functional constipation: A systematic review and meta-analysis of randomized and crossover studies.
Functional constipation (FC) is commonly treated with fruits whose efficacy remains unclear. We conducted a meta-analysis of fruit intervention for FC and provided evidence-based recommendations. We searched seven databases from inception to July 2022. All randomized and crossover studies on the effectiveness of fruits on FC were included. We conducted sensitivity and subgroup analysis. A total of 11 studies were included in this review. Four trials showed that kiwifruits have significantly increased stool frequency (MD = 0.26, 95% CI (0.22, 0.30), P < 0.0001, I2 = 0%) than palm date or orange juice in the fixed-effect meta-analysis. Three high-quality studies suggested that kiwifruits have a better effect than ficus carica paste on the symptom of the FC assessed by the Bristol stool scale in the fixed-effect meta-analysis [MD = 0.39, 95% CI (0.11, 0.66), P < 0.05, I 2 = 27%]. Besides, five trials showed that fruits can increase the amount of Lactobacillus acidophilus [MD = 0.82, 95% CI (0.25, 1.39), P < 0.05, I 2 = 52%], analyzed with the random-effect model. Subgroup meta-analysis based on the types of fruits suggested that fruits including pome fruit, citrus fruit, and berries have increased the effect of Bifidobacterium t more than the stone fruits in the random effect meta-analysis [MD = 0.51, 95% CI (0.23, 0.79), P < 0.05, I 2 = 84%]. Totally, fruit intake may have potential symptom alleviation on the FC as evidence shows that they can affect stool consistency, stool frequency, and gut microbiota. Further large-scale studies are needed to gain more confident conclusions concerning the association between fruit intake and FC in the future.


Understanding the Experience and Impacts of Brain Fog in Chronic Pain: A Scoping Review.
Approximately 15% to 40% of persons with chronic pain as a primary disorder experience brain fog. Prior research has investigated the etiology of "brain fog" in conditions in which pain presents as a key feature (e.g., fibromyalgia). However, it remains understudied in the context of chronic 10 musculoskeletal pain. Following current scoping review guidelines, we obtained stakeholder input from patient and health care professionals (HCPs) to define this phenomenon. Specific aims of this review were to (1) identify factors contributing to brain fog, (2) identify the functional correlates of brain fog and assessments used to measure them, and (3) establish a definition of brain fog that can be employed by researchers and HCPs to advance research and care. A scoping review was conducted using recommendations of the Joanna Briggs Institute methodology of scoping reviews and the Levac et al methodology. Embase, Cinahl, PsycINFO, and Medline was searched to identify relevant sources. Findings were verified with patient and healthcare professionals. We identified four 15 key features of brain fog: perceived variability, subjective cognitive dysfunction, participation limitations, and changes in functional activities. We developed a model of brain fog illustrating the overlapping categories of contributors to brain fog in chronic musculoskeletal pain: (1) neuroanatomical and neurophysiological, (2) mental health/emotional, and (3) environmental/lifestyle. The results of this scoping review conclude that the inconsistency in research regarding brain fog in 20 chronic musculoskeletal pain is obstructing a clear understanding of the phenomenon and therefore may be impeding persons with chronic pain and brain fog from receiving optimal care.


Acetylcysteine for the prevention of radiocontrast -induced nephropathy.
Radiocontrast-induced nephropathy is the 3rd most common cause of in-hospital acute renal failure after hypotension and surgery. Radio-graphic contrast media are used at a progressive rate for several diagnostic and therapeutic applications. Prevention of radiocontrast-induced nephropathy will become more important, including risk of patient impairment and costs. Radiocontrast-induced ne-phropathy is due to vasoconstriction-mediated renal medullary ischemia and direct toxic damage to renal tubular epithelial cells. These effects may in part be mediated by generation of reactive oxygen species. Several prospective, randomized, placebo-controlled studies in patients with moderate renal insufficiency showed that the prophylactic oral administration of acetylcysteine at a dose of 600 mg twice daily along with hydration prevents the reduction in renal function after radiocontrast administration. Recently, intravenous administration of acetyl-cysteine has also been shown to be effective. Use of acetylcysteine together with hydration is the treatment of choice to prevent radiocontrast-induced nephropathy.


Monocyte/macrophage infiltration in tumors: modulators of angiogenesis.
The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.


