First Report of Leptopilina japonica in Europe.
Drosophila suzukii (Matsumura; Diptera: Drosophilidae) is a key pest of sweet cherry and small fruits worldwide. Biological control remains unutilized in the framework of D. suzukii management. Nonetheless, natural enemies may play an important role in regulating this pest. We report for the first time the presence of Leptopilina japonica Novković and Kimura (Hymenoptera: Figitidae) in Europe. Two specimens emerged from ripened fruits and one was collected after direct observation on a cherry tree in June 2019. They showed the distinctive morphological traits already described and shared more than 99% sequence similarity with specimens of L. japonica collected in Asia. This first finding was confirmed by a wider survey carried out in 2020; L. japonica emerged from cherry fruit samples collected in five other sites across the Trentino region, suggesting that L. japonica has already colonized a wide area. Detection of this Asian species is relevant to the future direction in managing D. suzukii, both in Europe and North America. In fact, L. japonica showed similarity with Ganaspis brasiliensis (Ihering) (Hymenoptera: Figitidae), the most promising candidate for the classical biological control, in terms of developmental time, egg maturation, host age preference and lifetime fecundity.


Psychological Aspects of Return to Sport for the Female Athlete.
Female athletes represent a unique population of competitors who face distinct stressors when compared with male athletes. These include sport inequities, violence, abuse, body image concerns, disordered eating, relative energy deficiency, family planning challenges, hormonal challenges, and mental distress. When combined with sports injuries, these stressors can negatively impact the mental health of female athletes as well as their injury recovery and return to sports. It is essential for orthopaedic surgeons to be familiar with the unique aspects inherent to being a female athlete, along with the psychological aspects of sports injuries. By integrating questions about female athletes' psychological well-being into their routine practice and collaborating with a multidisciplinary team, orthopaedic surgeons can better address these unique stressors, support female athletes in achieving optimal outcomes, and enhance return to sport rates. V, expert opinion.


Prevalence of Legionella-specific IgG and IgM antibody in a dental clinic population.
This study was undertaken to determine the frequency of Legionella infection in a dental clinic setting. Serum samples from 270 dental clinic personnel were evaluated using an enzyme-linked immunosorbent assay to detect Legionella-specific IgM and IgG antibodies. The pooled-species whole-cell-antigen preparation used in these assays was derived from six Legionella pneumophila strains and one strain each from Legionella bozemanii and Legionella micdadei. Significant levels of IgG and IgM antibodies were found in 20% and 16%, respectively, of the samples. This compares with 8% and 10%, respectively, for a randomly selected non-clinical group from the region (P less than 0.005). Samples from clinic personnel with significant IgG titers (greater than 1:128) were also evaluated for activity to each of the eight single-species antigens, with the following results: L. pneumophila, 45% (combined six strains); L. micdadei, 37%; and L. bozemanii, 18%. Comparing individuals' "years spent in the clinic environment" with the incidence of significant antibody levels strongly suggests that the risk of Legionella infection increases proportionately with increased clinic exposure time (P less than 0.05). Analysis of these data implies that Legionella may be present in the dental clinic environment, thus creating an increased risk for clinical personnel or patients.


Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver.
Guidelines about recommendations for amounts of exercise/physical activity are variable in non-alcoholic fatty liver disease. Our aim was to determine the amount of exercise that was associated with two outcomes: a) development of incident liver fat and b) resolution of baseline liver fat, at five-year follow-up. In an occupational health screening program, weekly frequency of exercise was assessed using the validated Korean version of the International Physical Activity Questionnaire Short Form (IPAQ-SF). Liver fat was identified by ultrasonography (3.5MHz probe) at baseline and at five-year follow-up. Fully adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs and 95% confidence intervals [CI]) for incident fatty liver and resolution of fatty liver at follow-up. 233,676 men and women were studied between 2002 and 2014. 126,811 individuals were identified without fatty liver, and of these subjects, 29,014 subjects developed incident fatty liver during follow-up. At baseline, there were 42,536 individuals with liver fat and of these individuals, fatty liver resolved in 14,514, during follow-up. After full adjustment, compared to no exercise, exercise was associated with benefit for both outcomes; for exercise ⩾5times per week for incident fatty liver: HR 0.86 (95% CI 0.80,0.92), p<0.001, and for resolution of fatty liver HR 1.40 (95% CI 1.25,1.55), p<0.001. Moderate to vigorous exercise is beneficial in decreasing risk of development of new fatty liver or improving resolution of existing fatty liver during 5years of follow-up. The amount of exercise/physical activity to benefit fatty liver disease in non-alcoholic fatty liver disease is not known. In a large study of free-living people, our aim was to determine the amount of exercise that was linked with a decrease in new fatty liver and also improvement of existing fatty liver over 5years of follow-up. Compared to no exercise, exercise ⩾5times per week (lasting at least 10min on each occasion) was linked to a highly significantly benefit for both a decrease in new fatty liver and also improvement of existing fatty liver.


Meta-learning algorithm development to predict outcomes in patients with hepatitis C virus-related hepatocellular carcinoma.
Prediction of prognosis and treatment outcomes for patients with hepatocellular carcinoma (HCC) is complex for most patients. Machine learning predictive analysis can be used to explore the rich information in electronic health records to discover hidden patterns and relationships. We aimed to develop a noninvasive algorithm for predicting outcome treatment options for patients with HCC. This cross-sectional study included 1298 patients with Hepatitis C virus-related HCC attending an HCC multidisciplinary clinic, Kasr Al-Aini Hospital, Cairo University, between 2009 and 2016. Using machine learning analysis, we constructed Reduced Error Pruning (REP) decision tree algorithms and applied Auto-WEKA to select the best classifier out of 39 algorithms. The REP-tree algorithm predicted HCC management outcomes with a recall (sensitivity) of 0.658 and a precision (specificity) of 0.653 using only routine data. 854 (65.8%) instances were correctly identified, and 444 (34.2%) instances were incorrectly classified. Out of 31 attributes, liver decompensation was selected by REP-tree as the best predictor of HCC outcome (root node). With Auto-WEKA, the random subspace classifier was chosen as the best predictive algorithm with a recall (sensitivity) of 0.750 and a precision (specificity) of 0.75. There were 974 (75%) correctly classified instances and 324 (25%) incorrectly classified instances, which was better than REP-tree. Machine learning analysis explores data to discover hidden patterns and trends and enables the development of models to predict HCC treatment outcomes utilizing simple laboratory data. The random subspace classifier predicted the outcome more accurately than REP-tree.


Complete Genome Sequence of Strain BB001, a Novel Epibiont Bacterium from the Candidate Phylum Saccharibacteria (TM7).
Strain BB001 is cultivated from the human oral cavity on its basibiont bacterial host Actinomyces sp. It is an ultrasmall bacterium with a reduced genome that grows obligately on its bacterial host. BB001 is the first member of human microbiome taxon 957.


[Intraoperative monitoring of the spinal cord. Personal results and an inventory of the current status].
The concept of intraoperative monitoring as continuous surveillance of sensory pathways by intraoperative sensory evoked potentials is described. The need for intraoperative monitoring is derived from the morbidity of certain spinal operations. First experiences from 25 own cases are outlined and the advantages of different methods discussed. The current status of spinal cord monitoring is briefly reviewed.


2-Acetylaminofluorene inhibits the activation of immune responses by blocking cell cycle progression at G1 phase.
2-Acetylaminofluorene (AAF) inhibited in a dose dependent manner mouse spleen cell blastogenesis in response to phorbol 12-myristate 13-acetate (PMA)/Ionomycin (Io) activation, the T-cell lectin, concanavalin A (Con A), and following stimulation by alloantigens as measured by the mixed lymphocyte response (MLR). AAF also markedly suppressed the T-cell dependent antibody forming cell (AFC) response to sRBC. AAF was most inhibitory on both the sRBC IgM AFC response and Con A stimulated proliferation when added during the first 24 h following initiation of culture. Direct addition of high concentrations of AAF (100 microM) to spleen cell cultures at 48 h following Con A stimulation produced a very modest inhibition (< 20%) of T-cell proliferation as compared to 90% when added at the time cultures were initiated. Similarly, AAF (75 and 100 microM) produced a greater than 80% inhibition of the in vitro AFC response when spleen cells were sensitized with antigen in presence of AAF. In contrast, no inhibition of the IgM AFC response was produced when AAF (75 microM) was added to spleen cell cultures 48 or 72 h after antigen sensitization. Con A-triggered cell-cycle progression was attenuated at the G1 stage by the addition of AAF (50 and 100 microM) with no inhibition of S to G2/M phase transition. These results suggest that the mechanism of AAF-mediated immune suppression is through a blockade of cell cycle progression from G1 to S phase.


Medication Adherence and Discontinuation of Aripiprazole Once-Monthly 400 mg (AOM 400) Versus Oral Antipsychotics in Patients with Schizophrenia or Bipolar I Disorder: A Real-World Study Using US Claims Data.
Few studies have compared adherence between long-acting injectable antipsychotics, especially for newer agents like aripiprazole once-monthly 400 mg (AOM 400; aripiprazole monohydrate) and oral antipsychotics, in patients with schizophrenia or bipolar I disorder (BD-I) in a real-world setting. Two separate retrospective cohort analyses using Truven MarketScan data from January 1, 2012 to June 30, 2016 were conducted to compare medication adherence and discontinuation in patients with schizophrenia or BD-I who initiated treatment with AOM 400 vs. patients changed from one oral antipsychotic monotherapy to another. Adherence was defined as proportion of days covered (PDC) ≥ 0.80 in the year following the index date. Linear regression models examined the association between AOM 400 and oral antipsychotic cohorts and medication adherence. Kaplan-Meier curves and Cox regression estimated time to and risk of discontinuation, while adjusting for baseline covariates. A sensitivity analysis was conducted using a combination of propensity score matching and exact matching to create matched cohorts. Final cohort sizes were as follows-Schizophrenia: AOM 400 n = 408, oral antipsychotic n = 3361; BD-I: AOM 400 n = 413, oral antipsychotic n = 15,534. In patients with schizophrenia, adjusted mean PDC was higher in patients in the AOM 400 cohort vs. the oral antipsychotic cohort (0.57 vs. 0.48 P < 0.001), and patients in the oral antipsychotic cohort had a higher risk of discontinuing treatment vs. the AOM 400 cohort (HR 1.45, 95% CI 1.29-1.64). For patients with BD-I, adjusted mean PDC was higher for the AOM 400 cohort (0.59 vs. 0.44, P < 0.001), and patients in the oral antipsychotic cohort had a higher risk of discontinuation (HR 1.71, 95% CI 1.53-1.92). In a real-word setting, AOM 400 resulted in a significantly higher percentage of patients with a PDC ≥ 0.80 and significantly longer time to treatment discontinuation compared to patients with schizophrenia or BD-I who received treatment with an oral antipsychotic. Otsuka Pharmaceutical Development and Commercialization, Inc. and Lundbeck.


