Multiple whole bacterial antigens in polyvalent vaccine may result in inhibition of specific responses in rainbow trout (Oncorhynchus mykiss).
The goal of fish vaccination today is to protect fish against multiple bacterial fish pathogens simultaneously using polyvalent vaccines. However, many immunological processes such as antigenic cross-reaction, antigenic competition, affinity maturation and antigen-induced suppression may affect the specificity, avidity and level of antibodies. Consequently, the biological function of antibodies may be markedly different from that predicted by conventional serologic tests. Here, we investigated the effects of vaccination and composition of vaccine on the plasma antibody levels, biological function of antibodies in opsonophagocytosis as well as the effects of vaccination on the blood leucocyte counts. Rainbow trout were vaccinated with saline or with two different polyvalent, mineral oil-adjuvanted vaccines. Vaccine 1 contained Aeromonas salmonicida, Listonella anguillarum and both Th and Fd serotypes of Flavobacterium psychrophilum antigens and vaccine 2 contained A. salmonicida, L. anguillarum and only Fd serotype of Fl. psychrophilum. The antibody-mediated opsonophagocytosis was determined as the respiratory burst (RB) activity of blood monocytes and granulocytes against the tested bacterial antigens. Three weeks after vaccination both vaccine groups and the control group showed increased RB activity against all bacterial strains. However, the increase in RB activities was non-specific and originated from the increased number of circulating granulocytes and monocytes. On the other hand, at 6 weeks post-vaccination both specific antibodies and antibody-dependent opsonophagocytosis appeared in both vaccine groups. However, the composition of the vaccine had a marked effect on the magnitude of specific responses. The Fd+Th vaccine enhanced the target specific opsonophagocytosis, to a lesser extent than the Fd vaccine. Both polyvalent vaccines appeared to mainly affect the numbers of circulating monocytes and our results suggest that the monocytes play a more significant role than the granulocytes in antibody-dependent opsonophagocytosis. Our results also suggest that the presented opsonophagocytic assay is an advantageous method to predict vaccine efficiency and that the number, and properties, of bacterial antigens in polyvalent vaccines should be carefully selected in order to avoid inhibitory effects of antigens on the specific response of fish.


Head lice on pillows, and strategies to make a small risk even less.
Due to a lack of evidence, controversy exists about the role of bedding in the transmission of head lice. To determine the proportion of the head lice population found on pillowcases of people with head lice, and to test strategies available to householders to kill head lice on pillowcases. To assess the incidence of head lice on pillowcases, people with active pediculosis had their head lice collected and counted and the pillowcase they had used the night before examined for head lice. To test strategies to kill head lice on pillowcases, live head lice were experimentally placed in miniature pillowcases, and the cases were subjected to a hot wash, a cold wash, hot dryer, and hanging out to dry on an outdoor clothes line. Forty-eight people and their pillowcases were recruited from Townsville, Qld, Australia (dry tropics). One thousand, eight hundred and forty-five lice were collected from their heads to give an average and median intensity of infection of 38.4 and 21 lice, respectively. Two of the 48 pillowcases contained live lice, one nymph on each, 2 h and 9 h after the pillowcases had been removed from the bed. Another pillowcase contained a dehydrated nymph. The incidence of live lice on pillowcases was 4.2% per night and the proportion of the head louse population on the pillowcases was 0.11%. Heat (hot wash and hot clothes dryer) killed head lice experimentally placed in pillowcases. Cold wash and hanging pillowcases out to dry did not kill head lice. Head lice transfer to pillowcases at night, but the incidence is low. Pillowcases pose a risk for re-infection with head lice, but the risk is low, and changing the pillowcase is a reasonably cost-efficient strategy to minimize this risk. Lice on pillowcases can be killed by heating the pillowcase by immersion in water at > 60 degrees C, by a hot wash, or by 15 min in a hot clothes dryer.


Development of 4,5-dihydro-benzodiazepinone derivatives as a new chemical series of BRD4 inhibitors.
Bromodomains (BRDs) are protein interaction modules that selectively recognize ε -N-lysine residues, serving as key epigenetic readers and play a key role in epigenetic regulation of gene transcription. Bromodomain-containing protein 4 (BRD4), a protein containing two BRDs termed BD1 and BD2, has emerged as an attractive candidate for the development of inhibitors targeting gene transcription in several types of cancers. In this study, we made structural modifications of previously reported BRD4 inhibitors, to develop new chemical scaffold 3,4-dihydroquinoxalin-2(1H)-one. Four series of compounds (compounds 7-10) were synthesized, and the BRD4-inhibitory activity and anti-proliferative effect of these compounds were evaluated. We found compound 10d has remarkable anti-proliferative activities toward leukemia cells and could induce apoptosis by mitochondrial pathways. Notably, the analysis of molecular docking suggested that hydrophobic interaction was essential for compound 10d to bind to BD1. In conclusion, these results demonstrate the potential of compound 10d to be utilized as a BRD4 inhibitor with apoptosis inducing effect in future leukemia therapy.


Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide.
Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed. Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro. Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml(-1) min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml(-1) min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 microm) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed. The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.


Reduction in obesity and coronary risk factors after high caloric exercise training in overweight coronary patients.
The majority of patients with coronary heart disease (CHD) are overweight. However, little weight loss occurs with participation in a standard cardiac rehabilitation (CR) program. Fifteen overweight patients (average body mass index of 31.0 kg/m2) with CHD completed a 4-month exercise training program in a CR program. The exercise program consisted primarily of walking long duration (60-90 minutes per session) 5 to 7 days per week at a relatively low intensity of 50% to 60% of peak VO2. Measures of body composition by dual-energy x-ray absorptiometry, body fat distribution by computed tomography, plasma lipid-lipoprotein, glucose and insulin concentrations, and peak VO2 were obtained before and after the exercise intervention. Patients maintained an isocaloric diet throughout the study. Patients had reductions in total body weight (-4.6 kg), fat mass (-3.6 kg), percent body fat (-2.9%), and waist circumference (-5.6 cm) (all P <.001) while maintaining fat-free mass. Subcutaneous adipose tissue was reduced by 12% (P <.001) and visceral adipose tissue was lowered by 14% (P <.001). There were favorable changes in the lipid-metabolic profile with reductions in triglyceride levels (-23.7%), total cholesterol/HDL-C ratio (-14.3%), and fasting insulin levels (-22.3%) (all P <.05). Peak VO2 increased by 21.2% (P <.001). The present pilot study results suggest that a high caloric training exercise training program in the CR setting may be effective in promoting weight loss and improving coronary risk factors in overweight coronary patients. Although additional research with randomized control patients is needed, this alternative to traditional CR may be considered to maximize weight loss as part of a secondary prevention program.


Face processing and exploration of social signals in Prader-Willi syndrome: a genetic signature.
Faces are critical social cues that must be perfectly processed in order to engage appropriately in everyday social interactions. In Prader-Willi Syndrome (PWS), a rare genetic disorder characterized by cognitive and behavioural difficulties including autism spectrum disorder, the literature referring to face processing is sparse. Given reports of poor social interactions in individuals with PWS, we sought to assess their face and emotion recognition skills during eyetracking recordings. Compared with controls, patients with PWS performed more poorly on face/emotion recognition. We observed atypical facial exploration by patients with maternal disomy. These patients looked preferentially at the mouth region, whereas patients with a deletion and controls were more attracted to the eye region. During social scenes, the exploration became more atypical as the social content increased. Our comprehensive study brings new insights into the face processing of patients with PWS. Atypical facial exploration was only displayed by patients with the maternal disomy subtype, corresponding to their higher rate of autism spectrum disorder. This finding strongly argues in favor of early identification of this genetic subgroup in order to optimize care by implementing tailored interventions for each patient as soon as possible.


Long-term survival after multidisciplinary treatments for HER2-positive advanced gastric cancer with multiple liver and lung metastases.
Trastuzumab-based chemotherapy is a standard treatment regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. This is a case of a patient who has survived 12 years after being diagnosed with advanced gastric cancer with multiple liver and lung metastases. A woman in her 70s underwent total gastrectomy, cholecystectomy, and left hepatic lobectomy for gastric cancer with liver metastasis. One month after the surgery, multiple liver metastases appeared. After two courses of S-1 + CDDP chemotherapy, the liver metastases disappeared, and new lung metastases occurred. Because the primary tumor was HER2 positive, S-1 + CDDP + trastuzumab chemotherapy was performed. After one course of chemotherapy, the blood test showed pancytopenia, and CDDP was discontinued. S-1 + trastuzumab chemotherapy was then initiated, and as a result, the lung metastases disappeared. The patient is alive without recurrence 12 years after the surgery. We encountered a case of long-term survival after multidisciplinary treatments for HER2-positive advanced gastric cancer with multiple liver and lung metastases.


Similar mechanisms might be triggered by alternative external stimuli that induce dormancy release in grape buds.
The detection of genes having similar expression profiles following the application of different stimuli that trigger bud break may constitute potent tools for the identification of pathways with a central role in dormancy release. We compared the effects of heat shock (HS) and hydrogen cyanamide (HC) and demonstrated that HS leads to earlier and higher bud-break levels. Changes in transcript levels of catalase, alcohol dehydrogenase and pyruvate decarboxylase were induced following both treatments. However, timing and extent of changes in transcript level differed. Changes occurred earlier in HS-treated buds and were more intense in HC-treated buds. The changes in transcript levels after both treatments were temporary. The rapid and short-lasting changes in gene expression following HS treatment correlated with the faster and higher level of bud-break that this treatment exerted. This correlation may propose that the reported molecular events are mechanistically involved in dormancy release. To test the hypothesis that temporary oxidative stress is part of the mechanism inducing dormancy release, we analyzed the effect of HS and HC treatments on the expression of ascorbate peroxidase, glutathione reductase, thioredoxin h, glutathione S-transferase and sucrose synthase genes and found that they were induced by both treatments in a similar pattern. Taken together, these findings propose that similar cellular processes might be triggered by different stimuli that lead to dormancy release, and are consistent with the hypothesis that temporary oxidative stress and respiratory stress might be part of the mechanism that leads to bud break.


