Prediction of clinicopathological features, multi-omics events and prognosis based on digital pathology and deep learning in HR+/HER2- breast cancer.
Breast cancer has the highest incidence and mortality rates among women worldwide. Hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer is the most common molecular subtype, accounting for 50-79% of breast cancers. Deep learning has been widely used in cancer image analysis, especially for predicting targets related to precise treatment and patient prognosis. However, studies focusing on therapeutic target and prognosis predicting in HR+/HER2- breast cancer are lacking. This study retrospectively collected hematoxylin and eosin (H&E)-stained slides of HR+/HER2- breast cancer patients between January 2013 and December 2014 at Fudan University Shanghai Cancer Center (FUSCC) and scanned to generate whole-slide images (WSIs). Then, we built a deep-learning-based workflow to train and validate model to predict clinicopathological features, multi-omics molecular features and prognosis; the area under the curve (AUC) of the receiver operating characteristic (ROC) and the concordance index (C-index) of the test set were used to assess model effectiveness. A total of 421 HR+/HER2- breast cancer patients were included in our study. Regarding clinicopathological features, grade III could be predicted with an AUC of 0.90 [95% confidence interval (CI): 0.84-0.97]. Regarding somatic mutations, TP53 and GATA3 mutation could be predicted with AUCs of 0.68 (95% CI: 0.56-0.81) and 0.68 (95% CI: 0.47-0.89), respectively. Regarding gene set enrichment analysis (GSEA) pathways, the G2-M checkpoint pathway was predicted with an AUC of 0.79 (95% CI: 0.69-0.90). Regarding markers of immunotherapy response, intratumoral tumor-infiltrating lymphocytes (iTILs), stromal tumor-infiltrating lymphocytes (sTILs), CD8A, and PDCD1 were predicted with AUCs of 0.78 (95% CI: 0.55-1.00), 0.76 (95% CI: 0.65-0.87), 0.71 (95% CI: 0.60-0.82), and 0.74 (95% CI: 0.63-0.85), respectively. In addition, we found that the integration of clinical prognostic variables and deep features of images can improve the stratification of patient prognosis. Using a deep-learning-based workflow, we developed models to predict the clinicopathological features, multi-omics features and prognosis of patients with HR+/HER2- breast cancer using pathological WSIs. This work may contribute to efficient patient stratification to promote the personalized management of HR+/HER2- breast cancer.


Cisplatin-induced anorexia and ghrelin.
Cisplatin, a formidable anticancer treatment, is used for several varieties of cancer. There are, however, many cases in which treatment must be abandoned due to a decrease in the patient's quality of life from loss of appetite associated with vomiting and nausea. There is a moderate degree of improvement in prevention of cisplatin-induced nausea and vomiting when serotonin (5-HT) 3 receptor antagonists, neurokinin 1 receptor antagonists, and steroids-either alone or in combination-are administered. The mechanism of action for anorexia, which continues during or after treatment, is, however, still unclear. This anorexia is, similar to the onset of vomiting and nausea, caused by the action of large amounts of 5-HT released as a result of cisplatin administration on tissue 5-HT receptors. Among the 5-HT receptors, the activation of 5-HT2b and 5-HT2c receptors, in particular, seems to play a major role in cisplatin-induced anorexia. Following activation of these two receptors, there is reduced gastric and hypothalamic secretion of the appetite-stimulating hormone ghrelin. There is ample evidence of the usefulness of exogenous ghrelin, synthetic ghrelin agonists, and the endogenous ghrelin signal-enhancer rikkunshito, which are expected to play significant roles in the clinical treatment and prevention of anorexia in future.


Changes in cortical processing of pain in chronic migraine.
The aim of this study was to perform a topographic and dipolar analysis of nociceptive-evoked responses obtained by laser stimulus under basal conditions in a cohort of chronic migraine (CM) patients, compared with migraine without aura (MWA) patients and noncraniofacial pain controls. An increased activation of cortical areas devoted to the emotional and attentive components of pain was previously found during the course of the migraine attack; it was more pronounced in patients reporting higher frequency of migraine. Twenty-six outpatients were enrolled in the study; 16 fulfilled the criteria of CM, and 10 were affected by MWA. Fifteen noncraniofacial pain subjects were also selected. The pain stimulus was a CO2 laser pulses. The right-supraorbital zone was stimulated. Source localization analysis was performed on the most prominent laser-evoked potentials (LEPs) peak (P2) for each data set. The anatomical locations of the P2 sources were projected onto a standard normalized 3D MRI model. The CM group differed significantly from both MWA patients and controls for the x coordinate and from controls for the z coordinates. The P2 dipole localized in the rostral cingulate cortex in CM patients, lying in a more posterior location within the anterior cingulate cortex (ACC) in both controls and MWA patients. The x coordinate of the P2 dipole, expressing the postero-anterior location, was significantly correlated with frequency of headache. CM seems to be characterized by a distinctive pattern of cortical elaboration of pain, with a prevalent activation of the rostral portion of the ACC: our results suggest that this may be a predisposing factor to migraine chronicity.


Hydrogen Availability Is Dependent on the Actions of Both Hydrogen-Producing and Hydrogen-Consuming Microbes.
Hydrogen gas (H2) is produced by H2-producing microbes in the gut during polysaccharide fermentation. Gut microbiome also includes H2-consuming microbes utilizing H2 for metabolism: methanogens producing methane, CH4, and sulfate-reducing bacteria producing hydrogen sulfide, H2S. H2S is not measured in the evaluation of gaseous byproducts of microbial fermentation. We hypothesize that the availability of measured H2 depends on both hydrogen producers and hydrogen consumers by measuring H2 in vitro and in vivo. In the in vitro study, groups were Bacteroides thetaiotaomicron (B. theta, H2 producers), Desulfovibrio vulgaris (D. vulgaris, H2 consumers), and D. vulgaris + B. theta combined. Gas samples were collected at 2 h and 24 h after incubation and assayed for H2, CH4, and H2S. In the in vivo study Sprague-Dawley rats were gavaged with suspended bacteria in four groups: B. theta, D. vulgaris, combined, and control. Gas was analyzed for H2 at 60 min. In the in vitro experiment, H2 concentration was higher in the combined group (188 ± 93.3 ppm) compared with D. vulgaris (27.17 ± 9.6 ppm) and B. theta groups (34.2 ± 29.8 ppm; P < 0.05); H2S concentration was statistically higher in the combined group (10.32 ± 1.5 ppm) compared with B. theta (0.19 ± 0.03 ppm) and D. vulgaris group (3.46 ± 0.28 ppm; P < 0.05). In the in vivo study, H2 concentrations were significantly higher in the B. theta group (44.3 ± 6.0 ppm) compared with control (31.8 ± 4.3) and the combined group (34.2 ± 8.7, P < 0.05). This study shows that sulfate-reducing bacteria could convert available H2 to H2S, leading to measured hydrogen levels that are dependent on the actions of both H2 producers and H2 consumers.


Equilibrium studies of lecithin-cholesterol interactions I. Stoichiometry of lecithin-cholesterol complexes in bulk systems.
The maximum molar ratio of lecithin:cholesterol in aqueous dispersions has been reported to be 2:1, 1:1, or 1:2. The source of the desparate results has been examined in this study by analyzing (a) the phase relations in anhydrous mixtures (from which most dispersions are prepared) and (b) various methods of preparing aqueous dispersions, with the purpose of avoiding the formation of metastable states that may be responsible for the variability of the lecithin-cholesterol stoichiometry. Temperature-composition phase diagrams for anhydrous mixtures of cholesterol (CHOL) with dimyristoyl (DML) and with dipalmitoyl (DPL) lecithin were obtained by differential scanning calorimetry (DSC). Complexes form with molar ratios for lecithin:CHOL of 2:1 and 1:2; they are stable up to 70 degrees C. When x(CHOL) < 0.33, two phases coexist: complex (2:1) plus pure lecithin; when 0.33 < x(CHOL) < 0.67 complexes (2:1) and (1:2) coexist as separate phases. The corresponding phase diagram in water for these mixtures was determined by DSC and isopycnic centrifugation in D(2)O-H(2)O gradients. Aqueous dispersions were prepared by various methods (vortexing, dialysis, sonication) yielding identical results except as noted below. The data presented supports the following phase relations. When x(CHOL) < 0.33, two lipid phases coexist: pure lecithin plus complex (2:1) where the properties of the lecithin phase are determined by whether the temperature is below or above T(c), the gel-liquid crystal transition temperature. Therefore, complex (2:1) will coexist with gel state below T(c) and with liquid crystal above T(c). The densities follow in the order gel > complex (2:1) > liquid crystal. The density of complex (2:1) is less sensitive to temperature in the range 5 degrees -45 degrees C compared to the temperature dependence for DML and DPL where large changes in density occur at T(c). When x(CHOL) > 0.33, CHOL phase coexists with complex (2:1); anhydrous complex (1:2) is apparently not stable in H(2)O. The results are independent of the method and temperature used for preparing the lipid dispersions. However, when dispersions are prepared by sonication or with solvents at T > T(c), an apparent 1:1 complex is formed. Evidence suggests the 1:1 complex is metastable.


Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer.
To examine the survival outcomes in women with endometrial cancer who were taking low-dose aspirin (81-100 mg/d). A multicenter retrospective study was conducted examining patients with stage I-IV endometrial cancer who underwent hysterectomy-based surgical staging between January 2000 and December 2013 (N=1,687). Patient demographics, medical comorbidities, medication types, tumor characteristics, and treatment patterns were correlated to survival outcomes. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio for disease-free and disease-specific overall survival. One hundred fifty-eight patients (9.4%, 95% confidence interval [CI] 8.8-11.9) were taking low-dose aspirin. Median follow-up time for the study cohort was 31.5 months. One hundred twenty-seven patients (7.5%) died of endometrial cancer. Low-dose aspirin use was significantly correlated with concurrent obesity, hypertension, diabetes mellitus, and hypercholesterolemia (all P<.001). Low-dose aspirin users were more likely to take other antihypertensive, antiglycemic, and anticholesterol agents (all P<.05). Low-dose aspirin use was not associated with histologic subtype, tumor grade, nodal metastasis, or cancer stage (all P>.05). On multivariable analysis, low-dose aspirin use remained an independent prognostic factor associated with an improved 5-year disease-free survival rate (90.6% compared with 80.9%, adjusted hazard ratio 0.46, 95% CI 0.25-0.86, P=.014) and disease-specific overall survival rate (96.4% compared with 87.3%, adjusted hazard ratio 0.23, 95% CI 0.08-0.64, P=.005). The increased survival effect noted with low-dose aspirin use was greatest in patients whose age was younger than 60 years (5-year disease-free survival rates, 93.9% compared with 84.0%, P=.013), body mass index was 30 or greater (92.2% compared with 81.4%, P=.027), who had type I cancer (96.5% compared with 88.6%, P=.029), and who received postoperative whole pelvic radiotherapy (88.2% compared with 61.5%, P=.014). These four factors remained significant for disease-specific overall survival (all P<.05). Our results suggest that low-dose aspirin use is associated with improved survival outcomes in women with endometrial cancer, especially in those who are young, obese, with low-grade disease, and who receive postoperative radiotherapy.


Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling.
DEPDC5 mutations have recently been shown to cause epilepsy in humans. Evidence from in vitro studies has implicated DEPDC5 as a negative regulator of mTORC1 during amino acid insufficiency as part of the GATOR1 complex. To investigate the role of DEPDC5 in vivo we generated a null mouse model using targeted CRISPR mutagenesis. Depdc5 homozygotes display severe phenotypic defects between 12.5-15.5 dpc, including hypotrophy, anaemia, oedema, and cranial dysmorphology as well as blood and lymphatic vascular defects. mTORC1 hyperactivity was observed in the brain of knockout embryos and in fibroblasts and neurospheres isolated from knockout embryos and cultured in nutrient deprived conditions. Heterozygous mice appeared to be normal and we found no evidence of increased susceptibility to seizures or tumorigenesis. Together, these data support mTORC1 hyperactivation as the likely pathogenic mechanism that underpins DEPDC5 loss of function in humans and highlights the potential utility of mTORC1 inhibitors in the treatment of DEPDC5-associated epilepsy.


Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.
Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.


Upfront DPYD Genotype-Guided Treatment for Fluoropyrimidine-Based Chemotherapy in Advanced and Metastatic Colorectal Cancer: A Cost-Effectiveness Analysis.
Fluoropyrimidines are the most widely used chemotherapy drugs for advanced and metastatic colorectal cancer (CRC). Individuals with certain DPYD gene variants are exposed to an increased risk of severe fluoropyrimidine-related toxicities. This study aimed to evaluate the cost-effectiveness of preemptive DPYD genotyping to guide fluoropyrimidine therapy in patients with advanced or metastatic CRC. Overall survival of DPYD wild-type patients who received a standard dose and variant carriers treated with a reduced dose were analyzed by parametric survival models. A decision tree and a partitioned survival analysis model with a lifetime horizon were designed, taking the Iranian healthcare perspective. Input parameters were extracted from the literature or expert opinion. To address parameter uncertainty, scenario and sensitivity analyses were also performed. Compared with no screening, the genotype-guided treatment strategy was cost-saving ($41.7). Nevertheless, due to a possible reduction in the survival of patients receiving reduced-dose regimens, it was associated with fewer quality-adjusted life-years (9.45 vs 9.28). In sensitivity analyses, the prevalence of DPYD variants had the most significant impact on the incremental cost-effectiveness ratio. The genotyping strategy would remain cost-saving, as long as the genotyping cost is < $49 per test. In a scenario in which we assumed equal efficacy for the 2 strategies, genotyping was the dominant strategy, associated with less costs (∼$1) and more quality-adjusted life-years (0.1292). DPYD genotyping to guide fluoropyrimidine treatment in patients with advanced or metastatic CRC is cost-saving from the perspective of the Iranian health system.


Impairment in pulmonary bioenergetics following chlorphentermine administration to rats.
Biochemical alteration in pulmonary oxidative metabolism and morphological integrity of lung mitochondria were examined in rats following administration of chlorphentermine (30 mg/kg, ip, 5 days per week) for 1 or 2 weeks. During the first week of treatment, body weight gain and food intake were decreased markedly but returned to control levels during the second week. Phospholipid content of the lung was increased 31% and 110% after 1 and 2 weeks of treatment, respectively. This was accompanied by a striking intraalveolar accumulation of hypertrophic alveolar macrophages. The metabolism of both (1-14C)- and (6-14C)-glucose was decreased 27% and 26%, respectively, after 2 weeks of drug treatment. In rat lung mitochondria, chlorphentermine significantly lowered the RCR and ADP/O ratio and stimulated state 4 respiration. State 3 respiration and uncoupled state respiration were unaffected. These data indicate that chlorphentermine functions as a true uncoupler of oxidative phosphorylation when administered in vivo. Furthermore, disruption of mitochondrial membranes was observed frequently in lung mitochondria from treated animals. These combined data indicate that the induction of pulmonary phospholipidosis by chlorphentermine is accompanied by marked alterations in subcellular bioenergetics and mitochondrial structure.


Estimating the postmortem interval of human skeletal remains by analyzing their optical behavior.
The aim of this study was to figure out a new practically applicable method to distinguish between historical and recent human skeletal remains. Therefore, the optical behavior of bone cross sections was investigated using the combination of two methods: a modification of an already established test (UV-induced fluorescence) and a new method (490 nm-induced fluorescence). We evaluated the areal extent of fluorescence of 30 bone cross sections with known postmortem interval (PMI) using ultraviolet light and 490 nm light. For analysis, the areal extend of fluorescent surface was determined using photos of the samples and an image editing software. The results prove that there is a correlation between PMI and the areal extent of fluorescent surface in both tests. Furthermore, the combination of both methods is a good indicator to distinguish within the forensic relevant post mortem interval between PMI < 30 years and PMI > 30 years.


Visual hallucinations in schizophrenia: confusion between imagination and perception.
An association between hallucinations and reality-monitoring deficit has been repeatedly observed in patients with schizophrenia. Most data concern auditory/verbal hallucinations. The aim of this study was to investigate the association between visual hallucinations and a specific type of reality-monitoring deficit, namely confusion between imagined and perceived pictures. Forty-one patients with schizophrenia and 43 healthy control participants completed a reality-monitoring task. Thirty-two items were presented either as written words or as pictures. After the presentation phase, participants had to recognize the target words and pictures among distractors, and then remember their mode of presentation. All groups of participants recognized the pictures better than the words, except the patients with visual hallucinations, who presented the opposite pattern. The participants with visual hallucinations made more misattributions to pictures than did the others, and higher ratings of visual hallucinations were correlated with increased tendency to remember words as pictures. No association with auditory hallucinations was revealed. Our data suggest that visual hallucinations are associated with confusion between visual mental images and perception.


Hypothesis: myeloid-restricted hematopoietic stem cells with self-renewal capacity may be the transformation site in acute myeloid leukemia.
The transformation site in acute myeloid leukemia (AML) has been proposed to be pluripotent hematopoietic stem cells (PHSCs), and the lymphoid development of leukemic PHSCs may be suppressed by leukemogenic events. Recent data from multiple laboratories have contradicted the current hierarchical model of hematopoiesis and indicated the presence of myeloid HSCs with minimal lymphopoietic potential (MyHSCs) in mice. Based on these findings and re-evaluating the published data on AML stem cells, we hypothesize that MyHSCs may be the transformation site in AML. If so, therapy targeting leukemic MyHSCs but sparing PHSCs is worth investigating.


Electrochemical stimulation of microbial cis-dichloroethene (cis-DCE) oxidation by an ethene-assimilating culture.
This study investigated the feasibility of using a polarized graphite electrode as direct or indirect (via electrolytic oxygen generation) electron acceptor to stimulate the microbial oxidation of cis-dichloroethene (cis-DCE) in contaminated groundwater. A microbial culture was enriched in the anode chamber of a bioelectrochemical cell using a mixture of cis-DCE and ethene as substrates. The bioelectrochemical cell was operated by controlling the anode potential at +1.0 V or +1.5 V versus the standard hydrogen electrode (SHE). Enhanced cometabolic removal of cis-DCE, with ethene serving as the growth substrate, was observed in batch tests with the anode polarized at +1.5 V versus SHE. At this potential, (chloro)ethenes removal was probably sustained by molecular oxygen generated at the anode from water oxidation. Conversely, negligible anaerobic degradation was observed at +1.0 V versus SHE (a potential which does not allow oxygen generation), hence suggesting that molecular oxygen is needed to initiate (chloro)ethene degradation. PCR-DGGE analysis of the microbial culture followed by band sequencing and phylogenetic analysis evidenced the selective enrichment of a Bacillus species, providing a strong indication that this microorganism was responsible for cis-DCE and ethene degradation.


Review of bioprosthetic structural valve deterioration: Patient or valve?
With guidelines progressively recommending bioprosthetic aortic valves in younger patients, a greater emphasis is placed on structural valve deterioration (SVD) as an important clinical endpoint for both transcatheter and surgically implanted valves. However, SVD of bioprosthetic valves is a complex entity with varying definitions in the literature and a multifaceted pathogenesis. This review first aims to establish the most updated definitions of SVD as per the literature. We then explore the patient- and valve-related factors that play the greatest roles in facilitating early SVD. A PubMed literature review was conducted to identify the relevant research in this field within the past two decades. Increasing rates of obesity and metabolic syndrome pose a significant risk to the longevity of bioprosthetic valves. Additionally, externally mounted valves have proven to sacrifice durability for superior haemodynamics. Bioprosthetic SVD continues to be a multifactorial issue that will require various patient- and valve-related factors to be addressed.