Genomic data mining approaches for the discovery of anticancer peptides from Ganoderma sinense.
Drug discovery from traditional Chinese medicine (TCM) typically involves the extraction of active ingredients from natural products with high biological activity and function from the vast repertoire of traditional Chinese medicine. This strategy cannot fully exploit the vast resources of TCM. Known as the longevity mushroom, Ganoderma spp. has been used as medicine for thousands of years. Recent studies have demonstrated its anticancer activity. While most research on Ganoderma spp. has focused on their polysaccharides or small molecules as potential anticancer components, possible anticancer peptides (ACPs) or proteins have been neglected. In this study, genomic data mining approaches were used to discover potential ACPs from Ganoderma sinense. A search against known ACPs identified 477 proteins in the G. sinense proteome that possess putative ACP sequences and that thus may serve as parent proteins. After in silico digestion by trypsin, 34 G. sinense proteins were predicted to release putative ACPs (by the mACPpred program). A subsequent sequence similarity comparison against known ACPs identified 15 trypsin-digested fragments as possible ACPs, of which 3 sequences were identical to known ACPs. The results indicated that ACPs may be involved in the anticancer activity of G. sinense and that genomic mining approaches can be effective strategies for discovering active components in TCM resources. The accumulation of genomic and proteomic data will undoubtedly accelerate drug discovery from TCM resources.


MS³ fragmentation patterns of monomethylarginine species and the quantification of all methylarginine species in yeast using MRM³.
Protein arginine methylation is one of the epigenetic modifications to proteins that is studied in yeast and is known to be involved in a number of human diseases. All eukaryotes produce Nη-monomethylarginine (ηMMA), asymmetric Nη1, Nη1-dimethylarginine (aDMA), and most produce symmetric Nη1, Nη2-dimethylarginine (sDMA) on proteins, but only yeast produce Nδ-monomethylarginine (δMMA). It has proven difficult to differentiate among all of these methylarginines using mass spectrometry. Accordingly, we demonstrated that the two forms of MMA have indistinguishable primary product ion spectra. However, the secondary product ion spectra of δMMA and ηMMA exhibited distinct patterns of ions. Using incorporation of deuterated methyl-groups in yeast, we determined which secondary product ions were methylated and their structures. Utilizing distinct secondary product ions, a triple quadrupole multiple reaction monitoring cubed (MRM(3)) assay was developed to measure δMMA, ηMMA, sDMA and aDMA derived from hydrolyzed protein. As a proof-of-concept, δMMA and ηMMA were measured using the MRM(3) method in wild type and mutant strains of Saccharomyces cerevisiae and compared to the total MMA measured using an existing assay. The MRM(3) assay represents the only method to directly quantify δMMA and the only method to simultaneously quantify all yeast methylarginines.


Cefotetan: a review of the microbiologic properties and antimicrobial spectrum.
Cefotetan (formerly ICI 156834 and YM09330) is a 7-methoxy cephalosporin possessing some advantageous antimicrobial spectrum, safety, and pharmacokinetic characteristics compared with other so-called second-generation cephalosporins. The published literature was reviewed and the cefotetan quantitative susceptibility testing data from nearly 31,000 isolates was tabulated. Against 15,769 enteric bacilli, cefotetan was observed to have a potency and spectrum more closely resembling a third-generation cephalosporin and markedly superior to cefoxitin. The mean of all MIC 90s reported for the Enterobacteriaceae ranged from 0.06 to 13 micrograms/ml except for citrobacter species, E. cloacae, Enterobacter species, and C. freundii. The mean MIC 50 for all 22 recorded species was in the susceptible range. Cefotetan was very effective against B. catarrhalis, H. influenzae, and pathogenic Neisseria species. However, cefotetan and cefoxitin were not active against Pseudomonas species, Acinetobacter species, and some rarely isolated species. Cefotetan was moderately active against the staphylococci (mean MIC 50, 7.6 to 26 micrograms/ml) and streptococci (mean MIC 50, 0.9 to 6.6 micrograms/ml). The coagulase-negative staphylococcus species generally had higher cefotetan and cefoxitin minimum inhibitory concentrations compared with the S. aureus isolates. Oxacillin-resistant staphylococci were resistant to cefotetan. The enterococci, JK group diphtheroids, Corynebacterium species, and L. monocytogenes isolates were resistant. A review of 4,751 strict anaerobes showed cefotetan to have a very comparable activity and spectrum to cefoxitin. The 1,291 B. fragilis strains had a mean MIC 50 and MIC 90 of 5.4 and 23 micrograms/ml, respectively. These values were slightly superior to cefoxitin when tested in parallel. More elevated minimum inhibitory concentrations were observed for other B. fragilis group species for cefoxitin and cefotetan. The mean cefotetan MIC 90 for all other anaerobic bacteria except the Eubacterium species and Lactobacillus species predict favorable clinical efficacy. The beta-lactamase stability of cefotetan is very similar to that of other 7-methoxy cephalosporins. Cefotetan also inhibits Type Ia cephalosporinases with high enzyme affinity and is an inducer of these beta-lactamases, although cefotetan is not rapidly hydrolyzed. Synergy between cefotetan and numerous other antibiotics has been reported, but antagonism has also been occasionally observed.


Binding of scatter factor to epithelial cell membrane protein: identification of its receptor.
Binding of scatter factor (SF) to the surface protein of Madin-Darby canine kidney (MDCK) cells was investigated. The factor has a specific affinity for membrane proteins of MDCK cells and could be purified 10-20-fold using a membrane protein-affinity chromatographic procedure. The binding was pH- and salt-dependent. The factor did not bind to columns prepared with membrane proteins from non responder cells or with bovine serum albumin. Further purification to homogeneity was achieved using reverse phase and immunoaffinity chromatography. The factor dissociated into 92, 62 and 34/32 kDa bands on SDS-PAGE under reducing conditions. A 230 kDa protein band, the receptor-SF complex, was observed when radiolabeled SF was crosslinked to surface proteins of MDCK cells and the complexes were subjected to electrophoresis. The binding of radiolabeled SF to the MDCK cells was decreased in presence of excess unlabeled SF. These observations suggest that the binding of SF to surface proteins of MDCK cells is specific and occurs predominantly to a 150 kDa protein.


Involvement of PKR and RNase L in translational control and induction of apoptosis after Hepatitis C polyprotein expression from a vaccinia virus recombinant.
Hepatitis C virus (HCV) infection is of growing concern in public health with around 350 million chronically infected individuals worldwide. Although the IFN-alpha/rivabirin is the only approved therapy with 10-30% clinical efficacy, the protective molecular mechanism involved during the treatment is still unknown. To analyze the effect of HCV polyprotein expression on the antiviral response of the host, we developed a novel vaccinia virus (VV)-based delivery system (VT7-HCV7.9) where structural and nonstructural (except part of NS5B) proteins of HCV ORF from genotype 1b are efficiently expressed and produced, and timely regulated in mammalian cell lines. Regulated transcript production and viral polypeptide processing was demonstrated in various cell lines infected with the recombinant VT7-HCV7.9, indicating that the cellular and viral proteolytic machineries are functional within these cells. The inducible expression of the HCV polyprotein by VV inhibits the synthesis of both host and viral proteins over the time and also induces apoptosis in HeLa and HepG2-infected cells. These effects occur accompanying with the phosphorylation of the translation initiation factor eIF-2alpha. In cells co-infected with VT7-HCV7.9 and a recombinant VV expressing the dominant negative eIF-2alpha-S51A mutant in the presence of the inductor isopropyl-thiogalactoside (IPTG), protein synthesis is rescued. The IFN-inducible protein kinase PKR is responsible for the translational block, as demonstrated with PKR-/- and PKR +/+ cell lines. However, apoptosis induced by VT7-HCV7.9 is mediated by the RNase L pathway, in a PKR-independent manner. These findings demonstrate the antiviral relevance of the proteins induced by interferon, PKR and RNase L during expression from a VV recombinant of the HCV polyprotein in human cell lines. HCV polyprotein expression caused a severe cytopathological effect in human cells as a result of inhibition of protein synthesis and apoptosis induction, triggered by the activation of the IFN-induced enzymes PKR and RNase L systems. Thus, the virus-cell system described here highlights the relevance of the IFN system as a protective mechanism against HCV infection.


The effects of FTO gene rs9939609 polymorphism on the association between colorectal cancer and dietary intake.
FTO gene is associated with obesity, dietary intake, and the risk of colorectal cancer (CRC). In this study, patients with colorectal cancer were assessed for the interactions between FTO gene polymorphisms and dietary intake. This case-control study was carried out on 450 participants aged 35-70 years including 150 patients with colorectal cancer and 300 healthy controls. Blood samples were collected in order to extract DNA and genotyping of FTO gene for rs9939609 polymorphism. A validated 168-item food frequency questionnaire (FFQ) and the Nutritionist-IV software were used to assess dietary intake. In the participants with the TT genotype of FTO rs9939609 polymorphism, CRC risk was significantly associated with higher intake of dietary fat (OR:1.87 CI95%:1.76-1.99, p = 0.04), vitamin B3 (OR:1.20 CI95%:1.08-1.65, p = 0.04), and vitamin C (OR:1.06 CI95%:1.03-1.15, p = 0.04) and lower intake of β-carotene (OR:0.98 CI95%:0.97-0.99, p = 0.03), vitamin E (OR:0.77 CI95%:0.62-0.95, p = 0.02), vitamin B1 (OR:0.15 CI95%:0.04-0.50, p < 0.01), and biotin (OR:0.72 CI95%:0.0.57-0.92, p = 0.01). No significant association was found between CRC and dietary intake in carriers of AA/AT genotypes after adjustments for the confounders. CRC risk may be decreased by β-carotene, vitamins E, B1, and biotin only in those without the risk allele of the FTO gene. The association of CRC and diet may be influenced by FTO genotype. Further studies are warranted.