Baseline prognostic factors affecting survival in recurrent and/or metastatic salivary gland adenoid cystic carcinoma.
Adenoid cystic carcinoma (AdCC) is a rare disease, with indolent behavior and poor long-term survival. Many studies have evaluated the role of clinical and pathological factors at presentation on the risk of recurrence. In this study we investigated whether baseline demographic, clinical, and pathological characteristics at the time of primary curative treatment could influence the prognosis of patients once local and/or distant recurrence occurred. All patients affected by primary salivary gland AdCC and treated with curative surgery from January 1997 to June 2016 were reviewed, evaluating those who later developed loco-regional recurrence and/or distant metastasis. Time from the first relapse to death (recurrent/metastatic overall survival, RMOS) was considered the outcome of interest. Out of 87 surgically treated AdCC patients, 36 relapsing lesions were included. Median ages at first presentation and recurrence were 55 and 60-year-old, respectively; 58% were females. Median disease-free-interval (DFI) was 22.0 months. Five-year RMOS was 47%. At univariate analysis, age ≥ 60-year-old (HR:2.67, p = 0.030), primary tumor lympho-vascular invasion (LVI) (HR:5.38, p = 0.003), adjuvant radiotherapy (RT) in the primary setting (HR:0.37, p = 0.043), and DFI < 30 months (HR:3.94, p = 0.008) significantly affected RMOS. Multivariable analysis confirmed the presence of LVI and shorter DFI as independent risk factors. Knowledge of baseline clinicopathological features is helpful in the prognostic stratification of patients with recurrent AdCC, with LVI as the most relevant baseline factor. Adjuvant RT demonstrated its protective role on survival even once recurrence occurred, further supporting its adoption in the primary setting.


[Systolic time intervals during sequential ultrafiltration and hemodialysis].
The effects of a forced withdrawal of fluid by ultrafiltration and the influences of a connected haemodialysis on the period of isometric contraction of the heart were recorded by periodical registration during the treatment. A statistically certain decrease of the LVET (-19.2%) and an increase of the PEP (+ 11.1%) were found. Since at least in the period of the isolated ultrafiltration several essential parameters of the interior milieu do not change decisively, as cause for the changes observed of the systolic intervals of the heart period the decrease of the preload is discussed. During the period of ultrafiltration on an average 15.3 +/- 3.3 ml of plasma water were taken per minute.


Gene transfection of hepatocyte growth factor attenuates the progression of cardiac remodeling in the hypertrophied heart.
Hepatocyte growth factor plays a significant role in angiogenesis, anti-apoptosis, and anti-transforming growth factor-beta1-mediated fibrosis in several organs. In this study, we investigated the effect of transfection of the hepatocyte growth factor gene in attenuation of cardiac remodeling in the hypertrophied heart. Two weeks after banding the ascending aorta of male Sprague-Dawley rats, a hemagglutinating virus of Japan-liposome complex with (H group) or without (C group) human hepatocyte growth factor cDNA was transfected into the left ventricle wall by direct injection. The hepatocyte growth factor, c-Met, and transforming growth factor-beta1 mRNA levels in the left ventricle were then analyzed by real-time quantitative reverse-transcriptase polymerase chain reaction. Two weeks after transfection, the expression of transforming growth factor-beta1 mRNA was significantly attenuated in the H group compared with the C group (P < .01). Myocardial collagen content after 4 weeks of banding was significantly lower in the H group (5.0 +/- 0.6 mg/g tissue) than in the C group (7.4 +/- 0.5 mg/g tissue, P < .01). Left ventricular diastolic function (E/A ratios quantified by Doppler echocardiography) showed a significant increase in the H group (1.9 +/- 0.1) compared with the C group (1.1 +/- 0.1, P < .01). Our results demonstrated that gene transfection of hepatocyte growth factor attenuated left ventricular diastolic dysfunction and cardiac fibrosis in association with a decrease in transforming growth factor-beta1 in the rat heart subjected to pressure overload. Thus, the transfection of the hepatocyte growth factor gene into the hypertrophied heart may be a strategy for the hypertrophied and failing heart even for cardiac surgery.


Cytotoxicity of sphingoid marine compound analogs in mono- and multilayered solid tumor cell cultures.
A subset of four synthetic sphingoid marine compound analogs was chosen from a preliminary in vitro cytotoxicity study for further analysis. The selected analogs were initially screened in monolayer cultures for their anticancer potential against a panel of eight human tumor cell lines, ovarian, colon and lung cancer, squamous cell carcinoma and leukemia producing IC50 values ranging from 1.5 to 6.9 microM. In a secondary screening, the sphingoid analogs were evaluated against multilayered postconfluent cultures of A2780 ovarian cancer and WiDr colon cancer cells. In this model, compounds 5 and 8 were the most active derivatives showing EC50 values in the range 25-32 microM. The performance of 5 and 8 against both cell lines was not dependent on the cell culture model as shown with resistance factor values in the range 8-12. Cell cycle studies in HL60 leukemia cells showed an arrest in G(0)/G1 at a low drug concentration (3 microM) but accumulation in S phase at a high drug concentration (9 microM). It can be concluded that the analogs showed a cell line independent activity, with an apparent selectivity against cells grown in more physiological three-dimensional condition compared to standard anticancer drugs.


Simultaneous determination of multiple coupling networks by high-resolution 2D J-edited NMR spectroscopy.
J coupling constitutes an important NMR parameter for molecular-level composition analysis and conformation elucidation. Dozens of J-based approaches have been exploited for J coupling measurement and coupling network determination, however, they are generally imposed to insufficient spectral resolution to resolve crowded NMR resonances and low measurement efficiency that a single experiment records one J coupling network. Herein, we propose a general NMR method to collect high-resolution 2D J-edited NMR spectra, which are characterized with advantages of pure absorptive lineshapes, decoupled chemical shift dimension, as well as eliminated axial peaks, thus facilitating J coupling partner assignments and J coupling constant measurements. More meaningfully, this protocol allows simultaneous determination of multiple coupling networks for highly efficient multiplet analyses via addressing multiple protons within one single experiment. Additionally, another variant is proposed for high-resolution applications under adverse magnetic field conditions. Therefore, this study provides a useful NMR protocol for configurational and structural studies with extensive applications in chemistry, biology, and material science.


Lnc5926 is essential for early embryonic development in goats through regulation of ZSCAN4 and EIF1AX.
Long noncoding RNAs (lncRNAs) are abundant in mammalian genomes and have been found to play important roles in many biological events. However, the mechanism by which lncRNAs regulate embryonic development remains to be fully elucidated. Here, we investigated the function of the lncRNA, TCONS_00135926 (referred to as lnc5926), through knockdown and overexpression experiments in goat early embryos. Lnc5926 expression at the eight-cell embryonic stage was significantly higher than that at other stages, which was consistent with the pattern of embryonic genome activation (EGA) gene expression. The blastocyst rate after lnc5926 knockdown in eight-cell embryos was significantly lower than that in the control group (0.2% vs. 17.1%, p < 0.05), whereas the cleavage rate was not affected (71.9% vs. 75.1%, p ˃ 0.05). After knockdown or overexpression of lnc5926 in embryos, we measured expression levels of the potential target genes, STAM, HACD1, UBL5, MIOX, ELF1, and the key EGA genes, ZSCAN4 and EIF1AX. Only ZSCAN4 and EIF1AX were significantly downregulated after lnc5926 knockdown, and this effect was reversed by lnc5926 overexpression. We conclude that lnc5926 plays an essential role in early embryonic development in goats by regulating expression of EGA-associated genes.


Landslide detection and inventory updating using the time-series InSAR approach along the Karakoram Highway, Northern Pakistan.
Karakoram Highway (KKH) is frequently disrupted by geological hazards mainly landslides which pose a serious threat to its normal operation. Using documented inventory, optical imagery interpretation, and frequency-area statistics, the features of slope failure, the spatial distribution, and their link to numerous contributing factors have all been effectively explored along the KKH. An updated inventory for the area was recreated using the interferometric synthetic aperture radar (InSAR) persistent scatterer (PS) technology to further investigate millimetre-accurate measurements of slope deformation (Vslope). Utilizing the PS approach, Sentinel-1 data from Jan 2018 to Jan 2022 were processed by which we obtained a deformation rate (VSlope) that varies between 0 and 364 mm/year. A total number of 234 landslides were cited from the literature and classified while 29 new potential landslides were detected and several pre-existing landslides were redefined by the InSAR approach, which was incorporated to generate an updated landslide susceptibility model with 86.6% of prediction precision in the area under curve method. As previous studies done by applying the InSAR technique incorporated a short span temporally and they missed some highly deforming zones like Budalas and Khanabad landslides, contain mean velocities > 50 mm/yr, which we studied individually in this work. In this study, a comprehensive application of the InSAR technique to assessing its performance in detecting and analysing landslides has been applied. The deformation velocity (Vslope) model shows high displacement in some regions, which needed to be further investigated by geoscientists, and the updated developed landslide inventory and susceptibility map can be used for land use planning and landslide mitigation strategies.


Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.
We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies.


Brassinosteroid signaling: from receptor kinases to transcription factors.
Unlike animal steroids, which rely on intracellular steroid receptors to directly alter gene activities, plant steroids use transmembrane receptor kinases to initiate a phosphorylation-mediated signaling cascade to convey their signals into the nucleus. Recent studies have begun to unravel the biochemical details of individual steps of the brassinosteroid signal transduction pathway, including ligand binding and receptor dimerization at the cell surface, signal transmission across the cell membrane, the phosphorylation of cellular targets in the cytosol, and gene regulation inside the nucleus.


Traumatic vesicourethral fistula: unusual case of male urinary incontinence.
The usual cause of urinary incontinence secondary to pelvic trauma is damage to the sphincter mechanism in the prostatic urethra. A case is presented of an unusual and correctable cause of incontinence, vesicourethral fistula. This complication can probably be prevented by adequate debridement, drainage, and diversion.