Longitudinal impact of psychosocial status on children's mental health in the context of COVID-19 pandemic restrictions.
Emerging research suggests that the prevalence of child and adolescent mental health problems has increased considerably during the COVID-19 crisis. However, there have been few longitudinal studies on children's mental health issues according to their social determinants in this context, especially in Europe. Our aim was to investigate the association between family socioeconomic status (SES) and children' mental health during the period of school closure due to COVID-19. Longitudinal data came from 4575 children aged 8-9 years old in 2020 and participating in the ELFE population-based birth cohort that focuses on children's health, development and socialization. Parents completed the Strengths and Difficulties Questionnaire (SDQ) when children were (a) 5 years of age and (b) 9 years of age, which corresponded to the period of school closure due to the COVID-19 pandemic in France. We retrieved data from the ELFE cohort collected on children from birth to age 5 years (birth, 1 year, 2 years, 3,5 years and 5 years). Socioeconomic status (SES) was measured based on information obtained when the child was 5 years old. Data were analyzed using multinomial logistic regression models. Children's elevated levels of symptoms of Attention-deficit/Hyperactivity disorder (ADHD) during the period of school closure were significantly associated with prior low family SES (aOR 1.26, 95% CI 1.08-1.48). Children's elevated symptoms of hyperactivity/inattention and of emotional symptoms were associated with decline in income during the COVID crisis (respectively, aOR 1.38, 95% CI 1.16-1.63 and aOR 1.23, 95% CI 1.01-1.51). Moreover, when testing interactions, a low prior SES was significantly associated with a higher risk of emotional symptoms aOR 1.54 (1.07-2.21), only for children whose families experienced a decline in income, while gender, parental separation and prior mental health difficulties were not associated. This study underlines the impact of the financial crisis related to the COVID-19 epidemic on children's mental health. Both pre-existing family SES before lockdown and more proximal financial difficulties during the COVID crisis were negatively associated with children's psychological difficulties during the period of school closure. The pandemic appears to exacerbate mental health problems in deprived children whose families suffer from financial difficulties.


Meta-analysis Comparing Combined Use of Eicosapentaenoic Acid and Statin to Statin Alone.
Role of omega-3-Fatty acids, especially eicosapentaenoic acid (EPA), in reducing cardiovascular events is not clear. We conducted a meta-analysis including trial sequential analysis (TSA) of all available randomized controlled trials (RCTs) assessing the impact of EPA + statin on cardiovascular risk reduction. The aim is to appraise cardiovascular risk reduction with EPA and statin taken together. A comprehensive search of PubMed and EMBASE databases was conducted for all RCTs that compared EPA + Statin versus statin alone and included outcomes related to cardiovascular health. We calculated a comprehensive odds ratio (ORs) and 95% confidence intervals (CIs) using a random-effects model. We included 5 RCTs totaling 27,415 patients. Our results demonstrated that EPA + statin resulted in 18% reduction in the incidence of MACE (OR = 0.78; 95% CI: 0.65 to 0.93, I2 = 54%, p value <0.01) and 30% reduction in myocardial infarction (MI) (OR = 0.71; 95% CI: 0.61 to 0.82, I2 = 0% p value <0.01) as compared with statin alone. With respect to MACE, the number needed to treat was 49. The statistical significance for reduction in the incidence of MACE with EPA+ statin was further augmented with trial sequential analysis. However, combined therapy of EPA + statin demonstrated no significant association on incidence of stroke when compared with statin alone or all-cause mortality. In conclusion, this meta-analysis demonstrated that EPA significantly reduced the incidence of MACE when combined with statin therapy, which is mainly driven by a significant reduction in myocardial infarction.


Binaural interaction in the frog dorsal medullary nucleus.
We have studied binaural and directional processing in cells in the frog dorsal medullary nucleus (DMN) stimulated with dichotic sound (couplers) and free-field sound. We present evidence that already at this stage of central processing the neural directionality is sharpened, probably by binaural interaction. Binaural interaction in the DMN was usually interpreted as inhibition, mostly driven from the contralateral side and dependent on a certain combination of interaural time differences (ITD) and interaural level differences (ILD). In free-field measurements, the strength and timing of the binaural inputs will depend on sound direction as processed by the auditory fibers. Thus, the directionality of DMN cells is caused by both monaural directional cues generated by acoustical coupling of the eardrums and non-tympanic pathways as well as binaural interaction. Most DMN cells show ovoidal directional characteristics and the directionality is sharpened compared to that of auditory nerve fibers. We suggest that the sharpening is due to the inhibitory interactions.


Swallowing outcomes following Intensity Modulated Radiation Therapy (IMRT) for head & neck cancer - a systematic review.
A systematic review to establish what evidence is available for swallowing outcomes following IMRT for head and neck cancer. Online electronic databases were searched to identify papers published in English from January 1998 to December 2009. Papers were independently appraised by two reviewers for methodological quality, method of swallowing evaluation and categorized according to the World Health Organisation's International Classification of Health Functions. The impact of radiation dose to dysphagia aspiration risk structures (DARS) was also evaluated. Sixteen papers met the inclusion criteria. The literature suggests that limiting the radiation dose to certain structures may result in favourable swallowing outcomes. Methodological limitations included variable assessment methods and outcome measures and heterogeneity of patients. There are only limited prospective data, especially where pre-treatment measures have been taken and compared to serial post-treatment assessment. Few studies have investigated the impact of IMRT on swallow function and the impact on everyday life. Initial studies have reported potential benefits but are limited in terms of study design and outcome data. Further well designed, prospective, longitudinal swallowing studies including multidimensional evaluation methods are required to enable a more comprehensive understanding of dysphagia complications and inform pre-treatment counselling and rehabilitation planning.


Inside-Out Meniscal Repair: Medial and Lateral Approach.
Preservation of meniscal tissue has been proven to be the best approach in most cases of meniscal tears. Currently available techniques for treating a peripheral meniscal tear include inside-out, outside-in, and all-inside techniques. Each of these techniques present potential advantages and disadvantages. Despite technologic advances in all-inside devices, because of implant-related complications, cost concerns, and device availability, the inside-out technique is still the preferred method among many surgeons. Although the inside-out repair technique is considered more technically demanding and requires additional incisions, it has several advantages such as the possibility for an increased number of sutures, creating a stronger construct, and greater versatility in their placement. This article describes the inside-out meniscal repair technique with its corresponding posterolateral and posteromedial surgical approaches.


Reduced consumption of analgesics in patients with diabetes mellitus admitted to hospital for acute myocardial infarction.
In a case-control study, the consumption of analgesics was analysed in 39 patients with diabetes, admitted with acute myocardial infarction (MI). The control group comprised of non-diabetics with MI was computer-matched to the diabetic group with respect to age and sex as well as enzyme-estimated size of the infarction. The median number of injections of opioid analgesics in the diabetes and non-diabetes groups was 2 and 5, respectively (0.01 less than P less than 0.05), and the median consumption of morphine was 20 mg and 35 mg, respectively (0.01 less than P less than 0.05). There was no statistically significant trend for the duration of pain to be shorter in the diabetes group. There was no difference between the two groups with respect to number of patients with Q-wave infarct, initial heart rate-blood pressure product or body weight, all of which are possible confounders. We conclude that diabetics admitted with acute myocardial infarction have a lower consumption of analgesics than non-diabetics.


Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition.
Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen's 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.


Combined antimicrobial finishing and pigment printing of cotton/polyester blends.
This study demonstrates the possibility of enhancing the antibacterial functionality and pigment printing properties of cotton/polyester blends (50/50 and 35/65) in one step. Inclusion of chitosan (10 g/kg), choline chloride (15 g/kg), triclosan derivative (20 g/kg), hyperbranched poly amide-amine/silver or zinc oxide nanoparticles (HBPAA/Ag-NP's hybrid or HBPAA/ZnO-NP's hybrid - 20 g/kg) into a pigment print formulation followed by printing and microwave curing at 386 W for 5 min results in an improvement in antibacterial activity and pigment printability. It was further noted that, in all cases, the G+ve (S. aureus) bacteria is more susceptible to the action of the immobilized antibacterial agents than the G-ve bacteria (E. coli). The functionalized pigment prints exhibited very sufficient antibacterial activity even after 20 washing cycles. Modes of interactions were proposed, and surface modification was also confirmed by SEM and EDX analysis.


Brain network characteristics separating individuals at clinical high risk for psychosis into normality or psychosis.
We aimed to separate individuals at clinical high risk for psychosis (CHR) state into subgroups according to neurobiological characteristics using structural and functional network constructs and examine their clinical characteristics. Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in 61 healthy controls (HC), 57 individuals at CHR and 29 patients with schizophrenia (SZ). The main outcome was a likelihood ratio calculated from measures of structural and functional network efficiencies, coupling strength of structural and functional networks, and a disease-specific data analysis, resulting in the most probable classification of CHR into HC or SZ. The likelihood ratios revealed that 33 individuals at CHR were likely similar to HC (CHR-HC), and the remaining 24 CHR individuals were similar to SZ (CHR-SZ). The CHR subgroups were comparable to each other in demographic characteristics and clinical symptoms. However, the verbal and executive functions of CHR-HC were similar to those of HC, and those of CHR-SZ similar to SZ. Additionally, CHR-SZ was more responsive to treatment than CHR-HC during the follow-up period. By combining structural and functional data, we could detect the vulnerable population and provide an active intervention in the early phase of the CHR state.