Cross-Resistance between Platinum-Based Chemotherapy and PARP Inhibitors in Castration-Resistant Prostate Cancer.
Patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair-related gene aberrations (HRRm) can derive meaningful benefits from both platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi). Cross-resistance between these agents is well-recognised in other tumour types but data on prostate cancer is lacking. In this retrospective pre-planned study, we assessed 28 HRRm mCRPC patients who received PlCh and PARPi. Progression-free survival (PFS) on initial therapy was longer than on subsequent therapy (median 5.3 vs. 3.4 months, p = 0.016). The median PFS of PlCh was influenced by the order of agents, with 3.6 months shorter PFS after PARPi than when administered first. The median PFS of PARPi was less influenced, with 0.9 months shorter PFS after PlCh than before. In the PARPi-first subgroup, six out of 16 evaluable patients (37.5%) had a >50% PSA decline to PlCh, and two of eight (25.0%) had a radiographic response to PlCh. In the PlCh-first subgroup, 6/10 (60.0%) had a >50% PSA decline, and 5/9 (55.6%) had a radiographic response to PARPi. These data show >40% of the cohort is sensitive to a subsequent HRR-targeting agent. PlCh appears to induce less cross-resistance than PARPi. Additional data on resistance mechanisms will be crucial in defining an optimal treatment sequence in HRRm mCRPC patients.


Effect of monolayer cells on sphere cells--two types of cells that emerge during the neural differentiation of mouse embryonic stem cells.
Embryonic stem (ES) cells represent a valuable resource for transplantation and tissue engineering applications. For derivation of neural cells, a five-stage differentiation protocol has been widely applied, which involves the propagation of ES cells, formation of embryoid bodies (EBs), selection of neural stem cells (NSCs), expansion of NSCs, and further maturation of NSCs to neurons. During the expansion stage (the fourth stage), two types of cells with distinct morphologies normally emerge, with one type being monolayer cells and the other sphere-like aggregates growing on top of the monolayer cells. In this study, we focus on how the monolayer cells may affect different aspects of aggregate cells, which may have important implications for regenerative medicine. We find that monolayer cells can support the proliferation and decrease the apoptosis rate of sphere cells, as well as facilitate the production of Tuj1-positive cells from sphere cells. In addition, transplantation of monolayer cells into nude mice does not result in tumor formation nor affects the tumorigenicity of sphere cells, when grafted together with monolayer cells.


[Comorbidities and psoriasis. Impact on clinical practice].
Psoriasis is a genetically determined, chronic inflammatory systemic disease. Besides skin symptoms, patients with moderate to severe forms of psoriasis show an association with other diseases, referred to as comorbidities. Metabolic disorders (e.g. diabetes mellitus, insulin resistance, dyslipidemia mainly in obese patients) and cardiovascular diseases (e.g. arterial hypertension, coronary artery disease, myocardial infarction and stroke) are of importance as they can increase patients' mortality. In addition, psychiatric diseases are more frequent in psoriasis patients and influence the therapeutic approach. The dermatologist in most cases is the primarily consulted physician for patients with psoriasis and therefore plays the role as a gatekeeper managing therapy. He is responsible for the early diagnosis of comorbidities and insuring their appropriate management. The anti-psoriatic treatment has to be adapted to existing comorbidities and their systemic treatments. The following article provides information on psoriatic comorbidities and their consequences for daily practice.


Cryosurgical treatment of early cervical intraepithelial neoplasia.
Two hundred forty patients, ages 12 to 54 years, with biopsy-confirmed early cervical intraepithelial neoplasia (CIN I) treated by cryosurgery were reviewed. CIN I has been viewed historically as having high rates of remission or stabilization. The initial cure rate was 89%, with a 97% cure rate after retreatment of failures. All failures were confirmed histologically. The initial cure rates are no better than those for higher grades of CIN. Thus, CIN I should be viewed with the same seriousness as CIN II or CIN III.


[Harmonisation of databases for the study of frailty in older people: INTAFRADE study].
The main objective of the present work is to evaluate the feasibility of harmonising the available information from different independent databases, in order to build an integrated database to study frailty. This work is based on the European project, Integral Approach to the Transition between Frailty and Dependence on older adults: Patterns of occurrence, identification tools and model of care (INTAFRADE), developed by 4 groups, 3 in Spain and one in France. Each partner provided their databases related to the study of frailty. As a previous step to the creation of an integrated database the characteristics and variables included in each study were mapped, specifying whether their harmonisation was possible or not. A total of 30 different variables that corresponded to 8 dimensions were identified: Sociodemographic and social characteristics, health status, lifestyle habits, anthropometric measures, other physical measurements, use of health services, and adverse health results. Of them all, 28 (93%) variables were harmonisable, although only 20% were present in all databases, with 47% in 3 of them. In relation to the frailty instruments, all of them were lacking at least 50% of the items. The harmonisation process will allow us to jointly analyse information available on 2,361 people. The European INTAFRADE study will allow a deeper understanding of the frailty process in older people by harmonising information from heterogeneous databases.


The clinical interaction analysis system: a system for observational recording of aphasia treatment.
This paper describes the Clinical Interaction Analysis System (CIAS), a system for recording events that occur in treatment sessions for aphasic individuals. The development of the CIAS is summarized, the event categories contained in the CIAS are described, and the uses of the CIAS are discussed. Information about the reliability of the CIAS is also presented.


Adsorptive refolding of histidine-tagged glutathione S-transferase using metal affinity chromatography.
Column-based protein refolding strategies are often advantageous due to their ease of integration with purification operations, improved refolding yields, and the high concentrations at which the refolded protein can be recovered. His6-tagged glutathione S-transferase (GST-(His6)) was refolded while it was adsorbed in a metal affinity chromatography column. The redox environment could be controlled during the refolding reaction by the addition of reduced and oxidized glutathione without reducing the immobilized nickel metal ions. Adsorptive refolding limited the interaction of refolding intermediates at elevated protein concentrations, and thus improved the yield compared to experiments performed using dilution refolding techniques. The protein concentration during refolding was increased by a factor of 6.8 without reducing the yield achieved compared to dilution refolding. The ability of GST-(His6) to refold to the correct tertiary structure was not significantly affected by the interaction between the poly-histidine-tag and the adsorbent. Decreased refolding yields were achieved at elevated adsorbed protein concentrations, which indicated that at high concentrations the refolding intermediates aggregated despite immobilization. Following adsorptive refolding it was observed that only correctly folded protein could be eluted with imidazole, while the misfolded and aggregated proteins were retained in the column via non-specific interactions with the adsorbent matrix. An iterative refolding strategy was therefore used to re-denature the retained proteins and repeat the adsorptive refolding step, which increased the adsorptive refolding yield that could be achieved at elevated protein concentrations. The yield of correctly folded GST-(His6) from an iterative refolding process was comparable to dilution refolding performed at a 10-fold lower protein concentration. Selective elution and iterative refolding is likely to improve the yields achieved for other poly-histidine-tagged proteins refolded in metal affinity chromatography columns.


Association between Leukoaraiosis and Poor Outcome is not due to Reperfusion Inefficiency after Intravenous Thrombolysis.
Leukoaraiosis (LA) is associated with structural and functional cerebrovascular impairment, which may compromise the capacity of ischemic tissue to maximize reperfusion after intravenous thrombolysis (IVT). We aimed to determine whether severe LA is correlated with reperfusion inefficiency, which contributes to infarct growth and poor functional outcome. We analyzed data from our consecutive acute ischemic stroke (AIS) patients who had acquired baseline and 24-h follow-up diffusion- and perfusion-weighted imaging. Reperfusion was defined as reduction of ≥70 % of hypoperfusion lesion at 24 h from baseline. Severe LA was defined as Fazekas score 2 or 3 on FLAIR images. We investigated the relationship between severity of LA and reperfusion status. Multivariate statistical analysis was carried out for modeling the independent predictors of reperfusion, infarct growth, and functional outcome. Finally, 79 patients were included, among them 30 (37.97 %) had severe LA. Reperfusion was observed in 41 (51.89 %) patients, the proportion of reperfusion was very similar in patients with and without severe LA (53.33 vs 51.02 %, p = 1.000). Large artery occlusion was the only independent unfavorable predictor for reperfusion (OR = 0.202, 95 % confidence interval, 0.060-0.673; p = 0.014). Multiple linear regression analysis revealed that severe LA was independently associated with infarct growth (standardized coefficients = 0.191, p = 0.040). Severe LA was also an independent predictor of poor outcome (mRS ≥ 3) (OR = 4.004, 95 % confidence interval, 1.267-12.656, p = 0.018) after adjusting for reperfusion and baseline severity of stroke. Severe LA was associated with infarct growth and poor outcome independent of reperfusion status, which may expand the notion that LA contributes the intrinsic vulnerability of brain tissue to acute ischemic insults. The burden of LA may not serve as an imaging indicator of reperfusion inefficiency after IVT for AIS patients.