Allele frequencies of 15 autosomal STRs in Chinese Nakhi and Yi populations.
Genetic characterization of ethnically and geographically diverse populations via short tandem repeats (STRs) is relevant to various fundamental and applied areas of forensic genetics, population studies, and even molecular anthropology. In the present study, genetic polymorphisms of 15 autosomal STR loci were firstly obtained from 918 individuals (495 Nakhis and 423 Yis) residing in the foothills of the Himalayas. The cumulative powers of discrimination and probabilities of exclusion in the two studied ethnic groups were both larger than 0.999999999999999982 and 0.9999961, respectively. Genetic similarities and differences among 61 populations were subsequently investigated by pairwise Cavalli-Sforza genetic distance, multidimensional scaling plots, principal component analysis, and phylogenetic relationship reconstruction. Both Nakhi and Yi had the genetically close relationships with Yunnan Bai and distinct relationships with Xinjiang Turkic-speaking populations (Uyghur and Kazakh) and Vietnamese.


Sulfuretin exerts anti-depressive effects in the lipopolysaccharide-induced depressive mouse models.
Herb-derived therapeutics is an attractive strategy to treat depression. Here we report the ameliorating effects of Sulfuretin, an anti-inflammatory compound in a depressive mouse model. Immobility times were obtained in the tail suspension test and forced swim test performed from day 14 to day 16. Quantitative real-time PCR (qRT-PCR) and Western blot were used to measure brain-derived neurotrophic factor (BDNF) and the extracellular signal-regulated kinase (ERK) pathway of the hippocampus tissue on day 17. SL327 was used to block the ERK pathway in mice to evaluate the interaction between Sulfuretin and the ERK pathway. Mice were treated with Sulfuretin for 14 days before lipopolysaccharide (LPS) injection (0.83 mg/kg/day, i.p.) for two days. Behavior tests showed that Sulfuretin dose-dependently decreased immobility times correlated with depression symptoms. BDNF levels and ERK signaling were significantly restored in the Sulfuretin-treated mice, showing the improvement of brain function. Blocking the p-ERK signaling abrogated the effects of Sulfuretin in improving behaviors and levels of BDNF. Our study suggests that Sulfuretin exhibits anti-depressive function in LPS-induced depressive mice, in which the ERK signaling plays an essential role.


Prothrombotic state in patients with stable COPD: an observational study.
COPD patients have an increased risk of cardiovascular disease and venous thromboembolism. This study aimed to investigate whether patients with stable COPD have a prothrombotic state compared to COPD-free smokers. We conducted an observational study comparing levels of: D-dimers, INR, aPTT, coagulation factors; fibrinogen, FII, FV, FVII, FVIII, FIX, FX and coagulation inhibitors; protein S, proteins C and antithrombin between stable COPD patients and control subjects. A total of 103 COPD patients and 42 controls with similar age, sex, current smoking status, comorbidity burden and cardiovascular risk met the inclusion criteria. Compared to controls, COPD patients had higher levels of D-dimers (median (interquartile range): 360 (230-600) ng·mL-1 versus 240 (180-400) ng·mL-1, p=0.001), fibrinogen (mean±sd: 399±82 mg·dL-1 versus 346±65 mg·dL-1, p<0.001), FII (122±22% versus 109±19%, p=0.004), FV (131±25% versus 121±19%, p=0.015), FVIII (143±32% versus 122±20%, p<0.001) and FX (111 (94-134)% versus 98 (88-107)%, p=0.002), and lower levels of protein S (95 (85-105)% versus 116 (98-121)%, p<0.001) and antithrombin (94.4±11.5% versus 102.3±13.2%, p=0.001). In the COPD group, patients with more severe airflow limitation and frequent exacerbations had significantly higher levels of FII, FV and FX, whereas patients with higher COPD assessment test score had significantly higher levels of FX and lower levels of protein S. Patients with stable COPD exhibited increased levels of key coagulation factors and decreased levels of coagulation inhibitors, namely protein S and antithrombin, compared to COPD-free smokers. Among COPD patients, increased levels of FII, FV and FX and decreased levels of protein S were found in patients with more severe disease.


Spatial variance-mass allometry of population density in felids from camera-trapping studies worldwide.
Power laws are cornerstone relationships in ecology and evolutionary biology. The density-mass allometry (DMA), which predicts an allometric scaling of population abundance, and Taylor's law (TL), which predicts a decrease in the population abundance variation along with a decrease in population density, have enhanced our knowledge of inter- and intra-specific variation in population abundance. When combined, these two power laws led to the variance-mass allometry (VMA), which states that larger species have lower spatial variation in population density than smaller species. The VMA has been predicted through theoretical models, however few studies have investigated if this law is also supported by empirical data. Here, to formally test the VMA, we have used the population density estimates obtained through worldwide camera trapping studies for an emblematic and ecologically important carnivorous taxa, the Felidae family. Our results showed that the VMA law hold in felids, as well as the TL and the DMA laws; bigger cat species showed less variation for the population density than smaller species. These results have important implications for the conservation of wildlife population and confirm the validity of important ecological concepts, like the allometric scaling of population growth rate and the slow-fast continuum of life history strategies.


The vacuolar H+-ATPase of clathrin-coated vesicles is reversibly inhibited by S-nitrosoglutathione.
It has been previously demonstrated that the vacuolar H+-ATPase (V-ATPase) of clathrin-coated vesicles is reversibly inhibited by disulfide bond formation between conserved cysteine residues at the catalytic site on the A subunit (Feng, Y., and Forgac, M. (1994) J. Biol. Chem. 269, 13224-13230). Proton transport and ATPase activity of the purified, reconstituted V-ATPase are now shown to be inhibited by the nitric oxide-generating reagent S-nitrosoglutathione (SNG). The K0.5 for inhibition by SNG following incubation for 30 min at 37 degreesC is 200-400 microM. As with disulfide bond formation at the catalytic site, inhibition by SNG is reversed upon treatment with 100 mM dithiothreitol and is partially protected in the presence of ATP. Also as with disulfide bond formation, treatment of the V-ATPase with SNG protects activity from subsequent inactivation by N-ethylmaleimide, as demonstrated by restoration of activity by dithiothreitol following sequential treatment of the V-ATPase with SNG and N-ethylmaleimide. Moreover, inhibition by SNG is readily reversed by dithiothreitol but not by the reduced form of glutathione, suggesting that the disulfide bond formed at the catalytic site of the V-ATPase may not be immediately reduced under intracellular conditions. These results suggest that SNG inhibits the V-ATPase through disulfide bond formation between cysteine residues at the catalytic site and that nitric oxide (or nitrosothiols) might act as a negative regulator of V-ATPase activity in vivo.


An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats.
1. Reserpine (2.5 mg kg-1 i.p.) decreased rat brain 5-hydroxytryptamine (5-HT) by 86% 24 h later but most components of the 5-HT-dependent behavioural syndrome induced by p-chloroamphetamine (PCA, 5 mg kg-1 i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg kg-1 i.p.) over 1 h after administration were unaffected. However, Straub tail was increased after giving PCA or 5-MeODMT and head weaving was decreased after giving 5-MeODMT. 2. Frontal cortex extracellular 5-HT concentrations of vehicle pretreated rats before injection of PCA, as calculated from dialysate 5-HT concentrations, were about 1/1000th of corresponding brain values. Extracellular 5-hydroxyindoleacetic acid (5-HIAA) and brain values were comparable with each other. Dialysate 5-HT increased after PCA with peak values at 20-40 min. 3. Reserpine pretreatment reduced dialysate 5-HT concentration before PCA was given but the net increase (AUC) over the 1 h after PCA did not differ significantly from that seen in animals pretreated with vehicle. Dialysate 5-HIAA values slowly decreased after PCA injection in both reserpine and vehicle pretreated groups. 4. The results suggest that PCA causes the 5-HT syndrome by releasing 5-HT from the neuronal cytoplasm but that physiological release of 5-HT occurs from vesicular stores.


Immunohistochemical analysis of the patterns of p53 and PCNA expression in odontogenic cystic lesions.
the role of p53 expression in odontogenic lesions has not been fully determined, but has been associated with cell proliferation. The purpose of this study was to analyze p53 and proliferating cell nuclear antigen (PCNA) expression in 4 different odontogenic lesions. expression of p53 and PCNA was analyzed in radicular and dentigerous cysts, odontogenic keratocysts, and calcifying odontogenic cysts (Gorlin cysts) using monoclonal antibodies for detection of p53 and PCNA. PCNA expression was significantly greater in the basal layer of radicular cysts and in the suprabasal layer of odontogenic keratocysts; the percentage of p53 positive cells was significantly greater in the suprabasal layer of odontogenic keratocysts. The patterns of p53 and PCNA expression in dentigerous and radicular cysts were similar although the two lesions are of different origin. In odontogenic keratocysts and Gorlin cysts, results indicate a different pattern of tumor growth.


The emergence of a concept in shallow neural networks.
We consider restricted Boltzmann machine (RBMs) trained over an unstructured dataset made of blurred copies of definite but unavailable "archetypes" and we show that there exists a critical sample size beyond which the RBM can learn archetypes, namely the machine can successfully play as a generative model or as a classifier, according to the operational routine. In general, assessing a critical sample size (possibly in relation to the quality of the dataset) is still an open problem in machine learning. Here, restricting to the random theory, where shallow networks suffice and the "grandmother-cell" scenario is correct, we leverage the formal equivalence between RBMs and Hopfield networks, to obtain a phase diagram for both the neural architectures which highlights regions, in the space of the control parameters (i.e., number of archetypes, number of neurons, size and quality of the training set), where learning can be accomplished. Our investigations are led by analytical methods based on the statistical-mechanics of disordered systems and results are further corroborated by extensive Monte Carlo simulations.


New Eocene damselflies and first Cenozoic damsel-dragonfly of the isophlebiopteran lineage (Insecta: Odonata).
The study of a new specimen of Petrolestes hendersoni from the Eocene Green Formation allows a more precise description of the enigmatic damselfly and the diagnosis of the Petrolestini. Petrolestes messelensis sp. nov. is described from the Eocene Messel Formation in Germany, extending the distribution of the Petrolestini to the European Eocene. The new damsel-dragonfly family Pseudostenolestidae is described for the new genus and species Pseudostenolestes bechlyi, from the Eocene Messel Formation. It is the first Cenozoic representative of the Mesozoic clade Isophlebioptera.