Illumina identification of RsrA, a conserved C2H2 transcription factor coordinating the NapA mediated oxidative stress signaling pathway in Aspergillus.
Chemical mutagenesis screens are useful to identify mutants involved in biological processes of interest. Identifying the mutation from such screens, however, often fails when using methodologies involving transformation of the mutant to wild type phenotype with DNA libraries. Here we analyzed Illumina sequence of a chemically derived mutant of Aspergillus nidulans and identified a gene encoding a C2H2 transcription factor termed RsrA for regulator of stress response. RsrA is conserved in filamentous fungal genomes, and upon deleting the gene in three Aspergillus species (A. nidulans, A. flavus and A. fumigatus), we found two conserved phenotypes: enhanced resistance to oxidative stress and reduction in sporulation processes. For all species, rsrA deletion mutants were more resistant to hydrogen peroxide treatment. In depth examination of this latter characteristic in A. nidulans showed that upon exposure to hydrogen peroxide, RsrA loss resulted in global up-regulation of several components of the oxidative stress metabolome including the expression of napA and atfA, the two bZIP transcription factors mediating resistance to reactive oxygen species (ROS) as well as NapA targets in thioredoxin and glutathione systems. Coupling transcriptional data with examination of ΔrsrAΔatfA and ΔrsrAΔnapA double mutants indicate that RsrA primarily operates through NapA-mediated stress response pathways. A model of RsrA regulation of ROS response in Aspergillus is presented. RsrA, found in a highly syntenic region in Aspergillus genomes, coordinates a NapA mediated oxidative response in Aspergillus fungi.


Apnea promotes glutamate-induced excitotoxicity in hippocampal neurons.
Patients with obstructive sleep apnea (OSA) exhibit hippocampal damage and cognitive deficits. To determine the effect of apnea on the synaptic transmission in the hippocampus, we performed electrophysiological studies in an in vivo guinea pig model of OSA. Specifically, we determined the cornu ammonis region 1 (CA1) field excitatory postsynaptic potential (fEPSP) response to cornu ammonis region 3 (CA3) stimulation and examined the presynaptic mechanisms underlying the changes in the fEPSP. Single episodes of apnea resulted in a maximal potentiation of the fEPSPs at 1 to 3 min after the termination of each episode of apnea. The mean amplitude and slope of the post-apneic fEPSP was significantly larger compared with the pre-apneic control. These changes were accompanied by a significant decrease in the paired-pulse facilitation ratio during the post-apneic period compared with the pre-apneic control. The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801, when applied locally to the CA1 recording site by pressure ejection, blocked the apnea-induced potentiation of the fEPSP. In the experimental animals that were subjected to extended periods of recurrent apnea, CA1 neurons exhibited positive immunoreactivity for fragmented DNA strands, which indicates apoptotic cell death. The present results demonstrate that apnea-induced potentiation of the hippocampal CA1 fEPSP is mediated by an NMDA receptor mechanism. We therefore conclude that recurrent apnea produces abnormally high levels of glutamate that results in the apoptosis of CA1 neurons. We hypothesize that this damage is reflected by the cognitive deficits that are commonly observed in patients with breathing disorders such as OSA.


[Primary hepatic carcinoid].
Primary hepatic carcinoid (PHC) is considered to be particularly sporadic diagnosis; in current world literature about 60 cases have been reported. Most of the patients present with abdominal pain, diarrhea, icterus, flush, weight loss or respiratory disease; even though the course of the disease might stay asymptomatic for a long time. An illuminating case of at presentation oligosymptomatic 72-year-old patient, which was after extensive examination based on OctreoScan and histological verification diagnosed to have generalized PHC, is reported. Paliative therapy with somatostatine analogues followed. At autopsy 8 months later the clinical diagnosis of PHC was confirmed. PHC is difficult to diagnose both due to radiological similarity to other hepatic lesions and demanding exclusion of other primary foci. The diagnosis of PHC is based on negative imaging techniques result in other possible localizations. Minimal symptomatology in stage of generalization, atypical primary localization and rapid progression is of interest in current case.