Changes in osteoporosis therapy in postmenopausal women from the RAC‑OST‑POL study: a 10‑year follow‑up.
Therapeutic regimens for osteoporosis are the key elements in the management of osteoporotic patients. The aim of the study was to present data on changes in osteoporosis therapy in women during a 10‑year follow‑up. We analyzed a population‑based sample recruited in the RAC‑OST‑POL study. At baseline, the cohort included 978 women, of whom 541 remained in the follow‑up. Mean (SD) age of the patients was 74.7 (6.6) years. The number of untreated women and those on alendronate decreased, while the number of patients receiving other forms of the antiresorptive therapy or calcium / vitamin D supplementation increased during the study. The percentage of untreated women in the rural areas and the urban areas was, respectively, 85% and 74.1% at baseline, and 74.3% and 63.3% at the end of the follow‑up. The percentage of untreated women decreased significantly, both in rural and urban cohorts. It was accompanied by a significant increase in calcium / vitamin D supplementation in both subgroups. Regarding the antiresorptive therapy, there was a significant increase in the frequency of its use only in the rural cohort. The use of therapeutic strategies was determined by the level of education. The frequency of calcium and / or vitamin D supplementation increased significantly in all education-related categories during the follow‑up. Changes in the therapy of postmenopausal women with osteoporosis, observed in a 10‑year follow‑up of the RAC‑OST‑POL study, indicated that the level of care did not improve in this group of patients.


Use of dual-energy CT for renal mass assessment.
Although dual-energy CT (DECT) may prove useful in a variety of abdominal imaging tasks, renal mass evaluation represents the area where this technology can be most impactful in abdominal imaging compared to routinely performed contrast-enhanced-only single-energy CT exams. DECT post-processing techniques, such as creation of virtual unenhanced and iodine density images, can help in the characterization of incidentally discovered renal masses that would otherwise remain indeterminate based on post-contrast imaging only. The purpose of this article is to review the use of DECT for renal mass assessment, including its benefits and existing limitations. KEY POINTS: • If DECT is selected as the scanning mode for most common abdominal protocols, many incidentally found renal masses can be fully triaged within the same exam. • Virtual unenhanced and iodine density DECT images can provide additional information when renal masses are discovered in the post-contrast-only setting. • For renal mass evaluation, virtual unenhanced and iodine density DECT images should be interpreted side-by-side to troubleshoot pitfalls that can potentially lead to erroneous interpretation.


Sleep Problems Before and During the COVID-19 Pandemic in Children with Autism Spectrum Disorder, Down Syndrome, and Typical Development.
Sleep problems are common in children and adolescents, particularly those with Neurodevelopmental Disorders. With the changes in daily habits resulting from the COVID-19 pandemic, we have analyzed sleep characteristics, during social isolation, in Brazilian children and adolescents aged between 4 and 12 years with Autism Spectrum Disorder (N = 267), Down Syndrome (N = 74), and typical development (N = 312). The ASD group presented with worse indicators of sleep habits in the Children's Sleep Habits Questionnaire (CSHQ-BR) and fell asleep later during the pandemic. The entire group started fall asleep and waking up later during the pandemic - as well as waking up more often during the night. These results may contribute to parental guidance and sleep habit-related interventions during and after the COVID-19 pandemic.


Oxygen radicals in cardiac surgery.
Most cardiac surgical procedures require the use of prolonged induced myocardial ischemia. Experimental models of global myocardial ischemia which mimic cardiac surgical techniques have been developed to investigate the possibility of oxygen free radical development during prolonged myocardial ischemia or upon reperfusion. In such experiments, various free radical scavenging agents, including superoxide dismutase, catalase, and mannitol, have been shown to improve the tolerance of the heart to protracted global ischemia. Use of these agents has improved cardiac functional recovery and has attenuated the biochemical and structural changes which occur due to prolonged ischemia and reflow. In a recently developed porcine experimental model, the effects of preexisting regional myocardial ischemia with superimposed global ischemia and reperfusion have been studied, with free radical scavenging agents administered in an attempt to reduce myocardial infarction and improve regional functional recovery. In most such studies completed to date, free radical scavenging agents have resulted in better myocardial preservation, suggesting, at least indirectly, that there may be an oxygen free radical-mediated component of the ischemia-reperfusion injury seen in such models. Techniques for directly measuring myocardial oxygen free radical levels may allow for early clarification of the development of such toxic species in the clinical cardiac surgical setting.


Relationship between chronic nasal obstruction and craniofacial growth: an experimental model.
The aim of this paper was to verify if the growth of the nasomaxillary complex can be influenced by a purely functional alteration such as nasal obstruction, which was induced experimentally in a genetically controlled animal model. Sixty albino rats were employed. Twenty of them had the right nostril occluded by a synthetic resin; another twenty had both nostrils occluded; the other 20 were taken as control group. When the growth was completed, the rats were sacrificed and cephalometric analysis was carried out. Both treated groups showed a statistically significant reduction in overall weight and height, in the vertical development of the nasomaxillary complex and in the skullbase longitudinal axis. After discussing the literature on the subject, the authors conclude that normal craniofacial growth in the rat must somehow depend on physiological nasal breathing, which should therefore be considered of crucial importance.


Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.
Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM.


The roles of hydrogenases 3 and 4, and the F0F1-ATPase, in H2 production by Escherichia coli at alkaline and acidic pH.
The hyc operon of Escherichia coli encodes the H2-evolving hydrogenase 3 (Hyd-3) complex that, in conjunction with formate dehydrogenase H (Fdh-H), constitutes a membrane-associated formate hydrogenlyase (FHL) catalyzing the disproportionation of formate to CO2 and H2 during fermentative growth at low pH. Recently, an operon (hyf) encoding a potential second H2-evolving hydrogenase (Hyd-4) was identified in E. coli. In this study the roles of the hyc- and hyf-encoded systems in formate-dependent H2 production and Fdh-H activity have been investigated. In cells grown on glucose under fermentative conditions at slightly acidic pH the production of H2 was mostly Hyd-3- and Fdh-H-dependent, and Fdh-H activity was also mainly Hyd-3-dependent. However, at slightly alkaline pH, H2 production was found to be largely Hyd-4, Fdh-H and F0F1-ATPase-dependent, and Fdh-H activity was partially dependent on Hyd-4 and F0F1-ATPase. These results suggest that, at slightly alkaline pH, H2 production and Fdh-H activity are dependent on both the F0F1-ATPase and a novel FHL, designated FHL-2, which is composed of Hyd-4 and Fdh-H, and is driven by a proton gradient established by the F0F1-ATPase.


Truncating Titin (TTN) Variants in Chemotherapy-Induced Cardiomyopathy.
Chemotherapy-induced cardiomyopathy (CCMP) is a complication of chemotherapy treatment occurring in 9% of patients treated with the use of anthracyclines. Currently, risk stratification is based on clinical risk factors that do not adequately account for variable individual susceptibility. This suggests the presence of other determinants. In this case series, we describe 2 women with breast cancer who developed severe heart failure within months after chemotherapy. Genetic screening revealed truncating frameshift mutations in TTN, encoding the myofilament titin, in both women. To our knowledge, this is the 1st report of an association between truncating TTN variants and CCMP. Because truncations in TTN are the most common cause of familial and sporadic dilated cardiomyopathy, further research is needed to establish their prevalence in patients presenting with CCMP.


Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark.
Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS). Retrospective trans-sectional study. One thousand and two premenopausal women with the diagnoses hirsutism or PCOS were divided according to ethnicity: Caucasian (CA, n = 784), Middle East (ME, n = 190), Asian (n = 14) and others (n = 14). Clinical evaluation (hirsutism, BMI, waist, blood pressure), hormone analyses (testosterone, sex hormone-binding globulin, prolactin, lipids, insulin, glucose) and transvaginal ultrasound were performed. Oral glucose tolerance tests (OGTT) (n = 499) and ACTH tests (n = 434) were performed in a subgroup of patients. (CA vs ME women) CA women were older [32(25-37) vs 25(18-32) years, median (quartiles)] and had increased BMI compared to ME women. After correcting for age and BMI, CA women were less hirsute, but had increased testosterone levels compared to ME women. The Rotterdam criteria were fulfilled in 56% of both populations, but PCO was diagnosed in 47% CA vs 29% ME women, P < 0·01. CA women had increased blood pressure and smoked at a higher frequency (40 vs 23%), whereas area under the curve for insulin during OGTT was decreased, all P < 0·001. Prolactin levels were significantly lower in CA women compared to ME women [7(5-10) vs 9(6-12) μg/l] and were inversely associated with smoking status. CA women had a more adverse cardiovascular profile than ME women, whereas insulin sensitivity was higher. The prevalence of the individual Rotterdam criteria differed significantly in the two study populations.


Intense pre-admission carriage and further acquisition of ESBL-producing Enterobacteriaceae among patients and their caregivers in a tertiary hospital in Rwanda.
To assess the presence and risk factors of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) among patients admitted to the University Teaching Hospital of Butare and among their attending caregivers, and to analyse the acquisition of ESBL-PE carriage during hospital stay and associated factors. We screened 392 patients and their attending caregivers at admission and discharge for ESBL-PE carriage. Bacterial species were determined using the API-20E system, and antimicrobial susceptibility testing was performed by agar disc diffusion. Data on socio-economic status, diet, behaviour, household assets, livestock and hospital procedures were collected. At admission, 50% of the patients showed intestinal ESBL-PE carriage (Escherichia coli, 51%; Klebsiella pneumoniae, 39%; Enterobacter cloacae, 19%) as did 37% of their caregivers. Co-resistance was common but no carbapenem resistance was detected. At discharge, the proportion of ESBL-PE-colonised patients increased to 65% (caregivers, 47%) with almost complete carriage in paediatric patients (93%). The acquisition rate among initially non-colonised patients was 55% (or, 71/1000 patient days). Independent predictors of admission carriage included a colonised caregiver, prior antibiotic intake, egg consumption and neglecting to boil drinking water, whereas being a paediatric patient, undergoing surgery and male gender predicted acquisition during hospitalisation. Abundant admission carriage of ESBL-PE and a high acquisition rate in a Rwandan university hospital point to potential intrahospital transmission and community dissemination. Caregivers are an additional source of possible spread. Risk factors of colonisation such as diet and water source need to be tackled to prevent the further emergence and spread of ESBL-PE.