A benign polymorphism in the aspartoacylase gene may cause misinterpretation of Canavan gene testing.
We found normal individuals whose aspartoacylase gene Y231X mutation site consistently gave no signal in a primer extension assay. We determined the nucleotide sequence of the relevant region of the gene in those individuals, and found a new allele with a thymidine residue at the mutation site instead of a cytidine. Since both TAC and TAT code for tyrosine, this sequence polymorphism has no effect on the amino acid sequence of the ASPA protein. We found the relative frequencies of the 693C and the 693T alleles in the tested population to be 0.75 and 0.25 respectively.


Cytogenetical characterization of Chinese hamster ovary X-ray-sensitive mutant cells xrs 5 and xrs 6. VII. Complementation analysis of X-irradiated wild-type CHO-K1 and xrs mutant cells using the premature chromosome condensation technique.
The complementation effect of wild-type CHO-K1 and xrs mutants after fusion, as judged by the frequencies of X-ray-induced G1 and G2 premature chromosome condensation (PCC), was studied. For induction of PCC, X-irradiated interphase cells (G1 and G2) were fused immediately with untreated mitotic cells of the same cell line or with mitotic cells of another line. The frequencies of breaks in G1-PCC, or breaks and chromatid exchanges in G2-PCC were determined and the latter parameter was compared with the frequency of chromosomal aberrations in mitotic cells following G2 irradiation. CHO-K1 cells were capable of complementing the X-ray sensitivity of both xrs 5 and xrs 6 cells. However, full restoration of the repair defect in xrs cells could never be accomplished. The mutants failed to complement each other. In CHO-K1 cells, the incidence of chromosomal aberrations was significantly higher in G2-PCC (2.5-fold) than that observed in mitotic cells at 2.5 h after irradiation. The ratio of the induced frequency of aberrations in G2-PCC to that in mitotic cells was correlated with the degree of repair of DNA double-strand breaks (dsb) and reached almost 1 in xrs 5 cells indicating no repair. In addition the data indicated that, during the period of recovery of CHO-K1 cells, X-ray-induced breaks decreased but exchanges remained at the same level. In contrast, due to a deficiency in rejoining of dsb in xrs mutants, breaks remained open for a long period of time, allowing the formation of additional chromatid exchanges during recovery time.


[The application of sodium hyaluronate in joint diseases].
To review the physiological function of sodium hyaluronate in joints and its clinical applications. Many literatures were reviewed and analysed on therapeutic mechanism and the application foreground of sodium hyaluronate. Extrinsic sodium hyaluronate plays an important role in improving synovial fluid and protecting cartilages as well as suppressing inflammation, so it is used in the treatment of joint diseases such as knee osteoarthritis, rheumatoid arthritis or temporomandibular osteoarthritis. Sodium hyaluronate possesses a good applied prospect in joint diseases.


The proportions of term or late preterm births after exposure to early antenatal corticosteroids, and outcomes: systematic review and meta-analysis of 1.6 million infants.
To systematically review the proportions of infants with early exposure to antenatal corticosteroids but born at term or late preterm, and short term and long term outcomes. Systematic review and meta-analyses. Eight databases searched from 1 January 2000 to 1 February 2023, reflecting recent perinatal care, and references of screened articles. Randomised controlled trials and population based cohort studies with data on infants with early exposure to antenatal corticosteroids (<34 weeks) but born at term (≥37 weeks), late preterm (34-36 weeks), or term/late preterm combined. Two reviewers independently screened titles, abstracts, and full text articles and assessed risk of bias (Cochrane risk of bias tool for randomised controlled trials and Newcastle-Ottawa scale for population based studies). Reviewers extracted data on populations, exposure to antenatal corticosteroids, and outcomes. The authors analysed randomised and cohort data separately, using random effects meta-analyses. The primary outcome was the proportion of infants with early exposure to antenatal corticosteroids but born at term. Secondary outcomes included the proportions of infants born late preterm or term/late preterm combined after early exposure to antenatal corticosteroids and short term and long term outcomes versus non-exposure for the three gestational time points (term, late preterm, term/late preterm combined). Of 14 799 records, the reviewers screened 8815 non-duplicate titles and abstracts and assessed 713 full text articles. Seven randomised controlled trials and 10 population based cohort studies (1.6 million infants total) were included. In randomised controlled trials and population based data, ∼40% of infants with early exposure to antenatal corticosteroids were born at term (low or very low certainty). Among children born at term, early exposure to antenatal corticosteroids versus no exposure was associated with increased risks of admission to neonatal intensive care (adjusted odds ratio 1.49, 95% confidence interval 1.19 to 1.86, one study, 5330 infants, very low certainty; unadjusted relative risk 1.69, 95% confidence interval 1.51 to 1.89, three studies, 1 176 022 infants, I2=58%, τ2=0.01, low certainty), intubation (unadjusted relative risk 2.59, 1.39 to 4.81, absolute effect 7 more per 1000, 95% confidence interval from 2 more to 16 more, one study, 8076 infants, very low certainty, one study, 8076 infants, very low certainty), reduced head circumference (adjusted mean difference -0.21, 95% confidence interval -0.29 to -0.13, one study, 183 325 infants, low certainty), and any long term neurodevelopmental or behavioural disorder in population based studies (eg, any neurodevelopmental or behavioural disorder in children born at term, adjusted hazard ratio 1.47, 95% confidence interval 1.36 to 1.60, one study, 641 487 children, low certainty). About 40% of infants exposed to early antenatal corticosteroids were born at term, with associated adverse short term and long term outcomes (low or very low certainty), highlighting the need for caution when considering antenatal corticosteroids. PROSPERO CRD42022360079.


Kinetics of 1H →31P NMR cross-polarization and dynamics in a layered crystalline α-Sn(IV) phosphate.
The proton-phosphorus (H-P) cross-polarization (CP) is effective in Sn(HPO4)2·H2O despite of the presence of paramagnetic ion impurities. Polarization constants TH-P and 1H T1ρ times are measured in static Sn(HPO4)2·H2O by the kinetic variable-temperature H-P CP experiments. The temperature dependence of the 1H T1ρ times is interpreted in terms of proton movements in the interlayer space occurring between the phosphate groups without participation of the water molecules. The process requires an activation energy of 8.7 ± 0.7 kcal/mol. The MAS effect on the 1H T1ρ times is shown and discussed.


Visual chromophore electronic structure.
The implications that recent work on the electronic structure of polyenes have for the low lying electronic states of retinal reviewed and a very simple model for the diffusenesss of the absorption spectra of visual chromophores is presented.


Computer analysis of allergic histories taken by questionnaire.
We report the development of a detailed allergy questionnaire designed so that the answers can be typed into a mini-computer. Computer programmes have been written to file and to retrieve these answers, and to print a summary which is then 'weighed', so as to produce a clinical atopy score which is then further broken down into indoor and outdoor scores. In a pilot survey of ninety patients, their clinical atopy scores and immunoglobulin E (IgE) profiles have been compared, and additional computer programmes have been written which will (a) assess if a more detailed IgE investigations is warranted, and (b) suggest which allergens, if any, are likely to be responsible for the patients' symptoms.


Internalized stigma and intimate relations in bipolar and schizophrenic patients: a comparative study.
The aim of this study was to determine characteristics of internalized stigma and intimate relations in bipolar and schizophrenia patients and to compare characteristics of intimate relations in bipolar and schizophrenia patients with or without internalized stigma. A total of 228 volunteers were included, 119 patients with bipolar disorder and 109 with schizophrenia. Schizophrenic and bipolar disorder patients were compared in terms of internalized stigma and intimate relations characteristics. Bipolar and schizophrenia patients with and without internalized stigma were compared in terms of characteristics of intimate relations. Internalized stigma was determined in one in three schizophrenia and one in five bipolar patients. Stigma resistance and relational esteem in intimate relations scores were higher in bipolar patients. Relational anxiety/fear of relationship, relational monitoring and external relational control scores were higher in schizophrenia patients with internalized stigma compared to those without, while their relational satisfaction, relational esteem and relational assertiveness scores were lower. Relational anxiety/fear of relationship and relational monitoring scores were higher in bipolar patients with internalized stigma compared to those without, while their relational satisfaction scores were lower. Internalized stigma in schizophrenia patients is a well-known subject that has been investigated previously. The results of our study are significant in terms of showing that internalized stigma is also frequent in bipolar disorder patients, and not solely in schizophrenia patients. Stigma resistance is higher in bipolar disorder patients. Internalized stigma is correlated with intimate relations in both bipolar and schizophrenia patients.


Item-Based Analysis of Some ADOS-2 Items with Typically Developing Participants Might help Improve Cross-Cultural Validity of ADOS-2.
Most internationally recognized instruments for the screening and diagnosis of autism spectrum disorder have been developed in the USA, which calls into question the degree of their cultural adaptation to diverse populations. The aim of this study is to examine the characteristics of social communication in typically developing Croatian-speaking participants (N = 220) using ADOS-2-defined item-level normative values. Croatian subjects showed the expected ("typical") results in the domain of verbal communication, slightly atpical results in nonverbal communication (primarily gesture use), and more significant deviations in pragmatics (offering and asking for information), relative to the expectations of the ADOS-2. As ADOS-2 has become an important component of thorough ASD diagnostic evaluations worldwide, identifying methods for increasing the cross-cultural validity is essential.