Methods for Investigating Cell Division Mechanisms in C. elegans.
The nematode Caenorhabditis elegans is a widely used model organism for the study of mitotic and meiotic cell division. These self-fertilizing worms are particularly advantageous for such studies because they rapidly reproduce (each worm lays ~250 eggs in only 3-4 days) and the cell division machinery is highly conserved between worms and humans. Worms are also genetically tractable and proteins can be readily depleted using RNA interference (RNAi), allowing for the characterization of protein function in vivo. To assess phenotypes, spindles can be directly visualized within the worm using fluorescent protein tags or embryos can be dissected out of the worm and immunostained. A combination of these techniques allows comprehensive characterization of a protein's function in a relatively short time span. Here, we describe methods for each of these techniques: RNA interference through feeding, in utero live imaging, in utero fixed imaging, and immunofluorescence.


Human-Gut-DNA Virome Variations across Geography, Ethnicity, and Urbanization.
The human-gut-DNA virome is highly diverse and individual specific, but little is known of its variation at a population level. Here, we report the fecal DNA virome of 930 healthy adult subjects from two regions in China (Hong Kong and Yunnan) spanning six ethnicities (Han, Zang, Miao, Bai, Dai, and Hani), and including urban and rural residents for each ethnicity. Twenty host factors were found to significantly correlate with the human-gut virome variation, with geography carrying the strongest impact and ethnicity-distinct diets associating with certain viral species. Urbanization enhances interindividual dissimilarities between gut viromes, with the duration of urban residence associating with multiple bacteriophages, including Lactobacillus phage and Lactococcus phage. Overall, the gut virome presents more heterogeneity relative to the bacterial microbiome across the examined Chinese populations. This study highlights population-based variations and the importance of host and environmental factors in shaping the DNA virome in the human gut.


Immobilization of aminoacylase in polyethyleneimine stabilized calcium alginate beads for L-phenylalanine production.
Aminoacylase I (E.C.126.96.36.199) was immobilized by entrapment in calcium alginate beads coated with polyethyleneimine for the production of L-phenylalanine by the hydrolysis of a racemic mixture of N-acetyl-DL-phenylalanine. The operational stability in terms of batch operation and continuous reaction in packed-bed bioreactor were studied. Kinetic constants, Km and Vmax values of free and immobilized enzymes were studied. Polyethyleneimine treatment was found to enhance the operational stability of the enzyme though its activity was substantially reduced. When polyethyleneimine-coated calcium alginate beads were packed into packed bed bioreactor, it was stable for at least 25 days under continuous operation without appreciable loss of activity.


Double-blind, placebo-controlled study of the efficacy of nandrolone laurate in the treatment of dobermanns with subclinical hepatitis.
Twenty-one three-year-old dobermanns with subclinical hepatitis were treated with nandrolone laurate or a placebo in a double-blind trial. The dogs were scored clinically before and after four months of treatment and they were evaluated by clinical biochemistry and liver biopsies. After the treatment no significant differences were observed between the two groups in any of the clinical biochemistry values; eight of the 21 dogs had no histological evidence of hepatitis and five other dogs had improved, but there was no significant difference between the responses of the two groups.


Role of lncRNAs in Remodeling of the Coronary Artery Plaques in Patients with Atherosclerosis.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide according to World Health Organization (WHO) data. Atherosclerosis is considered as a chronic inflammatory disease that develops in response to damage to the vascular intima-media layer in most cases. In recent years, epigenetic events have emerged as important players in the development and progression of CVDs. Since noncoding RNA (ncRNAs) are important regulators in the organization of the pathophysiological processes of the cardiovascular system, they have the potential to be used as therapeutic targets, diagnostic and prognostic biomarkers. In this study long noncoding RNA (lncRNA) and mRNA gene expression were compared between coronary atherosclerotic plaques (CAP) and the internal mammary artery (IMA) which has the same genetic makeup and is exposed to the same environmental stress conditions with CAP in the same individual. lncRNA and mRNA gene expressions were determined using the microarray in the samples. Microarray results were validated by RT-qPCR. Differentially expressed genes (DEGs; lncRNAs and mRNAs) were determined by GeneSpring (Ver 3.0) [p values < 0.05 and fold change (FC) > 2]. DAVID bioinformatics program was used for Gene Ontology (GO) annotation and enrichment analyses of statistically significant genes between CAP and IMA tissue. In our study, 345 DEGs were found to be statistically significant (p < 0.05; FC > 2) between CAP and IMA. Of these, 65 were lncRNA and 280 were mRNA. Thirty-three lncRNAs were upregulated, while 32 lncRNAs were downregulated. Some of the important mRNAs are SPP1, CYP4B1, CHRDL1, MYOC, and ALKAL2, while some of the lncRNAs are LOC105377123, LINC01857, DIO3OS, LOC101928134, and KCNA3 between CAP and IMA tissue. We also identified genes that correlated with statistically significant lncRNAs. The results of this study are expected to be an important source of data in the development of new genetically based drugs to prevent atherosclerotic plaque. In addition, the data obtained may contribute to the explanation of the epigenetic mechanisms that play a role in the pathological basis of the process that protects the IMA from atherosclerosis.


Fatigue in Arthritis: A Multidimensional Phenomenon with Impact on Quality of Life : Fatigue and Quality of Life in Arthritis.
An important factor which influences the quality of life of patients with arthritis is the fatigue they experience. The purpose of this study was to assess the relationship between fatigue and quality of life among patients with osteoarthritis and rheumatoid arthritis. Between January 2015 and March 2015, 179 patients with osteoarthritis and rheumatoid arthritis completed the Fatigue Assessment Scale and the Missoula-VITAS Quality of Life Index-15 (MVQoLI-15). The study was conducted in Rehabilitation Centers located in the area of Peloponnese, Greece. Data related to sociodemographic characteristics and their individual medical histories were recorded. Statistical analysis was performed using the IBM SPSS Statistics version 19. The analysis did not reveal statistically significant correlation between fatigue and quality of life neither in the total sample nor among patients with osteoarthritis (r = -0.159; p = 0.126) or rheumatoid arthritis. However, there was a statistically significant relationship between some aspects of fatigue and dimensions of quality of life. Osteoarthritis patients had statistically significant lower MVQoLI-15 score than rheumatoid arthritis patients (13.73 ± 1.811 vs 14.61 ± 1.734) and lower FAS score than rheumatoid patients (26.14 ± 3.668 vs 29.94 ± 3.377) (p-value < 0.001). The finding that different aspects of fatigue may affect dimensions of quality of life may help health care professionals by proposing the early treatment of fatigue in order to gain benefits for quality of life.


Low-density lipoprotein derived from atherosclerotic patients enhances macrophage cholesterol accumulation and in vitro platelet aggregation.
The aims of our study were to assess the differences between plasma lipoproteins separated from five angiographically normal subjects and five patients with proven CHD. The patients with CHD had significantly higher levels of LDL-cholesterol and apo-B, and reduced levels of HDL-cholesterol and apo-Al. The biological characteristics of LDL and HDL from both groups of patients demonstrated that the LDL from the CHD patients enhanced platelet aggregation and increased cholesterol content and cholesterol esterification in MPM compared to the normal patients. HDL had no significant effect on MPM; however, there was an increased platelet aggregation with HDL derived from the CHD patients, while the HDL from the normal group decreased platelet aggregation. The data suggest that lipoproteins isolated from CHD patients are more atherogenic than lipoproteins from normal patients.


Methionine cycle in nonalcoholic fatty liver disease and its potential applications.
As a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.


Effect of Methadone Maintenance on Expression of BDNF and CREB Genes in Brain VTA of Male Morphine Treated Rats.
Morphine independently reduces the expression level of Brain-derived Neurotrophic Factor (BDNF) and Cyclic-AMP Response Element Binding protein (CREB). BDNF and CREB play a vital role in protecting and regulating the proper functioning of neurons. There has not been any study on the effect of methadone maintenance treatment and its comparison with morphine. Therefore, this study was conducted to examine the effect of methadone maintenance on the expression of BDNF and CREB genes in brain VTA of male morphine treated rats. In this study, 24 Wistar rats (200-250g) were assigned to three experimental groups: 1) Animals without morphine treatment (control); 2) Morphine treated animals (10 mg/kg, twice/day through subcutaneous injection for 21 days); 3) Animals under methadone maintenance after treatment with morphine (maintenance dose of methadone was achieved during 14 days equal to 1 mg per 100 ml at the first week and 2.5 mg per 100 ml at second week). To evaluate the expression of BDNF and CREB genes, real time PCR method was used, and ELISA was applied to measure the serum level of BDNF protein at the end of the experiment. According to the findings of this study, similar to morphine treated group, methadone maintenance in morphine treated animals led to a significant reduction in the expression of BDNF and CREB genes at VTA as well BDNF serum level compared with the control group. It was concluded that methadone, like morphine, causes a significant reduction in the expression of BDNF and CREB genes in the brain VTA area of rats as well as BDNF serum level compared with the control group.


A novel thiourea derivative for preconcentration of copper(II), nickel(II), cadmium(II), lead(II) and iron(II) from seawater samples for Flame Atomic Absorption Spectrophotometry.
A novel adsorbent, 3-phenyl-1-(2-pyridyl)thiourea (PPTU) was synthesized and its adsorption capabilities were studied for Cu(II), Cd(II), Ni(II), Pb(II) and Fe(II) cations in the waters such as tap and polluted seawaters. The kinetics, Langmuir and Freundlich isotherms were discussed related to the adsorptions. The adsorption capacities of PPTU were found 9.4; 12.6; 90.9; 57.1 and 30.4 mg g-1 and preconcentration with PPTU including the FAAS step yielded the LOQ values 0.46; 2.65; 1.12; 2.65 and 1.72 ng mL-1 for Cu(II), Cd(II), Ni(II), Pb(II) and Fe(II), respectively. The adsorbent after the elutions and washings could be reused three times in the next adsorptions. The interferences on the adsorptions arising from the major cations of the seawater and the usability of PPTU for interested metals in the seawater were discussed. The proposed method is simple with highly efficient and green preconcentration procedure for trace analysis of the target metal ions.