Social media and its relationship with mood, self-esteem and paranoia in psychosis.
An evidence-base is emerging indicating detrimental and beneficial effects of social media. Little is known about the impact of social media use on people who experience psychosis. Forty-four participants with and without psychosis completed 1084 assessments of social media use, perceived social rank, mood, self-esteem and paranoia over a 6-day period using an experience sampling method (ESM). Social media use predicted low mood, but did not predict self-esteem and paranoia. Posting about feelings and venting on social media predicted low mood and self-esteem and high paranoia, whilst posting about daily activities predicted increases in positive affect and self-esteem and viewing social media newsfeeds predicted reductions in negative affect and paranoia. Perceptions of low social rank when using social media predicted low mood and self-esteem and high paranoia. The impact of social media use did not differ between participants with and without psychosis; although, experiencing psychosis moderated the relationship between venting and negative affect. Social media use frequency was lower in people with psychosis. Findings show the potential detrimental impact of social media use for people with and without psychosis. Despite few between-group differences, overall negative psychological consequences highlight the need to consider use in clinical practice.


Radiotherapy in Pregnancy-Associated Breast Cancer.
Breast radiotherapy during pregnancy is a matter of debate as both the efficacy of treatment and the safety of the developing fetus should be considered. Currently there is not enough data to support the safety of in-utero exposure to radiation even with modern radiotherapy techniques. So it is highly recommended that breast radiotherapy is postponed to after delivery, though it might be considered in very selected patients according to risk-benefit assessment.


It's all good on the surface: care coordination experiences of migrant cancer patients in Australia.
Migrants diagnosed with cancer in Australia have high unmet need and poorer psychosocial outcomes than comparable Australian-born patients. It is possible that migrants also experience worse coordination of their cancer care. The purpose of this study was to describe migrant patients' experience of care coordination to inform the development of items for inclusion in a cancer care coordination questionnaire sensitive to the specific cultural needs of these patients. Eighteen Chinese (Mandarin and Cantonese), Arabic and Macedonian patients and carers from two metropolitan cancer centres in Sydney, Australia, were recruited. Two focus groups and 11 telephone interviews were conducted in the participants' own language. A semi-structured interview format was utilised to qualitatively explore participants' experiences of cancer care coordination during treatment. Themes were identified using a thematic analysis. Cancer care was generally perceived to be well coordinated. Four themes were identified that impacted on the quality of care coordination as a direct result of a patient's migrant status: (1) the impact of language on understanding and information access, (2) the role of interpreters and (3) access to services and (4) understanding the roles and responsibilities of the team. Despite their care generally being well coordinated, migrants require additional assistance such as information in a form appropriate to their language proficiency and understanding of the new health system. Development of a culturally specific measure of cancer care coordination will enable evaluation of future strategies to improve care.


Impact of availability of catheter laboratory facilities on management and outcomes of acute myocardial infarction presenting with out of hospital cardiac arrest.
We aimed to identify whether the availability of catheter laboratory affects clinical outcomes of out-of-hospital cardiac arrest (OHCA) complicating myocardial infarction (AMI). Patients admitted with a diagnosis of AMI and OHCA from the Myocardial Ischaemia National Audit Project (MINAP) between 2010 to 2017 were stratified into three groups based on initial hospital's catheter laboratory status: hospitals without a catheter laboratory (No-catheter lab hospitals), hospitals with diagnostic catheter laboratory (Diagnostic hospitals), and hospitals with PCI facilities (PCI hospitals). We used multivariable logistic regression to evaluate factors associated with clinical outcomes. We included 12,303 patients of which 9,798 were admitted to PCI hospitals, 1,595 to no-catheter lab hospitals, and 910 to diagnostic hospitals. Patients admitted to PCI hospitals were more frequently reviewed by a cardiologist (96%, p < 0.001) than no-catheter lab hospitals (80%) and diagnostic hospitals (74%), and more likely to receive coronary angiography (PCI hospitals (87%), diagnostic hospitals (31%), no-catheter lab hospitals (54%), p < 0.001). They also were more likely to undergo PCI (PCI hospitals (42%), diagnostic hospitals (17%), no-catheter lab hospitals (17%), p < 0.001). After adjustment, there was no significant difference in the in-hospital mortality (OR 0.76, 95% CI 0.55-1.06) or re-infarction (OR 1.28, 95% CI 0.72-2.26) in patients admitted to PCI hospitals nor in patients admitted to diagnostic hospitals (mortality (OR 1.28, 95% CI 0.72-2.26), re-infarction (OR 1.38, 95% CI 0.68-2.82)). There is variation in coronary angiography use between hospitals without a catheter laboratory and PCI centres, which was not associated with better in-hospital survival.


Bio-/haemocompatibility: implications and outcomes for sensors?
Sensors are a sample contacting technology, and when exposed to biological matrices tend to suffer from the problem of poor biocompatibility and surface fouling. The effects are evidenced by time dependent signal drift (particularly for those devices which are implanted intravascularly). Practical methods to reduce such effects require an understanding of the interface between the electrode and its environment prior to assessment of the potential areas for improvement. Current procedures employed to overcome the observed losses in electrode sensitivity (following exposure to whole blood) include surface modification of the outer diffusion limiting membrane (via variation in film porosity) or even biomimicry of the fluid cell membrane. At amperometric electrodes incorporation of additional inner perm-selective membranes has achieved a reduction in electrode passivation from undesirable surface active compounds as has the use of low polarisation potentials. Other studies have attempted to induce an aqueous barrier between the matrix and the electrode tip which physically prevents passage of cellular components from the sensor surface. Careful choice of the system and materials will ultimately lead to biocompatible non-fouling devices capable of functioning in an array of bio-environments suitable for clinical monitoring of the critically ill patient.


Intense pulsed light (IPL) annealed sol-gel derived ZnO electron injector for the production of high efficiency inverted quantum dot light emitting devices (QLEDs).
Room temperature intense pulsed light annealing (photonic annealing, pulsed forge) renders the sol-gel derived ZnO films highly conductive and hydrophobic with improved interface with the colloidal quantum dots. The IPL annealed ZnO proved to be a better electron transporter/injector in inverted devices with QDs. Both the current and power efficiencies of red devices comprising IPL annealed ZnO were 13.75 and 37.5 fold higher than the identical devices produced with thermally annealed ZnO. The lifetime of the devices with IPL annealed ZnO was found to be fivefold longer than the thermally annealed ZnO counterpart. Thermally aged devices comprising IPL annealed ZnO gave a maximum current efficiency of 23 cd A-1 and a power efficiency of 30 lm W-1.


Abrogation of c-MYC protein degradation in human lymphocyte lysates by prior precipitation with perchloric acid.
Conventional lysis buffers, though containing cocktails of protease inhibitors, did not prevent the degradation of c-MYC recombinant protein added immediately prior to lysis to cell pellets from human mixed lymphocyte cultures. Treatment of the cells with 4.2% perchloric acid, however, prevented protein degradation and facilitated the detection of c-MYC protein by Western blotting even in unstimulated lymphocytes, where previously it had been reported to be undetectable or barely detectable using this technique. PHA stimulation of lymphocytes induced an approximately six fold increase in measured c-MYC protein within 5 h if cell extracts were prepared using perchloric acid precipitation. However, using conventional lysis buffer the proto-oncogene protein was undetectable until 48-72 h after mitogen addition. Pretreatment with perchloric acid may be useful for Western blotting analysis of protein in other systems where it may be desirable to dispense with the use of toxic protease inhibitors or where these may be incompletely effective.


Prevalence of Arsenic in chicken feed and its contamination pattern in different parts of chicken flesh: a market basket study.
Organoarsenic compounds are widely used in chicken feed for control of coccidial parasite, quick weight gain, and for imparting attractive color to the chicken flesh. A study was conducted to assess the level of arsenic in both chicken feed and flesh. Chicken feed was collected from 10 farm houses and total arsenic was estimated. The quantitative estimation suggests that the four levels of chicken feed contain different quantities of arsenic load. The results demonstrated that feed at stages III and IV levels contain 0.01 mg/g and 0.018 mg/g of arsenic respectively. However, at stages I and II levels, the feed contains 0.005 mg/g and 0.0052 mg/g of arsenic respectively. Proceeding similarly, chicken flesh was collected from ten vendors in the local markets of Burdwan. The experimental results revealed that deposition of arsenic in different parts of chicken body is not same. The highest accumulation was recorded in the flesh of chest followed by stomach, whereas flesh of the legs and heart showed lower levels of arsenic accumulation. A comprehensive calculation was thereafter done to assess the total amount of arsenic ingestion through consumption of chicken. If a person takes 60.0 g of chicken flesh (leg, breast, muscles, and stomach) everyday, then the person may consume 0.186-0.372 μg of arsenic per day. This study therefore clearly suggests that excessive consumption of poultry chicken may prove to be fatal. However, further research is necessary to confirm the present findings. To the best of our knowledge, this is probably the first report on the likelihood of arsenic contamination in the flesh of different body parts of poultry chicken from Eastern India.


Effect of extra running on running-based taste aversion in rats.
Voluntary running in an activity wheel endowed rats with aversion to a taste solution consumed before the running. This running-based taste aversion was attenuated by extra running opportunities interspersed among the taste-running pairings, but the attenuating effect was reduced by signaling the extra running by another taste cue. These results correspond to the so-called degraded contingency effect and cover-cue effect in the traditional preparations of Pavlovian conditioning.


Effect of nano-TiO2 on photochemical reaction of chloroplasts of spinach.
The effects of nano-TiO2 (rutile) on the photochemical reaction of chloroplasts of spinach were studied. The results showed that when spinach was treated with 0.25% nano-TiO2, the Hill reaction, such as the reduction rate of FeCy, and the rate of evolution oxygen of chloroplasts was accelerated and noncyclic photophosphorylation (nc-PSP) activity of chloroplasts was higher than cyclic photophosphorylation (c-PSP) activity, the chloroplast coupling was improved and activities of Mg2+-ATPase and chloroplast coupling factor I (CF1)-ATPase on the thylakoid membranes were obviously activated. It suggested that photosynthesis promoted by nano-TiO2 might be related to activation of photochemical reaction of chloroplasts of spinach.