[The treatment of Graves' disease with antithyroid drugs and small doses of radioiodine (author's transl)].
Three hundred and thirty Graves' disease patients (258 F. 72 M. ; mean age = 50 +/- 07 years) were treated by 131I from 1961 to 1979 ; 57 % had a goiter and 32 % had exophthalmos. One or several doses of radioiodine were given to each patient without dosimetry. The mean total dose (+/- SEM) was = 8,51 +/- 0,44 mCi and the mean for the first dose 4,34 +/- 4 ans 54,8 % of the patients received only one dose but 10,3 % of them had more than 3 doses. Data obtained by actuarial methods showed 66 % of the cases to be in remission in less than 2 years ; the frequency of hypothyroidism increased steadily by 3 % every year to give 15 % at 5 years and 30 % at 10 years. Remission was slower to occur in goitrous subjects and hypothyroidism was less frequent in this group despite doses significantly higher of radioiodine (p less than 0,001). Recovery was also slower among exophthalmos patients. Finally, the mean 3-hour radioiodine uptake and plasma T3 level were significantly lower six months after the first therapeutic dose among those who were cured of thier hyperthyroidism within two years.


Crack users show high rates of antisocial personality disorder, engagement in illegal activities and other psychosocial problems.
The aim of this study was to compare three groups of Brazilian psychoactive substance (PAS) abuse patients (crack cocaine users, cocaine snorters, and non-cocaine PAS users) in terms of psychiatric comorbidities and severity of psychosocial problems. A cross-sectional, multi-center study was conducted at five Brazilian research centers. A total of 738 current PAS abusers seeking specialized treatment (outpatient and inpatient clinics) were assessed using the sixth version of the Addiction Severity Index (ASI-6): 293 patients using crack cocaine were compared with 126 using powder cocaine and 319 using non-cocaine PAS (mostly alcohol and marijuana). Psychiatric comorbidities were assessed in a smaller sample (290 cases), originating from three of the centers, using the Mini International Neuropsychiatric Interview Plus (MINI-Plus). Crack and powder cocaine users were significantly younger than non-cocaine PAS users (31.1 ± 8.1 and 32.9 ± 8.8 vs. 42.4 ± 12, respectively; p < .001). Crack users presented a higher rate of antisocial personality disorder (25%) than powder cocaine (9%) and non-cocaine PAS users (9%), even when adjusted for confounding factors (Pr = 2.6; 95% CI 1.10-6.40). According to ASI-6 summary scores, crack users presented a significantly higher rate of occupational, family, and legal problems and reported more illegal and violent activities such as burglary and theft (23%) and threatening or assaulting (32%) than non-cocaine PAS users. Our findings, combined with the recent increase observed in the prevalence of crack use in Brazil, highlight the severity of psychiatric symptoms and psychosocial problems related to this powerful drug and corroborate the already suggested association between crack/cocaine, violence, and legal problems. Treatment programs for crack users should routinely consider the possibility of associated psychiatric comorbidities, such as antisocial personality disorder, which may affect treatment outcomes.


Architectural requirements for optimal activation by tandem CRP molecules at a class I CRP-dependent promoter.
The Escherichia coli cyclic AMP receptor protein (CRP) activates transcription at target promoters by interacting with the C-terminal domain of the RNA polymerase alpha subunit. We have constructed a set of promoters carrying tandem DNA sites for CRP with one site centred at position -61.5 and the other site located at different upstream positions. Optimal CRP-dependent activation of transcription is observed when the upstream DNA site for CRP is located at position -93.5 or at position -103.5. Evidence is presented to suggest that activation by the upstream-bound CRP molecule is due to interaction with the C-terminal domain of the RNA polymerase alpha subunit.