Early electrophysiological abnormalities and clinical neuropathy: a prospective study in patients with type 1 diabetes.
The aim of this study was to elucidate whether subclinical nerve dysfunction as reflected by neurophysiological testing predicts the development of clinical neuropathy in patients with type 1 diabetes. Fifty-nine patients were studied twice with neurophysiological measurements at baseline and at follow-up. At baseline, patients were 15.5±3.22 years (range 7-22 years) of age, and duration of diabetes was 6.8±3.3 years. At follow-up, patients were 20-35 years of age, and disease duration was 20±5.3 years (range 10-31 years). At baseline, patients showed modestly reduced nerve conduction velocities and amplitudes compared with healthy subjects, but all were free of clinical neuropathy. At follow-up, clinical neuropathy was present in nine (15%) patients. These patients had a more pronounced reduction in peroneal motor nerve conduction velocity (MCV), median MCV, and sural sensory nerve action potential at baseline (P<0.010-0.003). In simple logistic regression analyses, the predictor with the strongest association with clinical neuropathy was baseline HbA1c (R2=48%, odds ratio 7.9, P<0.002) followed by peroneal MCV at baseline (R2=38%, odds ratio 0.6, P<0.006). With the use of a stepwise forward analysis that included all predictors, first baseline HbA1c and then only peroneal MCV at baseline entered significantly (R2=61%). Neuropathy impairment assessment showed a stronger correlation with baseline HbA1c (ρ=0.40, P<0.002) than with follow-up HbA1c (ρ=0.034, P<0.007). Early defects in nerve conduction velocity predict the development of diabetic neuropathy. However, the strongest predictor was HbA1c during the first years of the disease.


Improvement of the parallel flow dialysis technique for the detection of drug-binding proteins in column effluents.
The parallel flow dialysis technique was improved for application to the detection of drug-binding proteins in a column chromatographic effluent. To prevent the baseline drift, the pressures of both protein and drug channels were maintained equal during chromatography, and Brij-35 was added to the solvents. The improved method was successfully applied to the detection of methyl orange-binding proteins in human serum and bromphenol blue-binding proteins in rat liver homogenate.


Cefuroxime selective electrodes for batch and FIA determinations in pharmaceutical preparations.
Different cefuroxime selective electrodes, without internal reference solution and comprising PVC membranes, were constructed and evaluated. Membranes were prepared with cefuroxime tetraoctylammonium (A) or cefuroxime bis(triphenylphosphoranylidene)ammonium (B) as ion-exchanger, 2-nitrophenyl octyl ether (X) or bis(2-ethylhexyl)sebacate (Y) as plasticizing mediator solvent and 4-tert-otcylphenol (TOP) as additive. From the comparative evaluation of the described electrodes, membranes comprising 2-nitrophenyl octyl ether, cefuroxime tetraoctylammonium and 4-tert-otcylphenol presented better working characteristics. For these electrodes (type XA-TOP), with a lifetime > 5 months, a lower limit of linear range of 2.8 x 10(-4) M, a practical detection limit of 1.3 x 10(-4) M, a reproducibility of approximately +/-0.6 mV day(-1) and a slope of -50.4 mV decade(-1), under H3PO4/NaH2PO4 solutions (pH 3.5; I =0.1 M), were found. The presence of the additive on the membranes was of crucial importance for the electrodes good characteristics. Interference from sulphate, chloride, nitrate, iodide, cefaclor, cefadroxil, cefazolin and cephradine, on the electrodes behaviour was evaluated. Only a slight interference from nitrate and iodide was recorded, being type XA-TOP electrodes the most selective units. Electrodes with a tubular configuration prepared with type XA-TOP membranes, aiming flow injection analysis, were also constructed. When these tubular potentiometric detectors were evaluated in a double-channel flow injection manifold, with 3.5 pH and 0.1 M ionic strength conditions, significantly better working characteristics than those of the corresponding conventional electrodes, namely higher slopes (-54.6 mV decade(-1)) and better reproducibilities (+/-0.2 mV day(-1)), were found. Both conventional and tubular type XA-TOP electrodes were used for injections analyses by batch and FIA, respectively, presenting low consumption of samples and reagents. Relative error deviations to the reference procedures <3.0% were found.


Galectin-3 Expression in High-Risk HPV-Positive and Negative Head & Neck Squamous Cell Carcinomas and Regional Lymph Node Metastases.
Despite higher stages at presentation, patients with high-risk (HR) HPV-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) have better survival rates compared to those with non-HPV-related (HPV-) disease. However, significant comorbidity and the number of patients who suffer failed treatment, recurrent disease, late metastasis, and death are increasing along with the incidence of HPV+ HNSCC. A cytotoxic T-cell-dependent immune response is required to clear these antigenic cancers. This provides a unique opportunity to employ immune modulators in therapy. Galectin-3 (Gal-3) is a lectin and glycoprotein involved in numerous immunosuppressive functions. Inhibitors are currently under clinical investigation for various diseases. Gal-3 expression was evaluated in HR-HPV+ and HPV- HNSCCs and regional lymph node metastases by tissue microarray. HR-HPV+ cases were more likely to be Gal-3-positive (Gal+) [50% (14/28)] than HPV- cases [18% (9/50), p = 0.004]. No difference in the number of Gal+ cases was identified between primary [30% (16/53)] and metastatic [28% (7/25)] cancers (p = 1); 53% (9/17) of primary HPV+ cancers were Gal+ and 45% (5/11) of metastatic HPV+ cancers were Gal+ (p = 1). Nineteen percent (7/36) of primary HPV- cancers were Gal+ and 14% (2/14) of metastatic HPV- cancers were Gal+ (p = 1). Gal-3 positivity was observed in a subset of HNSCC, suggesting a potential role for therapeutic inhibition in this tumor type. The significantly higher rates of expression seen in HR-HPV+ versus HPV- HNSCC suggest particular promise in the setting of HPV infection. The relatively consistent Gal-3 expression rates observed between metastatic and primary tumors argues against progressive Gal-3 expression in metastasis.


Comparative and Phylogenetic Analyses of the Complete Chloroplast Genomes of Six Almond Species (Prunus spp. L.).
As a source of genetic variation, almond germplasm resources are of great significance in breeding. To better reveal the mutation characteristics and evolution patterns of the almond chloroplast (cp) genome, the complete cp genomes from six almond species were analyzed. The lengths of the chloroplast genome of the six almond species ranged from 157,783 bp to 158,073 bp. For repeat sequence analysis, 53 pairs of repeats (30 bp or longer) were identified. A total of 117 SSR loci were observed, including 96 polymorphic SSR loci. Nine highly variable regions with a nucleotide variability (Pi) higher than 0.08, including rps16, rps16-psbK, atpF-atpH, rpoB, ycf3-rps4, rps4-ndhJ, accD-psaI and rps7-orf42 (two highly variable regions) were located. Based on the chloroplast genome evolution analysis, three species (P. tenella, P. pedunculata and P. triloba) and wild cherry (P. tomentosa) were grouped into clade I. Clade II consisted of two species (P. mongolica and P. tangutica) and wild peach (P. davidiana). Clade III included the common almond (P. dulcis), cultivated peach (P. persica) and GanSu peach (P. kansuensis). This result expands the researchers' vision of almond plant diversity and promotes an understanding of the evolutionary relationship among almond species. In brief, this study provides abundant resources for the study of the almond chloroplast genome, and has an important reference value for study of the evolution and species identification of almond.


Interaction of hybridoma antibodies with normal and mutant forms of Escherichia coli recA protein.
We have prepared hybridomas which secrete antibodies against E. coli recA protein, by fusing spleen lymphocytes from immunized mice with P3X63-AG8 myeloma cells. This paper describes a preliminary survey of properties of antibody from a hybridoma population designated 156, which inhibits the strand pairing, strand assimilation, repressor cleavage, and DNA-dependent ATPase activities of recA protein. The 156 antibody consists of one or two species which have been tentatively identified as IgG2b. 156 Globulin reacts 4.6-fold more efficiently with denatured recA protein, and it reacts partially with the native tif-1, lexB30, recA44, and recA629 proteins, as well as with peptide fragments which are not common to all four proteins.


Testosterone and acute stress are associated with fibrinogen and von Willebrand factor in African men: the SABPA study.
Low testosterone, acute and chronic stress and hypercoagulation are all associated with hypertension and hypertension-related diseases. The interaction between these factors and future risk for coronary artery disease in Africans has not been fully elucidated. In this study, associations of testosterone, acute cardiovascular and coagulation stress responses with fibrinogen and von Willebrand factor in African and Caucasian men in a South African cohort were investigated. Cardiovascular variables were studied by means of beat-to-beat and ambulatory blood pressure monitoring. Fasting serum-, salivary testosterone and citrate coagulation markers were obtained from venous blood samples. Acute mental stress responses were evoked with the Stroop test. The African group demonstrated a higher cardiovascular risk compared to Caucasian men with elevated blood pressure, low-grade inflammation, chronic hyperglycemia (HbA1c), lower testosterone levels, and elevated von Willebrand factor (VWF) and fibrinogen levels. Blunted testosterone acute mental stress responses were demonstrated in African males. In multiple regression analyses, higher circulating levels of fibrinogen and VWF in Africans were associated with a low T environment (R(2) 0.24-0.28; p≤0.01), but only circulating fibrinogen in Caucasians. Regarding endothelial function, a low testosterone environment and a profile of augmented α-adrenergic acute mental stress responses (diastolic BP, D-dimer and testosterone) were associated with circulating VWF levels in Africans (Adj R(2) 0.24; p<0.05). An interdependence between acute mental stress, salivary testosterone, D-dimer and vascular responses existed in African males in their association with circulating VWF but no interdependence of the independent variables occurred with fibrinogen levels.