Optimising mobility through the sit-to-stand activity for older people living in residential care facilities: A qualitative interview study of healthcare aide experiences.
To explore the experience of HCAs encouraging residents living in residential care to complete the sit-to-stand activity and to identify the strategies HCAs used to integrate the activity into their daily work routines. Decreased mobility in advanced ageing is further reduced when entering a residential care facility. Interventions such as the sit-to-stand activity have been shown to have a positive effect on the mobility of older people. There is evidence to suggest that healthcare aides are able to support residents to complete the sit-to-stand activity as part of their daily work routines; however, little is known about how healthcare aides actually do this with residents living in residential care. A qualitative interview study included seven purposively sampled HCAs working in residential care facilities. Semistructured interviews were analysed using inductive qualitative content analysis. The HCAs' experience with the sit-to-stand activity was represented by the following four categories: Resident participation, Feeling misunderstood and disrespected, Time and workload, and Management involvement. HCAs identified three strategies to help them support residents to complete the sit-to-stand activity: Motivating residents, Completing activity in a group and Using time management skills. HCAs reported some encouragement from managers and cooperation from residents to complete the sit-to-stand activity with residents; however, they also felt constrained by time limitations and workload demands and they felt misunderstood and disrespected. HCAs were able to identify several strategies that helped them to integrate the sit-to-stand activity into their daily routines. This study highlights the challenges and supportive factors of implementing the sit-to-stand activity into the daily work routine of HCAs. The study also identifies the strategic role of nurse managers when implementing interventions in residential care facilities.


Differential amygdala activation in schizophrenia during sadness.
Several studies have reported impaired emotion processing in schizophrenic patients. However, the corresponding functional cerebral correlates of such impairment have not been fully understood, leaving the neurobiological basis of their affective symptoms unknown. Functional magnetic resonance imaging (fMRI) was utilized to examine brain activity in subcortical and cortical regions of 13 medicated male schizophrenic patients and 13 matched healthy controls during happy and sad mood induction. Results show brain activity in the amygdala of normal controls during negative affect, which is in line with previous neuroimaging findings. Unlike controls, schizophrenic patients have not demonstrated amygdala activation during sadness despite matched ratings to normal controls indicating a similar negative affect. Recognizing that structural abnormalities exist in the amygdala of schizophrenic patients, our results provide new evidence of functional abnormalities in the limbic system.


Prenatal stress increases anxiety related behavior and alters cerebral lateralization of dopamine activity.
Effects of unpredictable (random) prenatal stress on the level of anxiety and cerebral lateralization of dopamine turnover rates were studied in rats. The observation of a decrease in the amount of time spent in the open arms of a "plus-maze" supported earlier findings of an increased fearfulness to stressful situations in the offspring in adulthood. We also observed elevated rates of dopamine turnover in the right prefrontal cortex and reduced dopamine activity in the right nucleus accumbens and left corpus striatum of the prenatally stressed animals. This resulted in directional shifts of left-right differences in dopamine activity in all 3 areas. These findings indicate that prenatal stress induces permanent alterations in dopaminergic activity and in cerebral asymmetry. We suggest that the changes in cerebral lateralization of dopamine function may underly the increase in reactivity to anxiety-provoking situations in prenatally stressed offspring.


Energy analysis of weak electron-donor-acceptor complexes and water clusters with the perturbation theory based on the locally projected molecular orbitals: charge-transfer and dispersion terms.
The third order single excitation perturbation theory corrected with the dispersion energy based on the locally projected molecular orbital was applied to study the weak electron-donor-acceptor (charge-transfer) complexes and the hydrogen bonds in the water clusters. In the weak electron-donor-acceptor complexes, the dispersion energy is larger than the charge-transfer energy in absolute value. The dispersion energy is as large as the charge-transfer energy in the hydrogen bond. The cage form of (H(2)O)(6) is the most stable among eight isomers examined, because the dispersion energy is the largest among them.


lncRNA HotairM1 Depletion Promotes Self-Renewal of Cancer Stem Cells through HOXA1-Nanog Regulation Loop.
In cancer cells, a gain of stemness may have profound implications for tumor initiation, aggressiveness, and clinical outcome. However, the molecular mechanisms underlying the self-renewal maintenance of cancer stem-like cells (CSCs) remain elusive. Here, based on analysis of transcriptome sequencing, we identified a long noncoding RNA (lncRNA) named HotairM1, which is weakly expressed in human colorectal carcinoma and uveal melanoma, and a much lower expression in corresponding CSCs. Our results showed that HotairM1 depletion could promote CSC self-renewal and tumor propagation. Mechanistically, HotairM1 recruit EZH2 and SUZ12 to the promoter of its target gene HOXA1, leading to histone H3K27 trimethylation and epigenetic silencing of HOXA1. The silence of HOXA1 subsequently induces the H3K27 acetylation at the enhancer site of Nanog gene to upregulate its expression. The enrichment of Nanog could further inhibit HOXA1 expression, forming a reciprocal regulation loop augmenting the stemness maintaining effect. In summary, our results revealed a lncRNA-based regulatory loop that sustains self-renewal of CSCs, which highlights the critical role of HotairM1 in CSC development through the HOXA1-Nanog signaling loop.


Dipeptidyl peptidase-IV inhibitory activity of dimeric dihydrochalcone glycosides from flowers of Helichrysum arenarium.
A methanol extract of everlasting flowers of Helichrysum arenarium L. Moench (Asteraceae) was found to inhibit the increase in blood glucose elevation in sucrose-loaded mice at 500 mg/kg p.o. The methanol extract also inhibited the enzymatic activity against dipeptidyl peptidase-IV (DPP-IV, IC50 = 41.2 μg/ml), but did not show intestinal α-glucosidase inhibitory activities. From the extract, three new dimeric dihydrochalcone glycosides, arenariumosides V-VII (2-4), were isolated, and the stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Of the constituents, several flavonoid constituents, including 2-4, were isolated, and these isolated constituents were investigated for their DPP-IV inhibitory effects. Among them, chalconaringenin 2'-O-β-D-glucopyranoside (16, IC50 = 23.1 μM) and aureusidin 6-O-β-D-glucopyranoside (35, 24.3 μM) showed relatively strong inhibitory activities.


Silent ischemia: to treat or not.
As worded, the question "Should silent ischemia be treated?" needs to be examined carefully, assuming that silent ischemia is even the correct topic of the question. The way the question is phrased influences the answer. The more the question's permutations are examined, the clearer it becomes that the problem is one of definition. Our conceptualization of the ischemic process is still incomplete, and the question of whether to treat silent ischemia remains. Ultimately, the decision will depend on demonstrable benefit for prognosis. Every acute ischemic syndrome is indicative of poor prognosis, independent of other factors associated with adverse outcome and of the method of measurement. The true determinant of the need to treat is the total ischemic pattern, and how silent ischemia and angina fit within that context is not yet known.


Indomethacin prevents the increase in urea synthesis capacity and the weight loss after hysterectomy in rats.
Prostaglandins have been suggested to be mediators of post-operative catabolism. Previous studies have shown that stimulation of urea synthesis contributes to post-operative nitrogen loss. The effect of prostaglandins on this hepatic function was assessed in hysterectomized rats on the first post-operative day by measurements of the Capacity of Urea-N Synthesis (CUNS) with and without indomethacin treatment. Hysterectomy increased CUNS by 1 3 and led to a weight loss of 10 g in one day. Indomethacin prevented the increase in CUNS and the post-operative weight loss in operated animals; it also decreased CUNS by 1 3 in control rats. Blood amino-nitrogen concentration of indomethacin treated hysterectomized rats was 1 3 lower than in untreated animals, indicating an even more marked effect of indomethacin on post-operative tissue amino-acid release than on CUNS. Indomethacin exerts a nitrogen sparing effect, possibly depending on normalization of both post-operative hepatic amino-nitrogen conversion and tissue proteolysis. This may be of clinical importance in controlling post-operative catabolism.


Processing multimode binding situations in simulation-based prediction of ligand-macromolecule affinities.
The linear response (LR) approximation and similar approaches belong to practical methods for estimation of ligand-receptor binding affinities. The approaches correlate experimental binding affinities with the changes upon binding of the ligand electrostatic and van der Waals energies and of solvation characteristics. These attributes are expressed as ensemble averages that are obtained by conformational sampling of the protein-ligand complex and of the free ligand by molecular dynamics or Monte Carlo simulations. We observed that outliers in the LR correlations occasionally exhibit major conformational changes of the complex during sampling. We treated the situation as a multimode binding case, for which the observed association constant is the sum of the partial association constants of individual states/modes. The resulting nonlinear expression for the binding affinities contains all the LR variables for individual modes that are scaled by the same two to four adjustable parameters as in the one-mode LR equation. The multimode method was applied to inhibitors of a matrix metalloproteinase, where this treatment improved the explained variance in experimental activity from 75% for the unimode case to about 85%. The predictive ability scaled accordingly, as verified by extensive cross-validations.


Effectiveness of physiotherapy plus acupuncture compared with physiotherapy alone on pain, disability and grip strength in people with carpal tunnel syndrome: A randomized clinical trial.
Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome in the upper extremities. Acupuncture is often used as a treatment method in CTS and numerous studies consider it effective. However, no study has yet compared the efficacy of physical therapy including bone and neural mobilization, exercise and electrotherapy with and without acupuncture in CTS patients. comparing the effect of physiotherapy plus acupuncture with physiotherapy alone on pain, disability and grip strength in CTS patients. Forty patients with mild to moderate CTS were randomly divided into two equal groups. Both groups received exercise and manual techniques for 10 sessions. Patients in the physiotherapy plus acupuncture group also received 30 min of acupuncture in every session. The visual analog scale (VAS) score, the score on the Boston carpal tunnel questionnaire for functional status and symptom severity, shortened disability of arm, shoulder, hand (Quick-DASH) score and grip strength were evaluated at pre-test and post-test. According to ANOVA results, there is a significant interaction between group and time for VAS, BCTQ and Quick-DASH parameters. At the post-test, while the parameters of VAS, BCTQ and Quick-DASH in the physiotherapy plus acupuncture group had a statistically significant difference compared to the physiotherapy group, no significant difference was observed between the two groups in the pre-test. Moreover, there is no significant difference between groups in grip strength improvement. This study shows preliminary evidence that physiotherapy plus acupuncture, was more effective than physiotherapy alone in pain relief and improving disability of patients suffering from CTS.