Gammadelta+ and CD4+ alphabeta+ human T cell subset responses upon stimulation with various Mycobacterium tuberculosis soluble extracts.
By using a flow cytometric technique which allows direct identification of proliferating cells within mixed cell populations, we have previously described that soluble extracts obtained from Mycobacterium tuberculosis or M. avium represent strong stimuli for human gammadelta+ T cells. In the present study, we demonstrate that the protocol used for the preparation of M. tuberculosis soluble extracts may have an impact on their gammadelta+ T cell stimulatory capacity. In agreement with our previous data, soluble extracts prepared from bacteria killed at 85 degrees C and directly disrupted by prolonged sonication (TBe), elicited a strong proliferation of gammadelta+ T cells after 6-7 days of stimulation. In contrast, when soluble extracts were obtained from bacteria autoclaved (121 degrees C, 25 min) and then washed by centrifugation, a predominant proportion of CD4+ alphabeta+ T cells was achieved in the responding population. The stimulatory activity for gammadelta+ T cells was recovered in the supernatant of the autoclaved bacteria, indicating that autoclaving of M. tuberculosis bacilli releases an antigen(s) into the supernatant which stimulates human gammadelta+ T cells. While protease digestion of TBe only partially reduced its stimulatory capacity on gammadelta+ T cells, the stimulatory component(s) released into the supernatant after autoclavation of bacilli was found to be sensitive to protease digestion. Interestingly, in contrast to the preponderant proportion of gammadelta+ T cells induced in the responding population by unfractionated TBe, when the extract was fractionated by fast performance liquid chromatography (FPLC), most of the fractions exhibited a strong stimulatory capacity on CD4+ alphabeta+ T cells only. The gammadelta+ T cell stimulatory activity was confined to the low molecular weight range FPLC fractions. Such results may suggest a possible regulatory role of gammadelta+ T cells on CD4+ alphabeta+ T cells.


Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease.
Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m(2)]. In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (-0.33, -0.44 and -0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.


Hospital Associated Respiratory Virus Infection in Children and Adults: It Does Not Just Occur During Cold and Flu Season.
Hospital-associated respiratory virus infections (HARVI) are an underappreciated source of morbidity and mortality. We examined HARVI incidence and clinical respiratory virus testing practices in a cohort of hospitalized patients with acute respiratory illness. HARVI were identified in patients of all ages, both during and outside of the influenza season.


[Pathophysiology, clinical and experimental possibilities of pericardial tamponade].
Acute pericardial tamponade is one of the most emergent clinical scenarios in cardiac surgery. With numerous causes in the background, pericardial tamponade can lead to cardiogenic shock and death. In modern diagnostic era, the recognition of pericardial tamponade is simple, but its management and the long-term effects can still be challenging. Without the detailed understanding of the pathophysiological pathways diagnostic and therapeutic management plans of pericardial tamponade is very difficult. The aim of this review was to give a complex picture of pericardial tamponade, from its role in medical history to pathophysiology and its significance in surgical experimental models. Orv Hetil. 2018; 159(5): 163-167.


Impact of community-orientated psychiatry on marriage and fertility of psychotic women.
A large representative sample of psychotic women of reproductive age was selected from patients admitted to a London mental hospital during 1955-63 and followed up during the years of developing community care. Before first admission the probability of marriage of schizophrenics was three-quarters of that of corresponding normal women, and after admission it was just over one-third of normal. Fertility of schizophrenics was slightly reduced both before and after illness, and much of this reduction remains due to their being in hospital. The probability of marriage and fertility of women suffering from severe affective disorders was very similar to that found in the corresponding general population. Despite a lessening of differentials between patients and normal women since the impact of community care the probability of marriage of schizophrenics with abnormal personalities is still significantly reduced.


Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells.
Pancreatic cancer is one of the most aggressive and devastating human malignancies. The present study was conducted to determine whether in vivo sst2 gene transfer into human pancreatic tumors would impair tumor progression, and to characterize sst2 antitumoral bystander mechanisms. sst2 administration, using the synthetic vector PEI, strongly inhibited tumor progression of human pancreatic adenocarcinoma, in vivo. sst2 gene transfer induced intratumoral production of its ligand somatostatin. Disruption of this autocrine loop by RNA interference completely reversed sst2 antitumoral activity. Mice depleted of natural killer (NK) cells did not hamper sst2 tumor growth inhibition. However, microvessel density and vascular endothelial growth factor (VEGF) expression were markedly reduced in sst2-transfected tumors, whereas sst3 somatostatin receptor was upregulated. Depleting somatostatin by RNA interference completely abolished the sst2 inhibitory effect on VEGF expression and tumor angiogenesis, and sst2-induced sst3 expression in peripheral tumor vessels. We conclude that in vivo sst2 gene transfer elicited intratumoral somatostatin production and strongly impaired human pancreatic tumor growth. NK cells were not involved in this antitumoral bystander effect. VEGF and tumor vascularization were identified as novel targets for sst2-mediated antitumoral bystander effect. sst3 somatostatin receptor was upregulated in sst2-transfected tumors. Therefore, in vivo gene delivery of sst2 receptor to target the angiogenic process in pancreatic ductal adenocarcinoma might be a new therapeutic approach for treatment of pancreatic cancer in patients with unresectable disease.