Development of an on-column enrichment technique based on C18-functionalized magnetic silica nanoparticles for the determination of lidocaine in rat plasma by high performance liquid chromatography.
In this study, a novel on-column enrichment technique filled with C(18)-functionalized magnetic silica nanoparticles was successfully developed for the determination of lidocaine in rat plasma by high performance liquid chromatography (HPLC). The synthesized Fe(3)O(4)@SiO(2)-C(18) nanoparticles were locally packed into the capillary by the application of magnets. Lidocaine in the sample solutions pumped into the capillary tube could be easily adsorbed by Fe(3)O(4)@SiO(2)-C(18) through hydrophobic interaction by the interior C(18) groups, and eluted by acetonitrile solution. Different extraction conditions were investigated. Method validations including linear range, quantification limit, detection limit, precision, accuracy and recovery were also studied. The results showed that the proposed method based on on-column enrichment by Fe(3)O(4)@SiO(2)-C(18) was a novel, little solvent and efficient approach for the determination of lidocaine in the complex plasma samples.


Selenium speciation from food source to metabolites: a critical review.
Especially in the last decade, a vast number of papers on Se and its role in health issues have been published. This review gives a brief, critical overview of the main analytical findings reported in these papers. Of particular interest is the Se content in different food sources worldwide and the extent to which their consumption is reflected in the Se content of human tissues and body fluids. Several food sources, both natural (Brazil nuts, garlic, Brassica juncea) and Se-enriched (yeast-based supplements), are discussed as to origin, characteristics, Se metabolism and impact of their consumption on the human body. The continuous development of new and improvement of existing analytical techniques has provided different powerful tools to unravel the Se species and their function. An up-to-date literature study on Se speciation analysis is given, illustrating how analytical chemistry in its different facets aids in the identification of Se compounds and provides insight into the complete metabolic pathway of Se throughout the human body. This review includes a detailed image of the current state-of-the-art of Se speciation analysis in these food sources and in human tissues and body fluids.


Metabolic changes at the early stage of sepsis induced by cecal ligation and puncture in rats and the interventional effects of Huang-Lian-Jie-Du-Tang.
Sepsis is a disease with high mortality that requires rapid diagnosis and treatment. This study used a metabolomic approach to profile the metabolic changes at the early stage of sepsis induced by cecal ligation and puncture (CLP) in rats and investigated the interventional effects of Huang-Lian-Jie-Du-Tang (HLJDT). Male SD rats were intragastrically administered 270mg/kg HLJDT 2h prior to CLP, serum extracts were profiled by liquid chromatography/quadrupole time-of-flight mass spectrometer (LC-Q-TOF-MS) and multivariate analytical (MVA) methods were employed to evaluate the metabolic changes of extracts. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that septic rats undergo significant metabolic changes 2h after CLP, and HLJDT administration could reverse the metabolic changes induced by CLP. Sixteen biomarkers involved in amino acid metabolism, unsaturated fatty acid metabolism, purine metabolism, and lipid metabolism were identified after Orthogonal Partial Least-Squares Analysis (OPLS). Among the 16 metabolites, 10 were regulated by HLJDT. This study established the foundation for further research of the early diagnosis biomarkers and therapeutic evaluation biomarkers discovery of sepsis.


The expression and localization of serine proteinase inhibitor PI-6 mRNA in developmental and ischemic mouse brain.
A serine proteinase inhibitor, PI-6, is a member of the serine proteinase inhibitor (serpin) superfamily. In the present study, we investigated the developmental expression of PI-6 in the mouse brain and the effect of experimental ischemia on the expression of PI-6 in the adult brain. Northern blot analysis showed a high level of expression of PI-6 mRNA in brain stem and diencephalon as compared with other regions in the adult brain. The expression of PI-6 mRNA in the whole brain was increased gradually until 11 days after birth and was decreased again in the adult brain. In situ hybridization analysis revealed that the mRNA was localized in pyramidal cell layer of the post-natal hippocampus, especially in CA3 region, and in layer V of the cerebral cortex. In the brain stem, two specific motor nuclei, the facial nucleus and the motor nucleus of trigeminal nerve, which are important to active feeding, were strongly positive for PI-6 mRNA. Brain ischemia induced by bilateral ligation of the common carotid artery led to an increase in PI-6 mRNA expression in the whole brain, accompanied by the degeneration of hippocampal pyramidal cells. These results indicate distinct temporal and spatial expression of PI-6 in the mouse brain and suggest the involvement of PI-6 in the maturation of neurons and degenerative and regenerative processes.


[Perianal Fistula: An Overview].
Perianal fistula is a common inflammatory condition in the general population and affects the area around the anal canal. Although most cases are benign, they cause serious morbidity and require surgical treatment due to a high risk of recurrence. MR imaging is a gold standard technique for the evaluation of perianal fistulas and provides accurate information on the anatomy of the anal canal, its relationship to the anal sphincter complex, accurate identification of secondary tracts or abscesses, and reporting associated complications. MR imaging can help monitor treatment effects and determine treatment methods. Crohn's disease-related fistulas often require medical rather than surgical treatment. The radiologist is required to know the anatomy and MR imaging findings of the perianal fistula to present an accurate diagnosis to the clinician.


The indirect effect of negative emotionality via alcohol craving on abstinence self-efficacy among women in alcohol treatment.
Women with alcohol use disorder (AUD) often present to treatment with heightened negative emotionality, including negative affect, anxiety, stress, and depression. Negative emotionality might impact women's alcohol abstinence self-efficacy (AASE), or confidence in their ability to remain sober, which is an important predictor of treatment outcomes. It is also plausible that other variables, such as alcohol craving, influence AASE. The present work examined the indirect effect of negative emotionality on AASE via alcohol craving as a mediator cross-sectionally among a sample of women enrolled in AUD treatment reporting co-occurring depressive symptoms (N = 73). Participants completed baseline measures of negative emotionality (e.g. anxiety and depression symptoms, stress, negative affect), alcohol craving, and AASE. All indices of negative emotionality were positively correlated with each other and alcohol craving (r's ranging from 0.244 to 0.671) and all but depression were inversely associated with AASE (r's ranging from -0.341 to -0.234; p <.05). In separate simple mediation models, we found that alcohol craving mediated the association of each of the four measures of negative emotionality with AASE. Further longitudinal and experimental work is necessary to determine if teaching skills to cope with alcohol craving in the context of co-occurring negative emotionality might lead to better therapeutic outcomes.


Regional flow during experimental hemorrhage and crystalloid resuscitation: persistence of low flow to the splanchnic organs.
BACKGROUND AND METHODS. Rapid changes in cardiac output (CO) and organ perfusion occur with hemorrhagic shock and fluid resuscitation. To assess regional alterations of flow, 40 Sprague-Dawley male rats were subjected to hemorrhagic shock and crystalloid resuscitation under halothane anesthesia. Polyethylene microspheres were injected before and after hemorrhage and after resuscitation. At sacrifice, brain, lungs, heart, liver, intestine, spleen and kidneys were harvested, weighed and radioactivity counted. Changes in mean arterial pressure, oxygen consumption, organ flow and CO were also measured. Cardiac output decreased during hemorrhage (P less than 0.01), it increased with resuscitation but did not return to baseline even with infusion of fluid volumes of three times the blood loss. Flow decreased during hemorrhage in all organs, but the difference was not statistically significant in the liver (P greater than 0.05), since a larger percentage of CO was maintained as hepatic perfusion. During resuscitation, flow to brain and kidneys increased over the percentage values expected by increased CO (P less than 0.01), but flow to the liver did not increase significantly. Flow to small bowel remained depressed (P less than 0.005). Following hemorrhage there is hypoperfusion of all splanchnic organs; however, flow to the liver decreases least. Crystalloid resuscitation in our model failed to return CO to baseline. Blood supply to intestine remained depressed in disproportion to CO both after hemorrhage and resuscitation and hepatic blood flow remained decreased after resuscitation.


Targeted Interventions in Tourette's using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette's syndrome.
Tourette's syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette's syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures). This study will recruit 50 youth with TS, aged 6-18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2-6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette's symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers. Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub. NCT03844919.


Patient-Specific Auto-segmentation on Daily kVCT Images for Adaptive Radiation Therapy.
This study explored deep-learning-based patient-specific auto-segmentation using transfer learning on daily RefleXion kilovoltage computed tomography (kVCT) images to facilitate adaptive radiation therapy, based on data from the first group of patients treated with the innovative RefleXion system. For head and neck (HaN) and pelvic cancers, a deep convolutional segmentation network was initially trained on a population data set that contained 67 and 56 patient cases, respectively. Then the pretrained population network was adapted to the specific RefleXion patient by fine-tuning the network weights with a transfer learning method. For each of the 6 collected RefleXion HaN cases and 4 pelvic cases, initial planning computed tomography (CT) scans and 5 to 26 sets of daily kVCT images were used for the patient-specific learning and evaluation separately. The performance of the patient-specific network was compared with the population network and the clinical rigid registration method and evaluated by the Dice similarity coefficient (DSC) with manual contours being the reference. The corresponding dosimetric effects resulting from different auto-segmentation and registration methods were also investigated. The proposed patient-specific network achieved mean DSC results of 0.88 for 3 HaN organs at risk (OARs) of interest and 0.90 for 8 pelvic target and OARs, outperforming the population network (0.70 and 0.63) and the registration method (0.72 and 0.72). The DSC of the patient-specific network gradually increased with the increment of longitudinal training cases and approached saturation with more than 6 training cases. Compared with using the registration contour, the target and OAR mean doses and dose-volume histograms obtained using the patient-specific auto-segmentation were closer to the results using the manual contour. Auto-segmentation of RefleXion kVCT images based on the patient-specific transfer learning could achieve higher accuracy, outperforming a common population network and clinical registration-based method. This approach shows promise in improving dose evaluation accuracy in RefleXion adaptive radiation therapy.