Simultaneous determination of benzene and phenol in heat transfer fluid by head-space gas chromatography hyphenated with ion mobility spectrometry.
The quantitative determination of some compounds such as benzene and phenol in a complex matrix by ion mobility spectrometry (IMS) can be a difficult task, due to the influence of other components present in the matrix and the chemical properties of both compounds, such as their high volatility and low proton affinity. Monitoring of these compounds in a heat transfer fluid (HTF) is essential to check the correct working of a thermosolar plant and for safety and environmental reasons. Benzene and phenol, among other compounds, are produced when HTF is exposed to high temperatures in continuous cycles and their presence can decrease the efficiency of HTF. For the first time, a headspace module coupled to a gas chromatography column in combination with an IMS (with a tritium ionization source) has been optimized and fully validated to simultaneously quantify benzene and phenol in HTF. The limit of detection (LOD) and limit of quantification (LOQ) achieved with the method proposed were 0.011 and 0.038 g L(-1) and 0.004 and 0.014 g L(-1) for benzene and phenol respectively. The precision of the method was evaluated in terms of repeatability and reproducibility with all values lower than 9.2% and 13.3%, respectively. Results demonstrated that benzene and phenol were generated in the HTF heating process, and its concentration increased with heating time (approximately 483 h). The average concentration values for benzene and phenol in degraded HTF samples were not significantly different to values obtained using a gas chromatography-flame ionization detector instrument. Therefore, IMS is a promising technique for in-field quality control of HTF in a thermosolar plant due to its speed, versatility, sensitivity and selectivity to quantify these degradation compounds.


Neuroprotective strategies for neonatal hypoxic-ischemic brain damage: Current status and challenges.
Neonatal hypoxic-ischemic brain damage (HIBD) is a prominent contributor to both immediate mortality and long-term impairment in newborns. The elusive nature of the underlying mechanisms responsible for neonatal HIBD presents a significant obstacle in the effective clinical application of numerous pharmaceutical interventions. This comprehensive review aims to concentrate on the potential neuroprotective agents that have demonstrated efficacy in addressing various pathogenic factors associated with neonatal HIBD, encompassing oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and apoptosis. In this review, we conducted an analysis of the precise molecular pathways by which these drugs elicit neuroprotective effects in animal models of neonatal hypoxic-ischemic brain injury (HIBD). Our objective was to provide a comprehensive overview of potential neuroprotective agents for the treatment of neonatal HIBD in animal experiments, with the ultimate goal of enhancing the feasibility of clinical translation and establishing a solid theoretical foundation for the clinical management of neonatal HIBD.


Evidence-Based Practices for Culturally Responsive Medical Education.
Medical education has a role to play in responding to the global call for social justice. Medical educators can lead the global transformation by adopting culturally responsive teaching (CRT) practices. The ultimate objective must be the achievement of equitable learning and success outcomes for all students, especially those from underrepresented and international communities. The strategies outlined in this paper offer specific, actionable, evidence-based strategies that will empower educators to apply the CRT framework within the course design, delivery, and evaluation. As a result, more inclusive classroom environments will be created, ultimately closing the outcome gaps that exist between students.


Short-Term Impact of Different Corneal Incision Positions on Postoperative Astigmatism and Visual Quality After SMILE Surgery.
This study aimed to evaluate the short-term impact of different incision positions on astigmatism and visual quality after small incision lenticule extraction (SMILE) surgery. This prospective study enrolled patients who decided to have SMILE to correct myopia. Patients were randomly allocated into three groups of different incision positions (group A, B, and C with incision position at 90°, 120°, and 150° respectively). Preoperative and postoperative visual acuity, spherical equivalent, and high-order aberrations (HOAs) were measured and compared among groups. Astigmatism was analyzed with the ASSORT Group Analysis Calculator based on the Alpins method. A total of 148 eyes were included for analysis (48 eyes in group A, 50 eyes in group B, and 50 eyes in group C). At 1 month postoperatively, the mean uncorrected distance visual acuity (UDVA) logMAR in group A, B, and C was - 0.03, - 0.03, and - 0.04, respectively. The mean corrected distance visual acuity (CDVA) logMAR in group A, B, and C was - 0.03, - 0.04, and - 0.04, respectively (P > 0.05). The mean postoperative spherical equivalent (SE) values were - 0.01 ± 0.38, - 0.07 ± 0.39, and - 0.16 ± 0.49 (D) in group A, B, and C, respectively (P > 0.05). There was no statistically significant difference in preoperative and postoperative magnitude of astigmatism among different groups (P > 0.05). Significant differences were found in the distribution of astigmatism axis among the three groups at 1 day (P = 0.02) and 1 week (P = 0.02) postoperatively. However, such differences were no longer significant at 1 month after surgery (P > 0.05). No significant differences were found in HOAs among different groups 1 month after surgery (P > 0.05). Different incision positions have no effect on postoperative astigmatism and visual quality 1 month after SMILE surgery, though differences were found in the distribution of the astigmatism axis within 1 week after the surgery.


Antigenic specificity of human serum gamma-globulin samples obtained under conditions of equimolar binding of copper and zinc cations.
Samples of human serum gamma-globulin modified by equimolar binding of copper and zinc cations were obtained using the method of molecular ultrafiltration. Conformation characteristics of the protein were studied by UV spectrophotometry. Immunochemical study included radial immunodiffusion test, direct and sandwich enzyme immunoassays. Conformation changes in gamma-globulin caused by incorporation of solitary metal cations into the protein molecule modified presentation of antigenic determinants on the globule surface and their availability for recognition by specific antibodies. New antigenic determinants and new antigenic specificity of gamma-globulin are not formed under these conditions.


Transforming growth factor-beta1 transcriptionally activates CD34 and prevents induced differentiation of TF-1 cells in the absence of any cell-cycle effects.
A number of cytokines modulate self-renewal and differentiation of hematopoietic elements. Among these is transforming growth factor beta1 (TGF-beta1), which regulates cell cycle and differentiation of hematopoietic cells, but has pleiotropic activities depending on the state of responsiveness of the target cells. It has been previously shown by us and other authors that TGF-beta1 maintains human CD34(+) hematopoietic progenitors in an undifferentiated state, independently of any cell cycle effects, and that depletion of TGF-beta1 triggers differentiation accompanied by a decrease in CD34 antigen expression. In the present work, we show that exogenous TGF-beta1 upregulates the human CD34 antigen in the CD34(+) cell lines TF-1 and KG-1a, but not in the more differentiated CD34(-) cell lines HL-60 and K-562. We further studied this effect in the pluripotent erythroleukemia cell line TF-1. Here, TGF-beta1 did not effect cell growth, but induced transcriptional activation of full-length CD34 and prevented differentiation induced by differentiating agents. This effect was associated with nuclear translocation of Smad-2, activation of TAK-1, and with a dramatic decrease in p38 phosphorylation. In other systems TGF-beta1 has been shown to activate a TGF-beta-activated kinase 1 (TAK1), which in turn, activates p38. The specific inhibitor of p38 phosphorylation, SB202190, also increased CD34 RNA expression, indicating the existence of a link between p-38 inhibition by TGF-beta1 and CD34 overexpression. Our data demonstrate that TGF-beta1 transcriptionally activates CD34 and prevents differentiation of TF-1 cells by acting independently through the Smad, TAK1 and p38 pathways, and thus provide important clues for the understanding of hematopoietic development and a potential tool to modify response of hematopoietic cells to mitogens or differentiating agents.


Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery.
The blood-brain barrier (BBB) limits the uptake of most drugs by brain, and the traditional approach to the BBB problem is the use of medicinal chemistry to increase drug lipid solubility, and increase lipid-mediated transport across the BBB. This review advocates a new model to CNS drug discovery of BBB-penetrating small molecules, whereby drug candidates are screened for carrier-mediated transport (CMT) across the BBB. CMT systems are expressed by genes within the Solute Carrier (SLC) Transporter Gene Family, which now totals > 400 transporter genes. Emphasis is placed on reconciliation of the substrate transporter profile (STP) of BBB transport in vivo with the STP of the cloned SLC transporter in vitro. This reconciliation is crucial to the identification, from sometimes a large number of candidates, of the respective SLC transporter that is responsible for BBB transport in vivo for a given class of nutrients. Dual track screening of a small molecule library for drugs that have the dual properties of affinity for a neural cell drug receptor target, and affinity for a BBB CMT transporter target, can lead to a revolution in how small molecule drugs are identified in CNS drug discovery programs.


B-1 lymphocytes in mice and nonhuman primates.
B-1 cells comprise subpopulations of B lymphocytes in mice that display developmental, phenotypic, and functional characteristics that are distinct from those of conventional B cell populations (B-2 cells). Despite the known importance of murine B-1a (CD5(+) ) and B-1b (CD5(-) ) cells in the production of natural antibodies and rapid antigen-specific humoral responses to infection, evidence for B-1 cells in primates, including humans, is very limited. Identifying these cells in humans proves challenging given the limited number of cells that can be obtained from sites expected to harbor increased frequencies of these cells (i.e., peritoneal and pleural cavities) and the need to perform functional analyses on these cells, which, in the case of B-1b cells, must be carried out in vivo. My laboratory has used cynomolgus macaques and African green monkeys to bypass these limitations and to identify and extensively analyze primate B cell populations with the phenotypic and functional characteristics of mouse B-1a and B-1b cells. Our results reveal striking similarities between primate and murine B-1 cells, including a conserved functional role for primate B-1b-like cells in immunity to T cell-independent type 2 antigens.