Paediatric nurses' perception of the child-family dyad's autonomy in managing a chronic disease situation: the experience of an Italian paediatric department.
Chronically ill patients have to take several medications and non-adherence to treatment can lead to severe and negative outcomes. Therefore, several interventions are suggested in literature to improve adherence rates in clinical practice. Adherence to treatment can be particularly troublesome in adolescents, who strive for autonomy and self-care independence. Literature suggests that improving adherence is useful to guarantee positive outcomes and reduce costs. To explore how nurses perceived autonomy in parents, adolescents, and children related to the management of chronic disease. A qualitative study including 1 focus group and 7 semi-structured interviews conducted between September 2011 and October 2011. The qualitative date were analysed with the thematic analysis method. The sample included 12 paediatric nurses working in a Children's Cystic Fibrosis Unit and Neuromuscular Disease Unit. The 5 main categories that emerged from this qualitative study after he process of categorization were: 'Changes in daily lifestyle', 'Nurses' attitude towards educating the dyad', 'Adolescence and transition', 'Parents' attitudes towards chronic disease', and 'Availability of information'. Correct information and education is crucial for families who have a chronically ill child. Internet can be a misleading source of information and provide wrong information also in relation to prevention.


The startle response during whiplash: a protective or harmful response?
Whiplash injuries are common following rear-end collisions. During such collisions, initially relaxed occupants exhibit brisk, stereotypical muscle responses consisting of postural and startle responses that may contribute to the injury. Using prestimulus inhibition, we sought to determine if the startle response elicited during a rear-end collision contributes to head stabilization or represents a potentially harmful overreaction of the body. Three experiments were performed. In the first two experiments, two groups of 14 subjects were exposed to loud tones (124 dB) preceded by prestimulus tones at either four interstimulus intervals (100-1,000 ms) or five prestimulus intensities (80-124 dB). On the basis of the results of the first two experiments, 20 subjects were exposed to a simulated rear-end collision (peak sled acceleration = 2 g; speed change = 0.75 m/s) preceded by one of the following: no prestimulus tone, a weak tone (85 dB), or a loud tone (105 dB). The prestimulus tones were presented 250 ms before sled acceleration onset. The loud prestimulus tone decreased the amplitude of the sternocleidomastoid (16%) and cervical paraspinal (29%) muscles, and key peak kinematics: head retraction (17%), horizontal head acceleration (23%), and head angular acceleration in extension (23%). No changes in muscle amplitude or kinematics occurred for the weak prestimulus. The reduced muscle and kinematic responses observed with loud tones suggest that the startle response represents an overreaction that increases the kinematics in a way that potentially increases the forces and strains in the neck tissues. We propose that minimizing this overreaction during a car collision may decrease the risk of whiplash injuries.


[Neglected shoulders reported at the Befelatanana Maternity Hospital (Antananarivo, Madagascar)].
We conducted a retrospective study on neglected shoulders during 12 months at the Maternity Hospital of Befelatanana, 31 cases among 4685 deliveries were reported. The majority of the pregnancies are not under medical supervision and no ultrasound is carried out during the third trimester. There were 8 cases of uterine rupture, 2 haemorrhage shocks, 6 syndromes of prerupture, 6 umbilical cord prolapses at the third degree and 6 tears of the cervix. 20 caesarean sections have been performed as well as a turning of foetus in utero in 3 women, 4 hysterectomies, and a conservative suture with uterine tube ligation in the other cases. Often linked to a large multiparity the neglected shoulder remains quite frequent in developing countries such as Madagascar and regular prenatal consultations together with a rigorous clinical exam are highly recommended by the authors to make an early diagnosis and provide a better care management.


Noninvasive detection of COPD and Lung Cancer through breath analysis using MOS Sensor array based e-nose.
This paper describes the research work done toward the development of a breath analyzing electronic nose (e-nose), and the results obtained from testing patients with lung cancer, patients with chronic obstructive pulmonary disease (COPD), and healthy controls. Pulmonary diseases like COPD and lung cancer are detected with MOS sensor array-based e-noses. The e-nose device with the sensor array, data acquisition system, and pattern recognition can detect the variations of volatile organic compounds (VOC) present in the expelled breath of patients and healthy controls. This work presents the e-nose equipment design, study subjects selection, breath sampling procedures, and various data analysis tools. The developed e-nose system is tested in 40 patients with lung cancer, 48 patients with COPD, and 90 healthy controls. In differentiating lung cancer and COPD from controls, support vector machine (SVM) with 3-fold cross-validation outperformed all other classifiers with an accuracy of 92.3% in cross-validation. In external validation, the same discrimination was achieved by k-nearest neighbors (k-NN) with 75.0% accuracy. The reported results show that the VOC analysis with an e-nose system holds exceptional possibilities in noninvasive disease diagnosis applications.