Immunocytochemical studies of substance P and leucine-enkephalin in Huntington's disease.
The distribution of substance P and leucine-enkephalin in selected regions of brain obtained postmortem from patients with Huntington's disease and from neurologically normal persons has been studied with immunocytochemical techniques. In the normal brain, substance P immunoreactivity was identified in medium-sized neurons in the neostriatum, in neurons of the external segment of the globus pallidus, and in fine fibers in teh neostriatum, inner segment of the globus pallidus, and in the pars reticulata of the substantia nigra. Huntington's disease brains all exhibited a marked decrease in substance P fiber density in the substantia nigra and globus pallidus. A few medium-sized neurons with substance P immunoreactivity remained in the neostriatal remnant. Leucine-enkephalin immunoreactive processes were present throughout the neostriatum of normal brain, and were densely packed in the external segment of the globus pallidus and in the substantia nigra. A uniform population of medium-sized neurons containing immunoreactive leucine-enkephalin was present in the caudate and putamen. By contrast, in the Huntington's disease brains there was a marked diminution of fiber staining in the globus pallidus and substantia nigra. A few medium-size neurons and sparse fibers with leucine-enkephalin immunoreactivity persisted in the atrophic neostriatum. These observations are consistent with previous reports of regional peptide concentrations in both normal and Huntington's disease brain. Cells containing substance P and leucine-enkephalin immunoreactivity persist in the basal ganglia in brains from patients with Huntington's disease, and we have no evidence that cellular content of one or the other peptide is associated with disproportionate cell death or survival.


Scurvy in an autistic child: MRI findings.
Scurvy results from a deficiency of vitamin C and is rarely seen in the United States. We describe the MRI findings of a case of scurvy in an autistic child with food-avoidant behavior. Advanced imaging is rarely performed in clinically well-understood disease entities such as scurvy. Typical radiographic findings are well described leading to definitive diagnosis, although the findings can be missed or misinterpreted given the rarity of scurvy in daily practice. To our knowledge, MRI features of scurvy in children in the US have been described in only one case report. This case of scurvy in an autistic child with food-avoidant behavior emphasizes that classic nutritional deficiencies, despite their rarity, must be included in the differential diagnosis of at-risk populations.


QTL Mapping and Identification of Candidate Genes in DO Mice: A Use Case Model Derived from a Benzene Toxicity Experiment.
Diversity Outbred (DO) mice are a multiparental advanced generation intercross population derived from eight inbred strains which are genetically very diverse. They are maintained as an outbred population using a randomized mating design. Thus DO mice represent an ideal population to map phenotypic traits. Here, we provide a case study in which male DO mice were exposed to benzene and phenotyped for the number of micronucleated reticulocytes. We provide step-by-step R scripts for the analysis of phenotypes, genotypes, mapping of resistance gene loci and identification of candidate genes.


Functional genomic analysis of the response of Atlantic cod (Gadus morhua) spleen to the viral mimic polyriboinosinic polyribocytidylic acid (pIC).
In order to improve our understanding of how Atlantic cod (Gadus morhua) respond to viruses, we characterized immune-related gene expression in spleen tissues following stimulation with a synthetic double-stranded RNA polyriboinosinic polyribocytidylic acid (pIC). We used reciprocal suppression subtractive hybridization (SSH) cDNA libraries and quantitative RTPCR (QPCR) to identify and quantify pIC-responsive transcripts. A total of 3874 expressed sequence tags (ESTs) were generated from SSH libraries enriched for genes responsive to pIC. Thirteen immune-relevant genes from the libraries were subjected to QPCR. Genes confirmed as up-regulated by pIC included interferon stimulated gene 15, a small inducible cytokine, interferon regulatory factors (1, 7, and 10), MHC class I, viperin, and ATP-dependent helicase LGP2. Alpha-1-microglobulin (bikunin) was down-regulated, suggesting that pIC may suppress the acute phase response. Since the SSH libraries built for this study identified genes involved in the antiviral response, they are important resources for studying the responses of Atlantic cod to viruses. Evidence is provided for the existence of a RIG-I-like RNA helicase viral recognition pathway in Atlantic cod. Taken together, our data show that Atlantic cod can recognize double-stranded RNA and mount a rapid and potent interferon pathway response that is similar to that observed in other fish species and higher vertebrates.


Liquid chromatographic determination of isoniazid, pyrazinamide and rifampicin from pharmaceutical preparations and blood.
Isoniazid (IN), pyrazinamide (Pz) and rifampicin (Rf) are separated on YMC-ODS column. IN was derivatized with 2-fluorene-carboxaldehyde (FA). The separation was achieved using ethanol-chloroform-acetonitrile water by isocratic elution and detected at 337 nm. The detection limits were 0.11 ng, 0.2 ng and 13 ng/injection (5 microl) for IN, Pz and Rf, respectively. The method of analysis was applied to the pharmaceutical preparations and in the blood samples of the patients suffering from tuberculosis after undergoing chemotherapy with IN, Pz and Rf. The amounts quantitated in blood showed 0.97 to 1.58 microg/ml IN, 3.44 to 4.09 microg/ml Pz and 1.98 to 3.5 microg/ml Rf with coefficient of variations 0.8-1.8%, 0.9-1.3% and 0.8-2.1%, respectively.


Patients' views on an education booklet following spinal surgery.
This study evaluated an evidence-based education booklet developed for patients undergoing spinal surgery which was used as a treatment intervention in a multi-centre, factorial, randomised controlled trial (FASTER: Function after spinal treatment, exercise and rehabilitation) investigating the post-operative management of spinal surgery patients. This study sought to determine the acceptability and content of the booklet to patients. Patients receiving the educational booklet before discharge from hospital as part of the FASTER study were asked to complete an evaluation, which rated the booklet "Your Back Operation" with regard to content, information, usability, etc. using forced and open questions. This assessment was conducted at the same time as the initial 6-week post-operative review performed as part of the larger study. Therefore, 97% of the 117 trial participants who returned their 6-week evaluation and randomised to receive a booklet returned their questionnaire. The booklet was highly rated receiving an overall rating of 7 or more out of 10 from 101/111 (91%), and high ratings for content, readability and information. The booklet's key messages were clear to the majority of patients; however, many patients highlighted deficiencies with respect to content particularly in relation to wound care and exercise. Patients valued the booklet and rated its content highly. Many suggested that the booklet be developed further and there was a clear desire for specific exercises to be included even though there is no evidence to support specific exercise prescription.


Bovine viral diarrhoea virus in beef cattle herds of Yucatan, Mexico: seroprevalence and risk factors.
A survey of bovine viral diarrhoea virus (BVDV) infection was carried out from June 2001 to July 2002 in a non-vaccinated beef cattle population from the livestock region of Yucatan, Mexico, to assess seroprevalence and identify risk factors related to seroprevalence. The aim was also to estimate the intra-herd correlation (r(e)) and design effect (D) of BVDV seropositivity. Cattle were selected by a two-stage cluster sampling. Blood samples were collected from 560 animals originating from 40 herds. Sera were tested for antibodies against BVDV using an indirect ELISA test. The sensitivity and specificity of the test was 97.9 and 99.7%, respectively. Risk factors regarding the herd and each animal sampled were recorded through a personal interview at the time of blood sampling. Twenty-four of the 40 herds had at least one seropositive animal. The animal true seroprevalence was estimated as 14%. The marginal logistic regression model used to describe the data found a significant (p<0.05) association of herd size-cow-origin interaction. The interaction was due to a higher risk of seropositivity in the category of herds with <or=100 animals and purchased cows (OR=1) as compared to herds with <or=100 animals and cows born in the farm (OR=0.23). Seropositivity between cows purchased and cows born in the farm was similar for herd sizes of 101-196 and >196 animals. The r(e) and D values were 0.17+/-0.05 and 3.16+/-0.57, respectively.


Novel amino acids indices based on quantum topological molecular similarity and their application to QSAR study of peptides.
A new source of amino acid (AA) indices based on quantum topological molecular similarity (QTMS) descriptors has been proposed for use in QSAR study of peptides. For each bond of the chemical structure of AA, eight electronic properties were calculated using the approaches of bond critical point and theory of atom in molecule. Thus, for each molecule a data matrix of QTMS descriptors (having information from both topology and electronic features) were calculated. Using four different criterion based on principal component analysis of the QTMS data matrices, four different sets of AA indices were generated. The indices were used as the input variables for QSAR study (employing genetic algorithm-partial least squares) of three peptides' data sets, namely, angiotensin-converting enzyme inhibitors, bactericidal peptides and the peptides binding to the HLA-A*0201 molecule. The obtained models had better prediction ability or a comparable one with respect to the previously reported models. In addition, by using the proposed indices and analysis of the variable important in projection, the active site of the peptides which plays a significant role in the biological activity of interest, was identified.


A bacteriological evaluation of a programme for preoperative total body-washing with chlorhexidine gluconate performed by patients undergoing orthopaedic surgery.
Twenty-eight orthopaedic patients were taught to wash their entire bodies with chlorhexidine gluconate on two consecutive days preoperatively, starting in their homes. The operation field was also washed a third time. A bacteriological evaluation was performed using contact plates. A significant reduction of the skin flora, including Staph. aureus, was registered. No adverse side effects of total body-washing were observed.


Is the patient a candidate for liver transplantation?
Identifying whether someone is a good candidate for liver transplantation is a complex process that requires a team approach. There are several medical and psychosocial considerations involved, each of which is thoroughly explored during the evaluation process. Both the indications and contraindications to transplantation can change over time, reflecting advances in understanding of, and ability to treat, certain disease processes. Ultimately, the goal of liver transplantation remains to provide a survival benefit to those with acute or chronic liver diseases.


Dendritic cells: driving the differentiation programme of T cells in viral infections.
Protective immunity against viral pathogens depends on the generation and maintenance of a small population of memory CD8(+) T cells. Successful memory cell generation begins with early interactions between naïve T cell and dendritic cells (DCs) within the inflammatory milieu of the secondary lymphoid tissues. Recent insights into the role of different populations of DCs, and kinetics of antigen presentation, during viral infections have helped to understand how DCs can shape the immune response. Here, we review the recent progress that has been made towards defining how specific DC subsets drive effector CD8(+) T-cell expansion and differentiation into memory cells. Further, we endeavour to examine how the molecular signals imparted by DCs coordinate to generate protective CD8(+) T-cell immunity.


Calculation of 18F, 99mTc, 111In and 123I calibration factor using the penelope ionization chamber simulation method.
A new method using the Monte Carlo code PENELOPE for ionization chamber simulation has already been successfully used for calculating calibration factors needed for the measurements of radionuclides with photon emission (2003, Appl. Radiat. Isot., to be published). This work has been continued at (Laboratoire National Henri Becquerel) in order to calculate the calibration factors for radionuclides with short half-lives used in medical services. Activity measurements of 18F, 99mTc,111In and 123I using the calculated calibration factors were obtained with standard uncertainties equal to 0.6% for 18F, 99mTc and 1.5% for 111In and 123I.