Transplacental transfer of 2-naphthol in human placenta.
To determine the transfer of 2-naphthol (2-NPH) in fullterm human placental tissues. Six placentas were studied. The ex-vivo dual closed-loop human placental cotyledon perfusion model was used. 2-NPH was added to the perfusate in the maternal compartment. Samples were obtained from the maternal and fetal up to 360 min measuring. The mean fetal weight was 2880 ± 304.2 g. Mean perfused cotyledon weight was 26.3 (±5.5) g. All unperfused placental tissue samples contained NPH with a mean level of 7.98 (±1.73) μg\g compared to a mean of 15.58 (±4.53) μg\g after 360 min perfusion. A rapid drop in maternal 2-NPH concentration was observed; from 5.54 μg\g in the first 15 min and 13.8 μg\g in 360 min. The fetal side increased from 0.65 μg\g in the initial 15 min to 1.5 μg\g in 360 min. The transfer rate of NPH was much lower than that of antipyrine. 2-NPH has the ability to rapidly across the placenta from the maternal to the fetal compartment within 15 min. The placenta seems to play a role in limiting the passage of 2-NPH in the fetal compartment.


Prenatal diagnosis of chromosome abnormalities in the presence of fetal structural defects.
A chromosomal abnormality was found in 42 (10.9%) out of 386 fetuses with a structural defect. Thirty-five of these were diagnosed prenatally, following ultrasonic detection of one or more structural anomalies and associated pathology such as marked intrauterine growth retardation and polyhydramnios. Termination of pregnancy was carried out in 16 fetuses aged less than 26 weeks, intrauterine and neonatal death occurred in 20 cases, the remaining 6 infants were alive at 3 months. The poor outcome in these pregnancies emphasizes the need for prenatal chromosome analysis in the presence of a fetal structural defect.


The value of determination of homovanillic and vanillylmandelic acids in plasma for the diagnosis and follow-up of neuroblastoma in children.
The plasma levels of homovanillic and vanillylmandelic acids were determined in 84 children with neuroblastoma prior to treatment to evaluate the usefulness of these parameters for the diagnosis of this disease. Elevated levels of one or both of these metabolites were observed in 50% of children with Stage I or II disease, in 88% of those with Stage III, in 93% of those with Stage IV and in 100% of children with Stage IV-S for a total of 88% of all patients. The clinical course of the disease can be followed readily by determination of these metabolites, successful therapy or surgery being accompanied by a corresponding decrease in the plasma levels and relapse by a corresponding increase. Determination of homovanillic and vanillylmandelic acids in plasma can obviate many of the problems associated with the collection of urine, especially in young children or ambulant patients, and thus facilitates a more frequent control with consequent advantages for the management of this disease.


PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: a retrospective analysis from the University of Southern California.
Approximately 5% of patients with cutaneous squamous cell carcinoma (CSCC) may develop recurrent or metastatic disease. The management of such cases is challenging and requires multi-disciplinary care. Immunotherapy using PD-1 inhibition was approved to treat unresectable or metastatic CSCC in 2018. Given limited data regarding clinical outcomes outside of published trials, we describe our experience using this therapy. We retrospectively reviewed all patients treated with PD-1 inhibition as therapy for locally advanced, regionally metastatic or distant metastatic CSCC at the University of Southern California. Clinicopathological characteristics, treatment data using PD-1 inhibitors, and outcomes were assessed. Among 26 patients treated with PD-1 inhibition, the objective response rate was 42.3%, with 19.2% of patients having partial response and 23.1% having complete response to therapy. The median progression-free survival was 5.4 months. Median tumor mutational burden (TMB) was higher among responders compared to non-responders (60 vs. 9 Mut/Mb, p = 0.04). Primary CSCC tumor location on the head/neck was also associated with response to PD-1 inhibition (p = 0.04). Two patients with mutations affecting mismatch repair deficiency were noted to have complete response to treatment. No other variables were associated with treatment outcomes. PD-1 inhibition produces durable responses among patients with advanced or metastatic CSCC. PD-1 inhibition therapy is well tolerated, but patients should be monitored closely for immune-related adverse events, particularly frail or immune-suppressed patients. Further investigation of potential biomarkers to help identify patients who will derive the most benefit from this therapeutic option is needed.


A quantitative analysis of the innervation of the pulp of the cat's canine tooth.
Although the cat's canine tooth has become the accepted model for the electrophysiological study of dental sensory mechanisms no examination of its innervation has been carried out at the electron-microscopical level. This study looked at the number and size distribution of both myelinated and non-myelinated fibers in the crown of the cat's canine. The material examined was prepared by routine methods and the measurements taken from electron-microscopical montages of pulpal cross-sections. The measurements were made using a Quantimet 720 image analysis system. In one complete cross-section 3,470 fibers were counted. Eighty-one percent of these were non-myelinated with a modal diameter of 0.35 micron. The modal diameter of the myelinated fibers was 2.5 micron. The relative preponderance of non-myelinated fibers increased from core to periphery. The largest myelinated fibers were concentrated in the core. The fiber size distribution was similar in the single complete and two partial sections examined. It is concluded that all the fibers in the crown of the cat's canine would be contained in the A-delta and C groups and that the strikingly large number of fibers present suggests that the peripheral pulp has a dense innervation, many of the cell processes found there being unsheathed axons.


Novel inhibitors of heat shock protein Hsp70-mediated luciferase refolding that bind to DnaJ.
Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes.


Longitudinal assessment of bone quality by quantitative ultrasonography in children and adolescents.
Among the techniques available to assess bone quality, quantitative ultrasonography of the proximal phalanges of the hand (QUS) has emerged as particularly attractive. In this study, amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were obtained by the sonographic device DBM Sonic BP IGEA in two sessions at two years' interval, in a school-age population (589 subjects, 290 mol/L and 299F, aged 3 to 16 y) with the aim to determine accuracy of QUS measurements, evaluate QUS variable changes during growth, relate these values with age and growth variables. Mean AD-SoS and BTT at age classes from 5 to 12 y as determined at the first and second measurement sessions were not significantly different. A significant increment (p < 0.0001) between the first and the second measurement was observed for both QUS variables. AD-SoS and BTT showed significantly different variations in the various age groups (ANOVA). Correlations were found of AD-SoS and BTT increments with age, height, weight, pubertal stage and with height growth velocity (p < 0.05). AD-SoS and BTT increment curves presented a very similar trend decreasing from 4 to 7 y of age. Thereafter a plateau was reached up to the age of 10 to 11 y in girls and 11 to 12 y in boys, when an increase was observed corresponding to pubertal growth rate acceleration. In conclusion, the present study would confirm that QUS measurements are accurate. Ad-SoS and BTT increment models are similar to most growth velocity curves and follow a strongly age- and growth-dependent pattern.


The requirement of a positive charge at the amino terminus can be compensated for by a longer central hydrophobic stretch in the functioning of signal peptides.
A variety of model presecretory proteins, proOmpF-Lpps, possessing different numbers of lysine residues (0, 2, and 4) as positively charged amino acid residues and different numbers of leucine residues (7, 8, and 9) as hydrophobic amino acid residues in their signal peptides were constructed. The effect of positive charges on the in vitro translocation efficiency markedly differed with the number of leucine residues. Positive charges were strongly required for translocation when the hydrophobic region comprised 7 or 8 leucine residues, whereas the translocation of proOmpF-Lpps possessing 9 leucine residues took place efficiently even in the absence of positive charges and the introduction of positive charges did not significantly enhance the translocation efficiency. The translocation of all the proOmpF-Lpps, including one possessing no positive charge, was ATP-, protonmotive force-, and SecA-dependent and accompanied by signal peptide cleavage, indicating that they are translocated via the usual secretory pathway. It is likely that the requirement of positive charges can be compensated for by a longer hydrophobic stretch in the functioning of the signal peptide.


Secondary sclerosing cholangitis following extracorporeal membrane oxygenation for acute respiratory distress in polytrauma.
Secondary sclerosing cholangitis is a recently identified phenomenon affecting the biliary tree. A subtype has been described in critically ill patients (SSC-CIP). However, underlying mechanisms are unknown, and few cases have been reported following extracorporeal membrane oxygenation (ECMO). We present a 19-year-old male with SSC-CIP after ECMO following major trauma.


An unusual foreign body in the floor of the mouth presenting as a gradually growing mass.
Foreign bodies in the upper aerodigestive tract represent one of the most common ENT emergencies, but patients with foreign bodies in the floor of the mouth rarely present to the otolaryngologist. Only a very small number of these foreign bodies are embedded under normal mucosa and can result in lethal complications. In this article, we report the case of a 3-year-old girl with a gradually enlarging mass in the floor of the mouth. On physical examination at admission, there was a 2x3-cm, elastic, tender mass on the left side of the floor of the mouth, with the overlying mucosa intact and normal in color. Taking the palpable lymph nodes into consideration, a congenital lesion or a pediatric malignancy was suspected initially. A blue pen cap with a surrounding pneumatocele was found intraoperatively. After a careful reevaluation of a previous MRI, a check valve mechanism at the possible site of entry was detected, leading to a pneumatocele, thus explaining the constant growth of the mass. This is a unique case of a foreign body in the floor of the mouth, mimicking a congenital lesion or a pediatric malignancy. Thus, the possibility of a foreign body should not be underestimated when evaluating a child with swelling in the floor of the mouth.


Laceration of a branch of the profunda femoris artery caused by a spike of the displaced lesser trochanter in an inter-trochanteric femoral fracture. A case report.
Injury of femoral vessels is an extremely rare complication in intertrochanteric femoral fractures. In most cases reported, the vascular lesion involves the superficial femoral artery, whereas in very few cases does it involve the profunda femoris artery. We report a case of acute bleeding due to laceration of a perforating branch of the profunda femoris artery caused by a sharp fragment of the displaced lesser trochanter in an intertrochanteric femoral fracture; the lesion was treated by transcatheter embolization. The arterial injury may be iatrogenic, occurring during intramedullary internal fixation, or less frequently, the injury may be due to the fracture itself, caused by a sharp bone fragment that damages the profunda femoris artery or one of its perforating branches. We believe that intertrochanteric femoral fractures with avulsed lesser trochanter are at risk for femoral vessel injuries caused by the displaced bone spike, and we advise meticulous clinical and laboratory monitoring pre- and post-operatively to prevent serious complications.