SMDT1 variants impair EMRE-mediated mitochondrial calcium uptake in patients with muscle involvement.
Ionic calcium (Ca2+) is a key messenger in signal transduction and its mitochondrial uptake plays an important role in cell physiology. This uptake is mediated by the mitochondrial Ca2+ uniporter (MCU), which is regulated by EMRE (essential MCU regulator) encoded by the SMDT1 (single-pass membrane protein with aspartate rich tail 1) gene. This work presents the genetic, clinical and cellular characterization of two patients harbouring SMDT1 variants and presenting with muscle problems. Analysis of patient fibroblasts and complementation experiments demonstrated that these variants lead to absence of EMRE protein, induce MCU subcomplex formation and impair mitochondrial Ca2+ uptake. However, the activity of oxidative phosphorylation enzymes, mitochondrial morphology and membrane potential, as well as routine/ATP-linked respiration were not affected. We hypothesize that the muscle-related symptoms in the SMDT1 patients result from aberrant mitochondrial Ca2+ uptake.


Electrocardiographic characteristics of right-bundle-branch-block premature ventricular complexes predicting absence of left ventricular scar in athletes with apparently structural normal heart.
Left ventricular scar is an arrhythmic substrate that may be missed by echocardiography and diagnosed only by cardiac magnetic resonance (CMR), which is a time-consuming and expensive imaging modality. Premature ventricular complexes (PVCs) with a right-bundle-branch-block (RBBB) pattern are independent predictors of late gadolinium enhancement (LGE) but their positive predictive value is low. We studied which electrocardiographic features of PVCs with an RBBB pattern are associated with a higher probability of the absence of an underlying LGE. The study included 121 athletes (36 ± 16 years; 48.8% men) with monomorphic PVCs with an RBBB configuration and normal standard clinical investigations who underwent CMR. LGE was identified in 35 patients (29%), predominantly in those with PVCs with a superior/intermediate axis (SA-IntA) compared to inferior axis (IA) (38% vs. 10%, P = 0.002). Among patients with SA-IntA morphology, the contemporary presence of qR pattern in lead aVR and V1 was exclusively found in patients without LGE at CMR (51.0% vs. 0%, P < 0.0001). Among patients with IA, the absence of LGE correlated to a narrow ectopic QRS (145 ± 16 vs. 184 ± 27 msec, P < 0.001). Among athletes with apparently idiopathic PVCs with a RBBB configuration, the presence of a concealed LGE at CMR was documented in 29% of cases, mostly in those with a SA-IntA. In our experience, the contemporary presence of qR pattern in lead aVR and V1 in PVCs with RBBB/SA-IntA morphology or, on the other hand, a relatively narrow QRS in PVCs with an IA, predicted absence of LGE.


Muscarine, imidazole, oxazole and thiazole alkaloids.
Novel and structurally diverse natural products containing imidazol-, oxazole-, or thiazole-unit(s) display a wide variety of biological activities. The isolation, biological activity and total synthesis of naturally occurring muscarine, imidazole, oxazole and thiazole alkaloids have been reviewed. The literature covers from January 2003 to June 2004.


Association of Neighborhood-Level Material Deprivation With Health Care Costs and Outcome After Stroke.
To determine the association between material deprivation and direct healthcare costs and clinical outcomes following stroke in the context of a publicly funded universal healthcare system. In this population-based cohort study of patients with ischemic and hemorrhagic stroke admitted to hospital between 2008 and 2017 in Ontario, Canada, we used linked administrative data to identify the cohort, predictor variables, and outcomes. The exposure was a five-level neighborhood material deprivation index. The primary outcome was direct healthcare costs incurred by the public payer in the first year. Secondary outcomes were death and admission to long-term care. Among 90,289 patients with stroke, the mean (standard deviation) per-person costs increased with increasing material deprivation, from $50,602 ($55,582) in the least deprived quintile to $56,292 ($59,721) in the most deprived quintile (unadjusted relative cost ratio and 95% confidence intervals 1.11 [1.08,1.13] and adjusted relative cost ratio 1.07 [1.05,1.10] for least compared to most deprived quintile). People in the most deprived quintile had higher mortality within one year compared to the least deprived quintile (adjusted hazard ratio (HR) 1.07 [1.03,1.12]) as well as within three years (adjusted HR 1.09 [1.05,1.13]). Admission to long-term care increased incrementally with material deprivation and those in the most deprived quintile had an adjusted HR of 1.33 [1.24,1.43]) compared to those in the least deprived quintile. Material deprivation is a risk factor for increased costs and poor outcomes after stroke. Interventions targeting health inequities due to social determinants of health are needed. This study provides Class II evidence that the neighborhood-level material deprivation predicts direct healthcare costs.


Industrial Wastewater Treatment by Nanofiltration-a Case Study on the Anodizing Industry.
The anodizing industry generates several alkaline and acidic wastewater streams often with high concentrations of heavy metals. In this study, nanofiltration (NF) was used to treat wastewater from individual baths, i.e., wastewater from color rinse, alkaline pickling rinse, acidic pickling rinse and anodizing rinse, as well as a mixture of all the wastewater streams. The experiments were carried out by using a commercial membrane (NF99HF) exhibiting pure water permeability of 10 L/(m2·h·bar). For all wastewater streams except one, pH was adjusted to bring it within the recommended pH limits of the membrane, whereby part of the heavy metals precipitated and was removed. The NF of the color rinse offered high-quality permeate (heavy metals below detection limit) and high permeability (9 L/(m2·h·bar)), whereas the nanofiltration of the alkaline pickling rinse exhibited no permeability. The NF of the acidic pickling rinse showed a permeability of 3.1-4.1 L/(m2·h·bar), but low ion rejection (7%-13%). NF of the neutralized mixed wastewater, after the removal of precipitate, produced high-quality permeate with a stable permeability of 1 L/(m2·h·bar). Treatment of the mixed wastewater is therefore the best option if the water has to be discharged. If the water has to be reused, the permeate conductivity in the color rinse and anodizing rinse baths have been reduced significantly, so the treatment of these streams may then be a better option.


Synthesis of natural products with polycyclic systems.
Herein we present our unique strategies to synthesize natural products. To prepare mersicarpine, an atypical indole alkaloid, our procedure features an Eschenmoser-Tanabe fragmentation to synthesize an alkyne unit, a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization to construct the indole skeleton, and a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Additionally, we synthesized a frog poison, histrionicotoxin, via a chirality transfer from an allenylsilane to prepare a pseudosymmetrical dienyne, dienyne metathesis to produce an optically active bicyclo [5.4.0] system, and an asymmetric propargylation. To synthesize lyconadin A, a Lycopodium alkaloid, a combination of an aza-Prins reaction and electrocyclic ring opening constructed the highly fused tetracyclic compound. The synthesis of isoschizogamine features a facile construction of the carbon framework through a Wagner-Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring-closing metathesis via a hemiaminal ether.


The use of evidence-based guidance to enable reliable and accurate measurements of the home environment.
High quality guidance in home strategies is needed to enable older people to measure their home environment and become involved in the provision of assistive devices and to promote consistency among professionals. This study aims to investigate the reliability of such guidance and its ability to promote accuracy of results when measurements are taken by both older people and professionals. Twenty-five health professionals and 26 older people participated in a within-group design to test the accuracy of measurements taken (that is, person's popliteal height, baths, toilets, beds, stairs and chairs). Data were analysed with descriptive analysis and the Wilcoxon test. The intra-rater reliability was assessed by correlating measurements taken at two different times with guidance use. The intra-rater reliability analysis revealed statistical significance (P < 0.05) for all measurements except for the bath internal width. The guidance enabled participants to take 90% of measurements that they were not able to complete otherwise, 80.55% of which lay within the acceptable suggested margin of variation. Accuracy was supported by the significant reduction in the standard deviation of the actual measurements and accuracy scores. This evidence-based guidance can be used in its current format by older people and professionals to facilitate appropriate measurements. Yet, some users might need help from carers or specialists depending on their impairments.