Performance of a capnodynamic method estimating cardiac output during respiratory failure - before and after lung recruitment.
Respiratory failure may cause hemodynamic instability with strain on the right ventricle. The capnodynamic method continuously calculates cardiac output (CO) based on effective pulmonary blood flow (COEPBF) and could provide CO monitoring complementary to mechanical ventilation during surgery and intensive care. The aim of the current study was to evaluate the ability of a revised capnodynamic method, based on short expiratory holds (COEPBFexp), to estimate CO during acute respiratory failure (LI) with high shunt fractions before and after compliance-based lung recruitment. Ten pigs were submitted to lung lavage and subsequent ventilator-induced lung injury. COEPBFexp, without any shunt correction, was compared to a reference method for CO, an ultrasonic flow probe placed around the pulmonary artery trunk (COTS) at (1) baseline in healthy lungs with PEEP 5 cmH2O (HLP5), (2) LI with PEEP 5 cmH2O (LIP5) and (3) LI after lung recruitment and PEEP adjustment (LIPadj). CO changes were enforced during LIP5 and LIPadj to estimate trending. LI resulted in changes in shunt fraction from 0.1 (0.03) to 0.36 (0.1) and restored to 0.09 (0.04) after recruitment manoeuvre. Bias (levels of agreement) and percentage error between COEPBFexp and COTS changed from 0.5 (- 0.5 to 1.5) L/min and 30% at HLP5 to - 0.6 (- 2.3 to 1.1) L/min and 39% during LIP5 and finally 1.1 (- 0.3 to 2.5) L/min and 38% at LIPadj. Concordance during CO changes improved from 87 to 100% after lung recruitment and PEEP adjustment. COEPBFexp could possibly be used for continuous CO monitoring and trending in hemodynamically unstable patients with increased shunt and after recruitment manoeuvre.


Unraveling hot spots in binding interfaces: progress and challenges.
Protein interface hot spots, as revealed by alanine scanning mutagenesis, continue to stimulate interest in the biophysical basis of molecular recognition. Although these regions apparently constitute fertile grounds for intermolecular interactions, no general algorithm has yet been developed that can predict hot spots based solely on their shape or composition. The discovery of structural plasticity in hot spot regions indicates that dynamic simulation techniques may be essential for achieving a predictive understanding of binding interface energetics. Future progress will depend as much on the application of new computational approaches for dissecting protein interfaces as on expanding our empirical databank of mutagenic substitutions and their effects. Despite our current theoretical shortcomings, recent methodological advances provide efficient experimental means of probing hot spots and enable immediate applications for hot spots in drug discovery.


Influence of alanylglutamine infusion on gastrointestinal glutamine and alanine metabolism in anesthetized dogs.
In this study we administered an infusion of alanylglutamine (10 mumol/kg.min) for 60 minutes to postoperative anaesthetized dogs with catheters placed in the portal and hepatic veins. Arterial plasma levels of alanylglutamine were 83 +/- 27 mumol/L 20 minutes after the onset of the infusion and remained constant throughout the infusion period. Plasma levels of glutamine and alanine approximately doubled compared with preinfusion levels, indicating a release of these amino acids from the dipeptide. The halflife of alanylglutamine, calculated after bolus injection of 2 g, was 1.7 +/- 0.5 minutes. Alanylglutamine was extracted from the liver and the gut (0.9 +/- 0.3 and 0.5 +/- 0.1 mumol/kg.min, respectively). In the basal period (without infusion of alanylglutamine), a glutamine uptake by the liver and the intestine was found. Alanine was taken up by the liver and released from the gut. The infusion of alanylglutamine significantly increased the hepatic uptake of glutamine and alanine (from 0.8 +/- 0.2 to 3.8 +/- 0.6 and from 3.0 +/- 0.4 to 7.5 +/- 0.7 mumol/kg.min respectively; P less than .01) and did not significantly change the intestinal uptake of glutamine and the release of alanine. We conclude that the infusion of alanylglutamine markedly influences the hepatic metabolism of glutamine and alanine, probably via the increased arterial and portal levels of glutamine and alanine.


Transition of Care in Epilepsy.
Transition of care is the planned, coordinated movement from a child and family environment of pediatrics to a patient centered adult care setting. Epilepsy is a common neurological condition. While seizures remit in a proportion of children, in around 50% of children seizures persist into adulthood. Also, with advances in diagnostics and therapeutics, more children with epilepsy survive into adulthood, and need services of adult neurologists. Clinical guidelines from the American Academy of Pediatrics, American College of Family Physicians and American College of Physicians called for "supporting the healthcare transition from adolescence to adulthood", but this occurs in a minority of patients. There are several challenges to implementing transition of care at the level of the patient and family, pediatric and adult neurologist and with systems of care. Transition needs vary based on the type of epilepsy and epilepsy syndrome and presence of co-morbidities. Transition clinics are essential to effective transfer of care, but implementation remains extremely variable, with a variety of clinics or program structures in countries around the world. There is a need to develop multidisciplinary transition clinics, enhance physician education and establish national guidelines for this important process to be put into practice. Further studies are also needed to develop best practices and assess outcomes of well executed transition programs on epilepsy.


New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics.
Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology.


Effects of skin elasticity on bite mark distortion.
Bite marks have been reported to have an evidentiary value similar to fingerprints. We believed bite mark distortion would impact the accuracy and reliability of bite mark interpretation. Inked denture-stamps were substituted for actual bite marks and were placed onto 40 participating volunteers' shoulders. Four changes in arm position were photographed using an ABFO #2 reference scale. The measurements of individual tooth widths and intercanine distances in each position were compared. The maximum tooth width distortion observed was 53.8%, whereas the maximum intercanine distance distortion was 41.9%. Distortion was found to increase with age and weight and was non-uniform across a dental arch.


Significance of the quantification and demonstration of hyaluronic acid in tissue specimens for the diagnosis of pleural mesothelioma.
Hyaluronic acid in pleural tissues from patients with mesothelioma, carcinoma, and asbestosis of the lung was quantified by using specific glycosaminoglycan-degrading enzymes. In all cases of pleural mesothelioma, the quantity of hyaluronic acid in mg/g of dry tissue was at least 0.10 mg, whereas carcinomatous pleural tissue and pleura in asbestosis contained 0.02 to 0.03 mg/g of dry tissue.


[Meckel syndrome (author's transl)].
Authors study four cases, two siblings in two different families, with several anomalies allowing to consider them as examples of the Meckel-Grüber syndrome. A review of the recent literature about this entity is made, as well as a comparative study of the anomalie present in the published cases.


Pharmacologic pupillary modulation in the perioperative period.
The perioperative management of the pupil is essential to the success of anterior segment surgery. A new dilating regimen was tested in 65 cases of cataract extraction and intraocular lens implantation. The alpha-adrenergic agonist, phenylephrine 2.5%, was used after pretreatment with the adrenergic beta-blocker, timolol 0.5%. This treatment successfully dilated the pupil in all but three cases, was maintained by intraoperative epinephrine infusion, and was readily reversed with intraocular acetylcholine. We conclude that this pharmacologic regimen provided a successful and easily reversible mydriasis during surgery.


Effects of 17β-estradiol on the release of monocyte chemotactic protein-1 and MAPK activity in monocytes stimulated with peritoneal fluid from endometriosis patients.
Hormones and inflammation have been implicated in the pathological process of endometriosis; therefore, we investigated the combined effects of 17β-estradiol (E2) and peritoneal fluid obtained from patients with endometriosis (ePF) or a control peritoneal fluid (cPF) obtained from patients without endometriosis on the release of monocyte chemotactic protein-1 (MCP-1) by monocytes and the role of signaling pathways. Monocytes were cultured with ePF and cPF in the presence of E2; the MCP-1 levels in the supernatants were then measured by ELISA. In addition, mitogen activated protein kinase (MAPK) activation was measured by Western blotting of phosphorylated proteins. E2 down-regulated MCP-1 release by lipopolysaccharide- or cPF-treated monocytes, but failed to suppress its release by ePF-treated monocytes. The release of MCP-1 by ePF- and cPF-treated monocytes was efficiently abrogated by p38 mitogen activated protein kinase (MAPK) inhibitors; however, the MCP-1 release by cPF-treated monocytes, but not by ePF-treated monocytes, was blocked by a MAPK kinase inhibitor. In addition, ePF and cPF induced the phosphorylation of extracellular stress regulated kinase (ERK)1/2, p38 MAPK and c-Jun N-terminal kinase (JNK). E2 decreased the phosphorylation of p38 MAPK, but not ERK1/2 in ePF-treated monocytes; however, E2 decreased the phosphorylation of p38 MAPK, ERK1/2 and JNK in cPF-treated monocytes. The ability of E2 to modulate MCP-1 production is impaired in ePF-treated monocytes, which may be related to regulation of MAPK activity. These findings suggest that the failure of E2 to suppress ePF-treated production of MCP-1 may be involved in the pathogenesis of endometriosis.


Angiopoietin-like protein 4 treated bone marrow-derived mesenchymal stem cells alleviate myocardial injury of patients with myocardial infarction.
Bone marrow-derived mesenchymal stem cells (BMSCs) and their exosomes are of great significance for the recovery of cardiac function in patients with myocardial infarction (MI). However, the underlying mechanisms of BMSCs applied to MI treatment remain unclear. Fluorescence-activated cell sorting (FACs) are performed to assess the apoptosis, reactive oxygen species levels and glucose uptake capacity of BMSCs. Reverse transcription polymerase chain reaction is conducted to detect the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), transforming growth factor-beta 1, connective tissue growth factor, and platelet-derived growth factor. The levels of apoptosis-related proteins were detected by Western blot. The levels of VEGF, bFGF, HGF, and IGF were assessed by enzyme-linked immunosorbent assay. The biochemical kits are applied to detect the levels of malondialdehyde, superoxide dismutase, and adenosine triphosphate/adenosine diphosphate. 2,3,5-triphenyltetrazolium and Masson staining and immunofluorescence are performed to assess myocardial function of rats. Angiopoietin-like protein 4 (ANGPTL4) alleviates apoptosis and oxidative stress of BMSCs induced by serum deprivation and hypoxia; ANGPTL4 activates paracrine and accelerate metabolic energy of BMSCs; and ANGPTL4 treated-BMSCs alleviate myocardial injury of rats with MI. ANGPTL4 treated-BMSCs alleviate myocardial injury in rats with MI, indicating the combination therapy of ANGPTL4 and BMSCs may alleviate myocardial injury in rats with MI.