Analysis of REM sleep without atonia in 22q11.2 deletion syndrome determined by domiciliary polysomnography: a cross sectional study.
Our aim is to evaluate the presence of REM sleep without atonia (RWA), the objective hallmark of REM sleep Behaviour Disorder (RBD), as prodromal marker of Parkinson's disease (PD), in an adult cohort of 22q11.2 deletion syndrome (22qDS). Sleep quality was assessed by means of Pittsburgh quality scale index (PSQI), and RBD symptoms by means of RBD questionnaire-Hong-Kong (RBDQ-HK). Attended domiciliary video-Polysomnography (v-PSG) were performed in 26 adults (18-51 years, 14 females) 22qDS patients. Electromyogram during REM sleep was analyzed by means of SINBAR procedure at 3-second time resolution (miniepochs). An overall poor sleep quality was observed in the cohort and high RBDQ-HK score in 7 of the 26 patients, two additional patients with positive dream enactment reported by close relatives had low score of RBDQ-HK. Nevertheless, SINBAR RWA scores were lower than cut-off threshold for RWA (mean 5.5%, range 0-12.2%). TST and the percentage of light sleep (N1) were increased, with preserved proportions of N2 and N3. Participants reported poor quality of sleep (mean PSQI > 5), with prolonged sleep latency in the v-PSG. No subjects exhibit evident dream enactment episodes during recording sessions. RWA was absent in the studied cohort of 22qDS adult volunteers according to validated polysomnographic criteria. High RBDQ-HK scores do not correlate with v-PSG results among 22qDS individuals.


[Ethanol: current theories on its toxic effect with special reference to the effect on the central nervous system of adult mammals and during individual development].
Present-day views on the molecular mechanism of ethanol action upon the central nervous system of adult mammals as well as consequences of the brain exposure to ethanol during fetal life, and upon the development and function of this organ in postnatal life are reviewed. Mechanisms of teratogenic effect of ethanol are also discussed.


Fluid Bolus for Renal Colic: Current Practice.
Historically the administration of intravenous fluid boluses in patients with urolithiasis and acute renal colic has been a standardized practice in the emergency department as a part of a conservative approach. In theory, an intravenous fluid bolus may promote ureteral fluid flow. However, randomized, controlled trials have shown no benefit of fluid boluses in this setting. We assessed current fluid bolus practices in community and tertiary care emergency departments. We analyzed all emergency department visits in the Cleveland Clinic health care network with an ICD-9 diagnosis of 592.0 and computerized tomography of the abdomen/pelvis between December 7, 2010 and May 6, 2013. The incidence of intravenous fluid bolus administration was assessed, and patient demographics, serum laboratory values and urinalysis were collected. Cases with a blood urea nitrogen-to-creatinine ratio greater than 20 were considered hypovolemic and urine specific gravity values greater than 1.030 were considered suggestive of hypovolemia. Overall 60.2% (3,037 of 5,048) of patients with nephrolithiasis and computerized tomography received intravenous fluid boluses. The majority of patients who received a fluid bolus (79.12%) did not meet the criteria for volume depletion based on blood urea nitrogen-to-creatinine ratio or urine specific gravity. In addition, there was no statistically significant difference in the proportion of patients with a blood urea nitrogen-to-creatinine ratio greater than 20 among those who received fluid boluses (25.50%, 617 of 2,420) and those who did not (25.45%, 408 of 1,603; p=1.00). The use of forced fluids continues to be a common practice in emergency departments and they are frequently administered despite normal blood urea nitrogen-to-creatinine ratios. Thus, it is likely that fluids are not administered due to hypovolemia but rather due to practice approaches rooted in historical dogma and the lack of guidelines on this topic.


The effect of the flexibility of hydrogen bonding network on low-frequency motions of amino acids. Evidence from Terahertz spectroscopy and DFT calculations.
Low-frequency modes of L-Asp and L-Asn were studied in the range from 0.1 to 3.0THz using time-domain Terahertz spectroscopy and density functional theory calculation. The results show that PBE-D2 shows more success than BLYP-D2 in prediction of THz absorption spectra. To compare their low-frequency modes, we adopted "vibrational character ID strips" proposed by Schmuttenmaer and coworkers [Journal of Physical Chemistry B, 117, 10444(2013)]. We found that the most intense THz absorption peaks of two compounds both involve severe distortion of their hydrogen bonding networks. Due to less rigid hydrogen bonding network in L-Asp, the side chain (carboxyl group) of L-Asp exhibits larger motions than that (carboxamide group) of L-Asn in low-frequency modes.


[Sleep disorders in depression. Suggestions for a therapeutic approach].
Sleep disorder is one of the major symptoms in depression. It can be a risk factor, predictor, or symptom of depressive episodes. Successful therapy of sleep disorder in severely depressed patients can be a problem of its own. So far, there are few data from systematic studies. Definite treatment recommendations and strategies do not exist. The use of sleeping aids is mainly based on clinical experience and arbitrary treatment preferences. This article tries to summarize the difficulties of a rational therapeutic approach to dyssomnia in depressive patients. In addition to medical treatment, the basics of sleep hygiene should be considered. From a pharmacological point of view, sedating antidepressants, short-term add-on benzodiazepines or nonbenzodiazepines, and long-term add-on low potency neuroleptics are considered appropriate treatments. The combination with atypical sedating antipsychotics or low-dose tricyclic antidepressants may be helpful. Drugs which primarily work through serotonin and noradrenalin have negative effects on sleeping disorders since they suppress REM sleep. In contrast to that, GABAergic, antihistaminic, and anticholinergic effects are beneficial for inducing and maintaining sleep. Half-time, pharmacodynamic and pharmacokinetic effects and interactions, and influence of the drugs on reaction time and personal well-being have to be considered.


Ultrasonic B-scanning of the human skin. An introduction of a new ultrasonic skin-scanner.
A high frequency, high resolution dynamic ultrasonic skin-scanner is described. The skin-scanner is shown to give a cross-sectional image of the skin and provides an accurate, simple and non-invasive method for measuring full-thickness human skin. In addition to the skin thickness it is demonstrated that the underlying subcutaneous fat and muscles can also be non-invasively explored with the possibility of identifying a variety of skin and underlying tissue lesions.


LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity.
Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2-/- mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2Ser27 and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis.


Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: a prospective study. The Childhood Diabetes in Finland Study Group.
To study the possible temporal association between primary cytomegalovirus infection and the appearance of islet cell autoantibodies or the development of insulin-dependent diabetes mellitus (IDDM) cytomegalovirus antibodies were analysed from follow-up sera of 46 initially non-diabetic siblings of diabetic children who either manifested clinical IDDM (22 siblings) or turned islet cell antibody positive (24 siblings) during the prospective observation (mean follow-up time 2.9 years). Secondly, cytomegalovirus antibodies were analysed during pregnancy in 96 mothers whose child presented with IDDM before the age of 7 years and in 96 control mothers who gave birth to a non-diabetic child. Thirdly, a case-control series including 90 newly-diagnosed young children with IDDM and their 90 control subjects was analysed. No seroconversions were found in cytomegalovirus antibodies during the follow-up of the 46 siblings indicating no temporal association with islet cell antibody seroconversion or manifestation of clinical diabetes. During the follow-up 17 (37%) siblings were constantly seronegative and 29 (63%) seropositive for cytomegalovirus IgG and there was no difference between islet cell antibody positive and negative siblings. Cytomegalovirus IgG and IgM were not different in pregnant mothers who gave birth to a subsequently diabetic child compared to control mothers, or in newly-diagnosed diabetic children compared to control children. Cytomegalovirus IgA was higher in newly-diagnosed diabetic children than in control children (p < 0.005). This difference disappeared when only cytomegalovirus IgG positive individuals were analysed. No correlation was found between islet cell antibodies and cytomegalovirus antibodies in newly-diagnosed diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional recovery after ischemic stroke--a matter of age: data from the Austrian Stroke Unit Registry.
To analyze the association between patient age and good functional outcome after ischemic stroke with special focus on young patients who were numerically underrepresented in previous evaluations. Of 43,163 ischemic stroke patients prospectively enrolled in the Austrian Stroke Unit Registry, 6,084 (14.1%) were ≤55 years old. Functional outcome was available in a representative subsample of 14,256 patients free of prestroke disability, 2,223 of whom were 55 years or younger. Herein we analyzed the effects of age on good functional outcome 3 months after stroke (modified Rankin Scale score ≤2). Good outcome was achieved in 88.2% (unadjusted probability) of young stroke patients (≤55 years). In multivariable analysis, age emerged as a significant predictor of outcome independent of stroke severity, etiology, performance of thrombolysis, sex, risk factors, and stroke complications. When the age stratum 56-65 years was used as a reference, odds ratios (95% confidence interval [95% CI]) of good outcome were 3.4 (1.9-6.4), 2.2 (1.6-3.2), and 1.5 (1.2-1.9) for patients aged 18-35, 36-45, and 46-55 years and 0.70 (0.60-0.81), 0.32 (0.28-0.37), and 0.18 (0.14-0.22) for those aged 66-75, 76-85, and >85 years (p < 0.001). In absolute terms, the regression-adjusted probability of good outcome was highest in the age group 18-35 years and gradually declined by 3.1%-4.2% per decade until age 75 with a steep drop thereafter. Findings applied equally to sexes and patients with and without IV thrombolysis or diabetes. Age emerged as a highly significant inverse predictor of good functional outcome after ischemic stroke independent of stroke severity, characteristics, and complications with the age-outcome association exhibiting a nonlinear scale and extending to young stroke patients.


Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments.
Sixty-three patients with life-threatening digitalis intoxication were treated with purified fragments of digoxin-specific antibodies (Fab) obtained from sheep. Twenty-eight patients developed toxicity as the result of digitalis ingestion in a suicide attempt, 5 ingested a large amount of digoxin accidentally and 30 developed toxicity in the course of treatment for underlying heart disease. The dosage of digoxin-specific Fab was calculated to be equimolar to the amount of cardiac glycoside in the patient's body. Digitalis toxicity was completely reversed in most cases, with onset of effect usually within 30 minutes of administration of Fab fragments. Unbound and, therefore, active digoxin serum concentrations decreased to undetectable levels within minutes after administration of the fragments. In all patients who had elevated serum potassium concentrations caused by massive digitalis toxicity, treatment with the Fab fragments reversed the hyperkalemia. There were no obvious adverse reactions to treatment. Potentially life-threatening digitalis intoxication can be rapidly and safely reversed by treatment with purified digoxin-specific Fab fragments.


Life before birth: effects of cortisol on future cardiovascular and metabolic function.
The concept of fetal programming is an area that is now under rigorous investigation in many laboratories throughout the world. We need to engender a fascination in all segments of society, not just pregnant women, about life in the womb. Everyone needs to understand that improving the condition of the fetus will have personal, social and economic benefits. The time has come to realize that, in a sense, it is not just women who are pregnant but it is the family and the whole of society.


Detection of Ki-ras and p53 mutations by laser capture microdissection/PCR/SSCP.
Efficient detection of somatic mutations is important for the development of clinical molecular diagnostic assays. However, the detection of somatic mutations in tissue is confounded by dilution of the tumor cell population by normal cells. Laser microdissection allows enrichment for tumor-associated genetic alterations to take place at the level of cell selection, eliminating the need to enrich for mutant alleles after amplification. In this chapter a method is described for somatic mutation analysis using cells acquired by laser capture microdissection.


Ascorbic acid modulates testicular toxicity of Ampligo® 150 ZC insecticide in male rabbit (Oryctolagus cuniculus).
The present study was designed to evaluate the protective effects of ascorbic acid (AA) against lambda cyhalothrin insecticide formulation Ampligo® (AP)-induced testicular toxicity in rabbit laboratory strain ITELV2006 (Oryctolagus cuniculus). Twenty rabbits were randomly divided into four equal groups and treated by oral gavage for 21 consecutive days: Group 1 served as a control and received 1 ml of distilled water, group 2 was supplemented with1ml of ascorbic acid (AA) dilution (200 mg/kg b.w), Group 3 was treated with a dose of AP at 20 mg/kg bw (1 µl/1 ml of distilled water/animal), whereas group 4 was co-administered AA and AP as the same dose of group 2 and 3, respectively. Hormonal, histomorphometrical, and immunohistochemical methods were performed at the end of the study to detect testes damage. The results showed that AP exposure significantly reduced body weight, absolute and relative testicular weights, and testosterone levels. AP caused changes in testes tissue, namely incomplete spermatogenic series and necrosis of the spermatogonial cells lining in the seminiferous tubules of rabbits. Co-administrating AA clearly modulated body and testes weights, hormonal parameters, and histopathological damage. Furthermore, the findings revealed a significant increase in alpha-fetoprotein (AFP) level expression in the testes of the AP group. However, supplementation of the AP rabbits with AA modulated the observed result. Taken together, these data suggest that AA may protect against Ampligo-induced testicular damage.


COVID-19-Related Facilitators and Barriers to In-Person Learning for Children With Intellectual and Development Disabilities.
Schools provide essential functions for children with intellectual and developmental disabilities (IDD), but their vulnerability to infection with SARS-CoV-2 are a barrier to in-person learning. This qualitative study aimed to understand how weekly SARS-CoV-2 screening testing of students and staff could best facilitate in-school learning during the pandemic. Thirty-one focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2020-2021 school year. Responses were analyzed using a directed thematic content analysis approach. Five principal themes were identified: risks of returning to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; messaging strategies; and preferred messengers. Staff and families agreed that saliva-based SARS-CoV-2 screening testing helps increase comfort with in-person learning. Screening testing increased family and school staff comfort with in-person learning particularly because many students with special needs cannot adhere to public health guidelines. To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important, particularly for students that cannot adhere to mitigation guidelines.


Dynamic changes in resilience among family caregivers in the face of healthcare challenges: A scoping review.
Resilience as a dynamic concept has already been described through various longitudinal studies. To better understand the changes in the resilience of caregivers over the course of care-providing, however, a scoping review can provide a clearer picture of their resilience process which, in turn, can be used to improve caregivers' well-being. To provide a comprehensive overview of dynamic change in the resilience of caregivers while caring for the family to enhance understanding and potential for future research. Following the methodological framework of Arksey and O'Malley, this scoping review was conducted using the Preferred Reporting Items for Systematic Reviews and the Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. Five electronic databases were searched for research published in English between January 2012 and May 2022, after which a manual search was performed. Key terms related to resilience and caregivers in longitudinal studies were included and screened for. Identified trajectories of patterns in resilience and factors associated with resilience process were categorized using content analysis. In total, 24 longitudinal studies met the eligibility criteria. Conceptually, our findings demonstrate three modes of change following healthcare challenges, each of which varies substantially. Methodologically, the results reveal three subcategories of assessment tools that can be used to impact caregivers' resilience when confronted with significant healthcare challenges. Consequentially, personal traits and environmental resources interacting with the resilience process will then lead to various outcomes in their resilience, including stability, growth, or decline. This review describes the change patterns of the resilience process, assessment instruments, and associated factors to offer a dynamic perspective for the investigation and intervention of psychological resilience. Major gaps nonetheless remain for future research regarding an operationalizing dynamic change in resilience.


Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors.
Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.


Effects of the Advanced Innovative Internet-Based Communication Education Program on Promoting Communication Between Nurses and Patients With Dementia.
Effective communication between nurses and patients with dementia promotes the quality of patient care by improving the identification of patient needs and by reducing the miscommunication-related frustration of patients and nurses. This study evaluates the effects of an advanced innovative Internet-based communication education (AIICE) program on nurses' communication knowledge, attitudes, frequency of assessing patient communication capacity, and communication performance in the context of care for patients with dementia. In addition, this study attempts to evaluate the indirect effects of this program on outcomes for patients with dementia, including memory and behavior-related problems and depressive symptoms. A quasi-experimental research design with a one-group repeated measure was conducted. Convenience sampling was used to recruit nurses from long-term care facilities in southern Taiwan. Data were analyzed using general estimating equations to compare changes over time across three points: baseline, fourth-week posttest, and 16th-week posttest. One hundred five nurses completed the AIICE program and the posttest surveys. The findings indicate that nurses' communication knowledge, frequency in assessing patients' communication capacity, and communication performance had improved significantly over the baseline by either the 4th- or 16th-week posttest (p < .01). However, communication attitude showed no significant improvement in the posttest survey (p = .40). Furthermore, the findings indicate that the memory and behavior-related problems and the depressive symptoms of patients had decreased significantly by the 16th-week posttest (p = .05). This study showed that the AIICE program improves nurses' communication knowledge, frequency to assess patients' communication capacity, and communication performance and alleviates the memory and behavior-related problems and depressive symptoms of patients. The continuous communication training of nurses using the AIICE program is thus recommended.


Anaesthesia for excision of an intraoral mass in a neonate: use of a laryngeal mask during removal of congenital epulis.
Congenital epulis is a rare intraoral tumour of the newborn arising from gingival mucosa, most commonly from the alveolar ridge. It may interfere with normal feeding or potentially compromise respiration. We describe the anaesthetic management of one such case of a female infant born with a single epulis, approximately 3 cm in diameter, protruding from her mouth. The lesion was removed one day after delivery, under general anaesthesia using a laryngeal mask airway to control the infant's airway. The rationale for this management plan and alternatives to this strategy are discussed.


Analysis of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and its brominated analogues in chlorine-treated water by gas chromatography coupled to triple quadrupole tandem mass spectrometry (GC-QqQ-MS/MS).
A simple, selective and sensitive method for the analysis of the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and its brominated analogues (BMXs) in chlorine-treated water has been developed. The method is based on gas chromatography coupled to triple quadrupole tandem mass spectrometry (GC-QqQ-MS/MS), previous liquid-liquid extraction (LLE) of a smaller sample volume compared to other methods and on-line derivatization with a silylation reactive. GC-QqQ-MS/MS has been raised as an alternative easier to perform than gas chromatography coupled to high resolution mass spectrometry (GC-HRMS) for the analysis of MX and BMXs, and it allows to achieve low LODs (0.3 ng/L for MX and 0.4-0.9 ng/L for BMXs). This technique had not been previously described for the analysis of MX and BMXs. Quality parameters were calculated and real samples related to 3 drinking water treatment plants (DWTPs), tap water and both untreated and chlorinated groundwater were analyzed. Concentrations of 0.3-6.6 ng/L for MX and 1.0-7.3 ng/L for BMXs were detected. Results were discussed according to five of the main factors affecting MX and BMXs formation in chlorine-treated water (organic precursors, influence of bromide ions, evolution of MX and BMXs in the drinking water distribution system, groundwater chlorination and infiltration of water coming from chlorination processes in groundwater).