State-of-the-arts techniques and current evolving approaches in the separation and detection of circulating tumor cell.
Circulating tumor cells (CTCs) are cancer cells that shed from the primary tumor and then enter the circulatory system, a small part of which may evolve into metastatic cancer under appropriate microenvironment conditions. The detection of CTCs is a truly noninvasive, dynamic monitor for disease changes, which has considerable clinical implications in the selection of targeted drugs. However, their inherent rarity and heterogeneity pose significant challenges to their isolation and detection. Even the "gold standard", CellSearch™, suffers from high expenses, low capture efficiency, and the consumption of time. With the advancement of CTCs analysis technologies in recent years, the yield and efficiency of CTCs enrichment have gradually been improved, as well as detection sensitivity. In this review, the isolation and detection strategies of CTCs have been completely described and the potential directions for future research and development have also been highlighted through analyzing the challenges faced by current strategies.


The modulation of cell adhesion molecule expression and intercellular junction formation in the developing avian inner ear.
The cells that constitute the membranous labyrinth in the vertebrate inner ear are all derived from a single embryonic source, namely, the otocyst. The mature inner ear epithelia contain different regions with highly differentiated cells, displaying a highly specialized cytoarchitecture. The present study was designed to determine the presence of adherens-type intercellular junctions in this tissue and study the expression of cell adhesion molecules (CAMs) associated with these junctions, namely, A-CAM and L-CAM, in the developing avian inner ear epithelia. The results presented here show that throughout the early otocyst, A-CAM is coexpressed with L-CAM. The formation of asymmetries between sensory and nonsensory areas in the epithelium is accompanied by the modulation of CAMs expression and the assembly of intercellular junctional complexes. A-CAM and L-CAM display reciprocal expression patterns, the former being expressed mostly in the mosaic sensory epithelium, while L-CAM becomes conspicuous in the nonsensory areas but its expression in the sensory region is markedly reduced. Adherens-type junctions and numerous desmosomes are found in the junctional complexes of early otocyst cells. The former persist to maturity of the various inner ear epithelia, whereas desmosomes disappear from junctional complexes of hair cells but remain in the intercellular junctional complexes of all other cell types in the membranous labyrinth. Thus, adherens type intercellular junctions comprise the only defined cytoskeleton-bound junction in mature hair cells. A-CAM-positive cells are also found in the region of the acoustic ganglion in early developmental stages but not in the mature neural elements.


Health-related quality of life deficits associated with diabetes and comorbidities in a Canadian National Population Health Survey.
To assess the impact of comorbid heart disease, stroke and arthritis on health-related quality of life (HRQL) in people with diabetes in the general Canadian population. Data were collected as part of the 1996-1997 Canadian National Population Health Survey. HRQL was assessed using overall Health Utilities Index Mark 3 (HUI3) and single attribute utility scores. Respondents (N = 66,093) were classified into 1 of 16 groups based on the presence or absence of diabetes, heart disease, stroke, and arthritis, in all possible combinations and HRQL scores were compared using analysis of covariance. Overall HUI3 scores for respondents with diabetes alone (0.88, 95% CI: 0.87-0.89) were lower than controls (0.92: 95% CI: 0.92-0.92, p < 0.001). Overall HUI3 scores for diabetes in combination with heart disease (0.77, 95% CI: 0.74-0.79), arthritis (0.78, 95% CI: 0.77-0.79) or stroke (0.79, 95% CI: 0.74-0.85) were considerably lower than diabetes alone. Triplets of comorbidities were associated with overall HRQL deficits of approximately 0.26-0.30, relative to controls. The illness burden experienced by individuals with diabetes is not only associated with diabetes itself, but largely with comorbid medical conditions.


Outdoor Worker Stress Monitoring Electronics with Nanofabric Radiative Cooler-Based Thermal Management.
Severe stress endangers outdoor workers who are in an exceedingly hot workplace. Although recent studies quantify stress levels on the human skin, they still rely on rigid, bulky sensor modules, causing data loss from motion artifacts and limited field-deployability for continuous health monitoring. Moreover, no prior work shows a wearable device that can endure heat exposure while showing continuous monitoring of a subject's stress under realistic working environments. Herein, a soft, field-deployable, wearable bioelectronic system is introduced for detecting outdoor workers' stress levels with negligible motion artifacts and controllable thermal management. A nanofabric radiative cooler (NFRC) and miniaturized sensors with a nanomembrane soft electronic platform are integrated to measure stable electrodermal activities and temperature in hot outdoor conditions. The NFRC exhibits outstanding cooling performance in sub-ambient air with high solar reflectivity and high thermal emissivity. The integrated wearable device with all embedded electronic components and the NFRC shows a lower temperature (41.1%) in sub-ambient air than the NFRC-less device while capturing improved operation time (18.2%). In vivo human study of the bioelectronics with agricultural activities demonstrates the device's capability for portable, continuous, real-time health monitoring of outdoor workers with field deployability.


Correlations among measures of quality in HIV care in the United States: cross sectional study.
To determine whether a selected set of indicators can represent a single overall quality construct. Cross sectional study of data abstracted during an evaluation of an initiative to improve quality of care for people with HIV. 69 sites in 30 states. Medical records of 9020 patients. Adjusted performance rates at site level for eight measures of quality of care specific to HIV and a site level summary performance score (the number of measures for which the site was in the top quarter of the distribution). Of 28 site level correlations between measures, two were greater than 0.40, two were between 0.30 and 0.39, four were between 0.20 and 0.29, and the 20 remaining were all less than 0.20. One site was in the top quarter for seven measures, but no sites were in the top quarter for six or eight of the measures. Across the eight quality measures, sites were in the top quarter no more often than predicted by a chance (binomial) distribution. The quality suggested by one measured indicator cannot necessarily be generalised to unmeasured indicators, even if this might be expected for clinical or other reasons.


Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis.
The apical transmembrane protein Crumbs is a central regulator of epithelial apical-basal polarity in Drosophila. Loss-of-function mutations in the human homologue of Crumbs, CRB1 (RP12), cause recessive retinal dystrophies, including retinitis pigmentosa. Here we show that Crumbs and CRB1 localize to corresponding subdomains of the photoreceptor apical plasma membrane: the stalk of the Drosophila photoreceptor and the inner segment of mammalian photoreceptors. These subdomains support the morphogenesis and orientation of the photosensitive membrane organelles: rhabdomeres and outer segments, respectively. Drosophila Crumbs is required to maintain zonula adherens integrity during the rapid apical membrane expansion that builds the rhabdomere. Crumbs also regulates stalk development by stabilizing the membrane-associated spectrin cytoskeleton, a function mechanistically distinct from its role in epithelial apical-basal polarity. We propose that Crumbs is a central component of a molecular scaffold that controls zonula adherens assembly and defines the stalk as an apical membrane subdomain. Defects in such scaffolds may contribute to human CRB1-related retinal dystrophies.


Prognostic effects of clinical and CT imaging features on critically ill patients with interstitial lung disease hospitalized in respiratory intensive care unit.
The study aimed to evaluate the clinical and imaging features of critically ill patients with interstitial lung disease (ILD) treated in respiratory intensive care unit (RICU) and assess the prognostic effects of these factors. A total of 160 severe ILD patients admitted to the RICU were finally enrolled in this study. The clinical, imaging and follow-up data of them were studied retrospectively. The in-hospital mortality and total mortality were 43.1% and 63.8% respectively. By multivariate cox regression analysis, shock (OR = 2.39, P = 0.004), pulmonary fibrosis on CT (OR = 2.85, P = 0.002) and non-invasive ventilation (OR = 1.86, P = 0.037) were harmful factors to survivals of critically ill patients with ILD. In contrast, oxygenation index (OR = 0.99, P = 0.028), conventional oxygen therapy (OR = 0.59, P = 0.048) and β-lactam antibiotics use (OR = 0.51, P = 0.004) were protective factors. There is significant difference of survivals between patients with and without fibrosing ILD on CT (Log-rank, p = 0.001). The prognosis of critically ill patients with ILD was poor. Shock, respiratory failure and fibrosing signs on chest CT affected the prognosis. Chest CT was considered as a valuable tool to indicate the prognosis.


Label-assisted chemical adsorption triggered conversion of electroactivity of sensing interface to achieve the Ag/AgCl process for ultrasensitive detection of CA 19-9.
Efficient strategies in enhancing sensitivity are pivotal to ultrasensitive detection of tumor markers. In this work, based on the strategy of label-assisted chemical adsorption triggered conversion of electroactivity of sensing interface, a Ag/AgCl process was achieved to enhance sensitivity of the constructed sandwich-type amperometric immunosensor for ultrasensitive detection of carbohydrate antigen 19-9 (CA19-9). Briefly, polydopamine-Ag nanoparticles (PDA-Ag NPs), as signal precursor, combined with labeling antibody were served as labels and graphene oxide-melamine (GO-MA) substrate with chemical absorption capacity was applied as smart sensing interface. After successfully incubating labels, there was primitively no current response due to the poor conductivity between labels and electrode. However, in the presence of H2O2, Ag NPs from labels can be etched into Ag ions, which were adsorbed by GO-MA to form GO-MA-Ag as electroactive substrate. Then, the substrate exhibited a sharp and stable electrochemistry peak of solid-state Ag/AgCl process in the buffer containing KCl. The sensitivity toward detection of CA19-9 was notably enhanced based on the appearance of sharp peak. Under optimum conditions, the designed immunosensor demonstrated a wide working range from 0.0001 to 100 U mL-1 and an ultralow detection limit 0.032 mU mL-1. Thus, utilizing this strategy to construct immunosensor was highly promising in clinical diagnosis for ultrasensitive detection of tumor makers.


Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening.
Factors that are predictive of carrying BRCA1 and BRCA2 germline mutations in patients with breast carcinoma are awaited widely. The genetically homogeneous Sardinian population may be useful for defining the role of such genetic alterations further through a clinical evaluation program. One hundred two of 659 patients with breast carcinoma (15.5%) who were collected consecutively had a family history of breast carcinoma and were screened for BRCA1/2 mutations by denaturing high-performance liquid chromatography and DNA sequencing. Three deleterious germline BRCA1/2 mutations were detected in 15 of 102 families (14.7%), including 13 families (86.7%) with BRCA2 mutations and 2 families (13.3%) with BRCA1 mutations. A single variant, BRCA2-8765delAG, was the most recurrent mutation in the series and was found in 12 of 102 families (11.8%) and in 18 of 657 patients (2.7%). The average age at diagnosis was significantly younger in families with BRCA1/2 mutations (48.6 yrs) compared with the age of patients who had no detectable mutation (52.9 yrs; P = 0.039). Moreover, BRCA1/2 mutations were found at a significantly higher rate in families who had at least 1 member with ovarian carcinoma or male breast carcinoma (5 of 12 families; 41.7%) than in families without such an association (10 of 90 families; 11.1%; P = 0.003). BRCA2 mutations were approximately 6 times more prevalent than BRCA1 mutations. A diagnosis of breast carcinoma before age 50 years, ovarian carcinoma, male breast carcinoma, and 3 affected generations all were associated significantly with BRCA1/2 mutations. Although the current findings provided further support for the hypothesis that additional breast carcinoma susceptibility genes remain to be identified, such indicators of the presence of BRCA1/2 mutations may be useful in counseling patients about undergoing genetic testing.


12-week combined strength and endurance exercise attenuates CD8+ T-cell differentiation and affects the kynurenine pathway in the elderly: a randomized controlled trial.
Age-related accumulation of highly differentiated CD8+ effector memory re-expressing CD45RA (EMRA) T-cells and disruption of the kynurenine (KYN) pathway are associated with chronic inflammation and the development of insulin resistance. In this study the aim was to investigate the effects of 12-week combined strength and endurance exercise on CD8+ T-cell differentiation and KYN pathway metabolites. Ninety-six elderly subjects (f/m, aged 50-70) were randomized to a control (CON) or exercise (EX) group. The EX group completed combined strength and endurance training twice weekly for one hour each time at an intensity of 60% of the one-repetition maximum for strength exercises and a perceived exertion of 15/20 for endurance exercises. The EX group was also randomly subdivided into two groups with or without a concomitant balanced diet intervention in order to examine additional effects besides exercise alone. Before and after the intervention phase, the proportions of CD8+ T-cell subsets and levels of KYN pathway metabolites in peripheral blood were determined. The CD8+ EMRA T-cell subsets increased in the CON group but remained almost unchanged in the EX group (p = .02). Plasma levels of kynurenic acid (KA) increased in the EX group and decreased in the CON group (p = .03). Concomitant nutritional intervention resulted in lower levels of quinolinic acid (QA) compared with exercise alone (p = .03). Overall, there was a slight increase in the QA/KA ratio in the CON group, whereas it decreased in the EX group (p > .05). Combined strength and endurance training seems to be a suitable approach to attenuate CD8+ T-cell differentiation in the elderly and to redirect the KYN pathway towards KA. The clinical relevance of these effects needs further investigation.


Attitudes and expectations of patients with neuromuscular diseases about their participation in a clinical trial.
This study aimed to gain a better understanding of the psychological impact of participating in a clinical trial for patients with Pompe disease (Acid Maltase Deficiency). Attitudes and expectations of adult patients with neuromuscular diseases regarding medical trials are as yet unreported. In order to learn about the psychological consequences of participating in a clinical trial, we conducted a prospective assessment of patients with late-onset Pompe Disease, a rare genetic condition, for which no treatment had been available before. This psychological study was carried out as an ancillary study to the randomized double-blind placebo-controlled trial described elsewhere (van der Ploeg et al., 2010). We assessed patients (n=8) at inclusion, and at 12 and 18 months for six psychological dimensions: depression (Beck Depression Inventory, BDI), hopelessness (Beck Hopelessness Scale, BHS), anxiety (STAI A-B), quality of life (Whoqol-26), social adjustment (S.A.S-self-report) and locus of control (IPC Levenson). We produced a self-administered questionnaire in order to assess the attitudes, motivations and expectations of patients during the trial. At 12 months, mean social adjustment (SAS-SR, P=0.02) had improved, and at 18 months mean depression score had improved as well (BDI, P=0.03). The quality of life of patients (Whoqol-26) remained unchanged. Throughout the study, patients were more likely to have an internal locus of control than an external one (IPC Levenson). The self-administered questionnaire showed that patients' expectations were disproportionate compared to the medical information they had received starting the trial. For all patients, the first motivation for being enrolled in a clinical trial was "to help research", for half of them the motivation was to "improve their health". Whether patients believed to be part of one group or another (placebo or treatment) depended on their subjective perception of improvement during the trial. Given the small sample size, the conclusions of this study are preliminary. However, findings do suggest that there is a positive psychological impact of participating in a treatment trial. Moreover, the patients' reactions upon unblinding have led us to recommend that patients be asked whether they would like their group assignation disclosed to them or not.


Multiple erythroid isoforms of human long-chain acyl-CoA synthetases are produced by switch of the fatty acid gate domains.
The formation of acyl-CoA by the action of acyl-CoA synthetases plays a crucial role in membrane lipid turnover, including the plasma membrane of erythrocytes. In human, five Acyl-CoA Synthetase Long-chain (ACSL) genes have been identified with as many as 3 different transcript variants for each. Acyl-CoA Synthetase Long-chain member 6 (ACSL6) is responsible for activation of long-chain fatty acids in erythrocytes. Two additional transcript variants were also isolated from brain and testis. We report the expression in reticulocytes of two new variants and of the one isolated from brain. All three represented different spliced variants of a mutually exclusive exon pair. They encode a slightly different short motif which contains a conserved structural domain, the fatty acid Gate domain. The motifs differ in the presence of either the aromatic residue phenylalanine (Phe) or tyrosine (Tyr). Based on homology, two new isoforms for the closely related ACSL1 were predicted and characterized. One represented a switch of the Phe- to the Tyr-Gate domain motif, the other resulted from the exclusion of both. Swapping of this motif also appears to be common in all mammalian ACSL member 1 and 6 homologs. We propose that a Phe to Tyr substitution or deletion of the Gate domain, is the structural reason for the conserved alternative splicing that affects these motifs. Our findings support our hypothesis that this region is structurally important to define the activity of these enzymes.


ACSL4 promotes colorectal cancer and is a potential therapeutic target of emodin.
Colorectal cancer (CRC) is an important death-related disease in the world and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that emodin, the main ingredient of Rheum palmatum, fights cancer but its potential anti-tumor effect on CRC is still unknown. The present study is aimed to explore the potential anti-tumor effects of emodin against CRC and the underlying molecular mechanism. CRC-related datasets were screened according to filter criteria in the GEO database and TCGA database. By using screened differentially expressed genes, GO, KEGG and survival analysis were carried out. The expressions of ACSL4, VEGFR1, and VEGFR2 were examined by immunohistochemistry and western blot. Then, pcDNA-ACSL4, pcDNA-VEGFR1, and pcDNA-VEGFR2 were used to overexpress ACSL4, VEGFR1, and VEGFR2, while ACSL4 siRNA was used to silence ACSL4 expression in HCT116 cells. CCK-8 assay and transwell migration assay were used to detect the cell proliferation and invasion. A docking simulation assay and an MST assay were performed to explore the potential mode of emodin binding to ACSL4. The HCT116 cells and CRC mouse model were established to investigate the effects of emodin on CRC. The ACSL4, VEGFR1, and VEGFR2 expression were upregulated in CRC tissues and ACSL4 was associated with a shorter survival time in CRC patients. ACSL4 downregulation reduced cell proliferation and invasion, while ACSL4 exhibited a positive correlation with the levels of VEGFR1, VEGFR2, and VEGF. In HCT116 cells, emodin reduced cell proliferation and invasion by inhibiting ACSL4, VEGFR1, and VEGFR2 expression and VEGF secretion. Docking simulation and MST assay confirmed that emodin can directly bind to ACSL4 target. Moreover, ACSL4 overexpression abolished the inhibitory effect of emodin on VEGF secretion and VEGFR1 and VEGFR2 expression, but VEGFR1 and VEGFR2 overexpression did not affect the inhibitory effect of emodin on ACSL4 expression and VEGF secretion. Furthermore, emodin reduced the mortality and tumorigenesis of CRC mice and reduced ACSL4, VEGFR1, VEGFR2 expression, and VEGF content. Our findings indicate that emodin inhibits proliferation and invasion of CRC cells and reduces VEGF secretion and VEGFR1 and VEGFR2 expression by inhibiting ACSL4. This emodin-induced pathway offers insights into the molecular mechanism of its antitumor effect and provides a potential therapeutic strategy for CRC.


[Doppler sonographic measurement of normal values of flow velocities in the internal carotid artery of premature infants, newborn infants and infants].
In 121 healthy premature born infants, full-term newborns and older infants (gestational age: 29 to 45 weeks; weight at investigation: 1070 g to 3750 g), the flow velocities in the internal carotid arteries were measured by pulsed doppler sonography. All infants were investigated by computer sonography (Acuson 128) with a 5 MHz transducer. The following parameters were measured: The maximal systolic velocity, the end-systolic and end-diastolic velocity as well as the mean flow velocities, the pulsatility-index and the resistance-index. For all parameters the relationship to the gestational age and weight were analysed. All flow velocities increased linearly with increasing gestational age and weight. In contrast to the flow velocities neither the pulsatility-index nor the resistance-index changed with increasing gestational age and weight. As flow velocities in the internal carotid arteries increase with increasing gestational age and weight these parameters must be taken into consideration when pathologic flow velocities are analysed.


The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics.
More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems.