New immature hominin fossil from European Lower Pleistocene shows the earliest evidence of a modern human dental development pattern.
Here we present data concerning the pattern of dental development derived from the microcomputed tomography (microCT) study of a recently discovered immature hominin mandible with a mixed dentition recovered from the TD6 level of the Gran Dolina Lower Pleistocene cave site in Sierra de Atapuerca, northern Spain. These data confirm our previous results that nearly 1 million years ago at least one European hominin species had a fully modern pattern of dental development with a clear slowdown in the development of the molar field regarding the anterior dental field. Furthermore, using available information about enamel formation times and root extension rates in chimpanzees, early hominins, and modern humans, we have estimated that the formation time of the upper and lower first molars of individual 5 (H5) from TD6, which had just erupted at the time of the death of this individual, ranges between 5.3 and 6.6 y. Therefore, the eruption time of the first permanent molars (M1) in the TD6 hominins was within the range of variation of modern human populations. Because the time of M1 eruption in primates is a robust marker of life history, we suggest, as a working hypothesis, that these hominins had a prolonged childhood in the range of the variation of modern humans. If this hypothesis is true, it implies that the appearance in Homo of this important developmental biological feature and an associated increase in brain size preceded the development of the neocortical areas leading to the cognitive capabilities that are thought to be exclusive to Homo sapiens.


A qualitative study of the adoption of buprenorphine for opioid addiction treatment.
Qualified physicians may prescribe buprenorphine to treat opioid dependence, but medication use remains controversial. We examined adoption of buprenorphine in two not-for-profit integrated health plans, over time, completing 101 semi-structured interviews with clinicians and clinician-administrators from primary and specialty care. Transcripts were reviewed, coded, and analyzed. A strong leader championing the new treatment was critical for adoption in both health plans. Once clinicians began using buprenorphine, patients' and other clinicians' experiences affected decisions more than did the champion. With experience, protocols developed to manage unsuccessful patients and changed to support maintenance rather than detoxification. Diffusion outside addiction and mental health settings was nonexistent; primary care clinicians cited scope-of-practice issues and referred patients to specialty care. With greater diffusion came questions about long-term use and safety. Recognizing how implementation processes develop may suggest where, when, and how to best expend resources to increase adoption of such treatments.


Appropriate Insulin Level in Selecting Fortified Diet-Fed, Streptozotocin-Treated Rat Model of Type 2 Diabetes for Anti-Diabetic Studies.
Pathophysiological investigation of disease in a suitable animal model is a classical approach towards development of a credible therapeutic strategy. This study examined appropriate insulin level in selecting animal model for type 2 diabetes (T2D) studies. Albino Wistar rats (150-200g) were divided into two groups fed with commercially available normal-diet-feed (NDF) and water or fortified diet feed (FDF) (10g NDF per gram of margarine) with 20% fructose solution as drinking water. After 6 weeks of dietary regimen both groups were divided into 5 sub-groups and injected intraperitoneally with a graded dose of streptozotocin (STZ) (0, 25, 35, 45 & 55mg/kg bw.). The result showed that the FDF-fed rats increased significantly in body weight, basal serum insulin, total cholesterol, triglycerides and blood glucose levels as compared to NDF-fed rats. Ten days post STZ induction, the groups treated with STZ (45 & 55 mg/kg) developed frank hyperglycaemia with < 46.8% serum insulin, a severe deficiency typical of diabetes type 1. The NDF25 and NDF35 groups with 75.7% and 64.4% serum insulin respectively presented relative normoglycemia, whereas the FDF35 (85.8% serum insulin) were notably hyperglycaemia (>300 mg/dL) throughout the 6weeks post diabetes confirmation. These FDF35 rats were sensitive to glibenclamide, metformin and pioglitazone in lowering hyperglycaemia, hypertriglyceridemia and hypercholesterolemia. The hyperglycaemia stability of the FDF35 rats (85.5% insulin) together with their sensitivity to 3 different hypoglycaemic drugs strongly suggests their suitability as a non-genetic model of T2D. Hence the study shows that circulating serum insulin ≥ 85.8% with overt hyperglycaemia may be utilized as the benchmark in selecting rat models for T2D studies.


The production and degradation of trichloroacetic acid in soil: results from in situ soil column experiments.
Previous work has indicated that the soil is important to understanding biogeochemical fluxes of trichloroacetic acid (TCA) in the rural environment, in forests in particular. Here, the hydrological and TCA fluxes through 22 in situ soil columns in a forest and moorland-covered catchment and an agricultural grassland field in Scotland were monitored every 2 weeks for several months either as controls or in TCA manipulation (artificial dosing) experiments. This was supplemented by laboratory experiments with radioactively-labelled TCA and with irradiated (sterilised) soil columns. Control in situ forest soil columns showed evidence of net export (i.e. in situ production) of TCA, consistent with a net soil TCA production inferred from forest-scale mass balance estimations. At the same time, there was also clear evidence of substantial in situ degradation within the soil ( approximately 70% on average) of applied TCA. The laboratory experiments showed that both the formation and degradation processes operate on time scales of up to a few days and appeared related more with biological rather than abiotic processes. Soil TCA activity was greater in more organic-rich soils, particularly within forests, and there was strong correlation between TCA and soil biomass carbon content. Overall it appears that TCA soil processes exemplify the substantial natural biogeochemical cycling of chlorine within soils, independent of any anthropogenic chlorine flux.


[Direct determination of phenylalanine in serum by derivative spectrophotometry (author's transl)].
A simple and precise method is described for the determination of phenylalanine in serum or plasma, using derivative spectrophotometry. After the removal of protein and uric acid, 100 microliters serum or plasma are analysed directly for phenylalanine. The magnitude of the difference between the peak minimum at 254 nm and the peak maximum at 257 nm of the derivative spectrum (2nd derivative of the absorption spectrum) is directly proportional to the phenylalanine content. The precision was 2.1-10.3%, depending on the concentration of phenylalanine. Recovery was between 97.1 and 101.1%. Sensitivity was 5 mg/l serum. The method was compared with a column chromatographic determination of phenylalanine.


[Decitabine treatment in myelodysplastic syndromes--results of a compassionate patient program in Israel].
Hypermethylation of tumor suppressor genes (TSG) has been recognized as an important factor in the pathogenesis of malignancies, including myelodysplastic syndromes (MDS). Decitabine (trade name Dacogen; 5-aza-2'-deoxycytidine) is a cytosine analog which inhibits the enzyme DNA methyltransferase (DNMT), inducing hypomethylation and activates TSG, leading to tumor cell growth inhibition. In clinical trials with hypomethylating agents in advanced MDS, a total response rate of 30-73% has been observed, with a complete response (CR) of 9-37%, partial response (PR] of similar rate and a hematologic improvement (HI] in 20-48% of the patients. We report the results of a national Israeli compassionate program of decitabine administration to patients with advanced MDS. From July 2007 through August 2008, under the joint sponsorship of The Israel Society of Hematology and Blood Transfusions and Janssen, Israel, a compassionate program was conducted. Decitabine was administered to patients with advanced MDS who were not candidates for any other anti-MDS treatment, except for supportive care. The selected regimen was a 5-day intravenous administration of 20 mg/m/d, every 28 days. After the program had been completed, an approval of the institutional Helsinki committees was obtained, and the data were collected in an attempt to evaluate the results of this novel treatment. The standard response criteria, i.e. total response, CR, PR and HI were applied. Toxicity, survival and leukemic transformation rate were also analyzed. Twenty-four patients with advanced MDS participated in the program but evaluable information could be collected only on 17 patients. The median number of therapeutic cycles was two per patient. Twelve patients were transfusion-dependent at program onset, of whom 7 either benefited from reduced transfusion requirements or became transfusion-free. The overall response rate was 26%, with 23% PR and 13% HI. Two patients (13%) demonstrated leukemic transformation. The median overall survival was 17 months and the median event-free survival was 13 months. Nine out of 12 patients, who could be evaluated, experienced 3-4 degree bone marrow suppression. A single patient suffered from vocal cord paralysis, apparently, unrelated to the treatment. The overall response rate was 26% in this national compassionate program of decitabine administration to patients with advanced MDS. Although somewhat low, this is similar to other reports. Possible reasons for the relatively low response rate include a small number of patients, the nature of a compassionate program, the limited number of therapeutic cycles, and the very advanced degree of the disease in most patients who had been on several treatment lines prior to the program. Nevertheless, understanding the role of epigenetics in the pathogenesis of neoplasms and MDS, which led to the introduction of hypomethylation agents such as decitabine into clinical practice, is an encouraging step towards better care of cancer, including MDS.


Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed.
There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy. Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101). Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups. Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.


Widening disparity in survival between white and African-American patients with breast carcinoma treated in the U. S. Department of Defense Healthcare system.
In the U. S., age-adjusted breast carcinoma mortality rates among white and African-American women have been diverging during the last 20 years. Some investigators speculate that the widening disparity is due to inequalities in access to healthcare, with African Americans having less access to necessary healthcare and improved therapies. Others argue that differences in tumor biology or some extrinsic influences on cancer etiology and behavior may account for the widening disparity. To examine this issue further, the authors compared trends in survival among white and African-American women diagnosed with breast carcinoma in the U. S. Department of Defense (DoD), an equal access healthcare system. The medical records of all women diagnosed with primary breast carcinoma between 1980-1999 were retrieved from the U. S. DoD Automated Central Tumor Registry (ACTUR). Variables selected for further analysis were date of diagnosis, date of birth, vital status and date of death if applicable, race (black, white, and others), and stage of tumor. Because the database does not contain causes of death, overall survival was investigated. The effect of year of diagnosis and race on overall survival was analyzed using the Cox proportional hazards model stratified by age at diagnosis (1-year age groups). Calculations were performed separately by disease stage for all stages combined and stratified by stage. Statistical analyses were performed using the statistical software package SAS. After deleting observations with missing or implausible information regarding patient age, gender, and follow-up time, the final dataset was comprised of 23,612 women with primary breast carcinoma. The survival of African-American women compared with white women demonstrated an increasing ratio with calendar period. Although the hazard ratio was 1.269 for women diagnosed with breast carcinoma during the calendar period 1980-1984, it increased to 1.849 for those diagnosed between 1995-1999, which is a ratio of 1.46. For this period, the interaction between race and period was found to be significant (P = 0.04). The results of the current study demonstrated that breast carcinoma survival rates among white and African-American patients, adjusted for age and stage, are diverging in the U. S. DoD healthcare system. Thus, inequalities in access to healthcare most likely are not solely responsible for the widening racial disparities in outcome reported among women diagnosed with breast carcinoma.


First description of phosphofructokinase deficiency in spain: identification of a novel homozygous missense mutation in the PFKM gene.
Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain.


Comparison of two methods for detection of transmissible gastroenteritis virus in feces of pigs with experimentally induced infection.
An indirect, double-antibody sandwich-type ELISA for detection of transmissible gastroenteritis virus (TGEV) was developed, using a solid phase of rabbit hyperimmune serum and a pool of 3 antipeplomer monoclonal antibodies to trap and to detect the virus, respectively. The technique was used to detect viral antigen in feces of pigs that had been infected with the virulent Miller strain, the attenuated Purdue strain, or the Erica strain (a Dutch field isolate) of TGEV. The results were compared with those of a solid-phase immunosorbent electron microscopy (SPIEM) technique for virus detection. Both techniques detected shedding of virulent virus in feces obtained from pigs on the first or second day after infection, and virus excretion continued for 6 to 8 consecutive days. Virus shedding started later in pigs infected with the attenuated Purdue strain of TGEV and lasted only 2 to 4 days. In comparison with the 2 virulent strains, infection with the attenuated strain appeared to be limited to a smaller portion of the small intestine. Of 242 fecal specimens that were tested by use of ELISA and SPIEM, 119 had positive results in both tests. Additionally, virus could be detected by ELISA in 21 and by SPIEM in 16 specimens. Fecal specimens obtained from pigs before infection always reacted negatively by ELISA for TGEV antigen; there was no cross-reactivity with fecal specimens containing porcine rotavirus or porcine epidemic diarrhea virus. The ELISA and SPIEM were found to be specific and sensitive for the detection of TGEV in feces.


Smoking, smoking cessation, and risk of sudden cardiac death in women.
Few prospective studies have examined quantitative cigarette consumption and smoking cessation on sudden cardiac death (SCD) risk with long-term follow-up. We prospectively examined the association between cigarette smoking and smoking cessation on the risk of SCD among 101 018 women participating in the Nurses' Health Study without known coronary heart disease, stroke, and cancer at baseline 1980. During 30 years of follow-up, we identified 351 SCD events. Compared with never smokers, current smokers had a 2.44-fold (95% CI, 1.80-3.31) increased risk of SCD after controlling for coronary risk factors. In multivariable analyses, quantity of cigarettes smoked daily (P value for trend, <0.0001) and smoking duration (P value for trend, <0.0001) were linearly associated with SCD risk among current smokers. Small-to-moderate amounts of cigarette consumption (1-14 per day) were associated with a significant 1.84-fold (95% CI, 1.16-2.92) increase in SCD risk and every 5 years of continued smoking was associated with an 8% increase in SCD risk (hazard ratio, 1.08; 95% CI, 1.05-1.12; P<0.0001). The SCD risk linearly decreased over time after quitting and was equivalent to that of a never smoker after 20 years of cessation (P value for trend, <0.0001). In this large prospective cohort of women without coronary heart disease at baseline, a strong dose-response relationship between cigarette smoking and SCD risk was observed, and smoking cessation significantly reduced and eventually eliminated excess SCD risk. This suggests efforts to prevent SCD among women should include aggressive strategies for smoking cessation.


Target Specificity of the CRISPR-Cas9 System in Arabidopsis thaliana, Oryza sativa, and Glycine max Genomes.
Clustered regularly interspaced short palindromic repeats (CRISPR), a class of immune-associated sequences in bacteria, have been developed as a powerful tool for editing eukaryotic genomes in diverse cells and organisms in recent years. The CRISPR-Cas9 system can recognize upstream 20 nucleotides (guide sequence) adjacent to the protospacer-adjacent motif site and trigger double-stranded DNA cleavage as well as DNA repair mechanisms, which eventually result in knockout, knockin, or site-specific mutagenesis. However, off-target effect caused by guide sequence misrecognition is the major drawback and restricts its widespread application. In this study, global analysis of specificities of all guide sequences in Arabidopsis thaliana, Oryza sativa (rice), and Glycine max (soybean) were performed. As a result, a simple pipeline and three genome-wide databases were established and shared for the scientific society. For each target site of CRISPR-Cas9, specificity score and off-target number were calculated and evaluated. The mean values of off-target numbers for A. thaliana, rice, and soybean were determined as 27.5, 57.3, and 174.7, respectively. Comparative analysis among these plants suggested that the frequency of off-target effects was correlated to genome size, chromosomal locus, gene density, and guanine-cytosine (GC) content. Our results contributed to the better understanding of CRISPR-Cas9 system in plants and would help to minimize the off-target effect during its applications in the future.


The effect of virtual reality on pain, kinesiophobia and function in total knee arthroplasty patients: A randomized controlled trial.
Virtual reality (VR) has emerged as a promising new therapeutic approach, showing promise in the treatment of patients with a variety of diseases. This study aimed to investigate the effect of VR on pain, kinesiophobia, and function in patients undergoing total knee arthroplasty (TKA). This randomized controlled trial was performed on patients who had TKA due to osteoarthritis at Gazi University Hospital from October 2019 to August 2021. For this study, 21 female TKA patients were divided into two groups by the blocked randomization method: VR (n = 10) and exercise (n = 11). The exercise group was given a home exercise program. The VR group received immersive VR application in addition to the exercise. Pain, kinesiophobia, pain catastrophizing, knee range of motion, functional status, and quality of life were assessed. The Wilcoxon Test and Mann-Whitney U Test were used for comparison of the results. The VR group had a statistically significant difference in the intensity of pain at rest, at night, and during the Timed Up and Go Test (TUG), kinesiophobia, pain catastrophizing, active knee flexion, the TUG, and the stair-climb test scores (P = 0.005 (95% confidence interval (CI) (-5.000, -1.000)), P = 0.005 (95% CI (-7.000, -2.000)), P = 0.023 (95% CI (-4.000, 0)), P = 0.006 (95% CI (-15.000, -3.000)), P = 0.012 (95% CI (-19.000, -3.000)), P = 0.010 (95% CI (4.000, 17.333)), P = 0.017 (95% CI (-14.700, -0.850)), P = 0.011 (95% CI (-23.100, -1.000)), respectively). In the early period following total knee arthroplasty, using virtual reality integrated with exercise helps to reduce pain, kinesiophobia and pain catastrophizing, and to improve functional outcomes in female patients.


B cell-activating factor is a novel diagnosis parameter for asthma.
Asthma is a life-threatening immediate-type allergic disease. B cell-activating factor (BAFF) is a key regulator of B lymphocyte development and is required to generate and maintain the mature B cell pool. To investigate the level of BAFF in the serum of asthma patients and the role of BAFF on T cells. The BAFF level was measured by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMC) from asthma patients were analyzed by flow cytometry. T8.1 cells were used to test the role of BAFF on T cell-antigen-presenting cell (APC) conjugate formation. The BAFF level in patient serum was elevated relative to normal serum. Immunoglobulin E (IgE) concentration and the percentage of CD3+ T and CD19+ B cells vary according to the serum BAFF level. Patients with high BAFF and high IgE (group II) and those with high BAFF and low IgE (group III) show a high ratio of CD3+ T to CD19+ B cells, and the opposite is seen for patients with low BAFF and high IgE (group I) and those with low BAFF and low IgE (group IV). The addition of BAFF increased PBMC proliferation and T cell-APC conjugate formation. BAFF concentration in serum decreased after treatment with antiasthmatic drugs including glucocorticoids and immunosuppressants. These findings suggest that the serum BAFF level is high in both IgE-mediated asthma and non-IgE-mediated asthma and extend our knowledge about the fact that BAFF may play a stimulatory role on the proliferation of T cells. Thus, BAFF could be a parameter to monitor the severity of asthma symptoms.


Anterior thalamus deep brain stimulation at high current impairs memory in rats.
Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS.


Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.
A defect in urine concentrating ability occurs in individuals with sickle cell trait (HbAS). This may result from intracellular polymerization of sickle hemoglobin (HbS) in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. To test the hypothesis that the severity of the concentrating defect is related to the percentage of sickle hemoglobin present in erythrocytes, urinary concentrating ability was examined after overnight water deprivation, and intranasal desmopressin acetate (dDAVP) in 27 individuals with HbAS. The HbAS individuals were separated into those who had a normal alpha-globin genotype (alpha alpha/alpha alpha), and those who were either heterozygous (-alpha/alpha alpha) or homozygous (-alpha/-alpha) for gene-deletion alpha-thalassemia, because alpha-thalassemia modulates the HbS concentration in HbAS. The urinary concentrating ability was less in the alpha alpha/alpha alpha genotype than in the -alpha/alpha alpha or -alpha/-alpha genotypes (P less than 0.05). After dDAVP, the urine osmolality was greater in patients with the -alpha/-alpha genotype than with the -alpha/alpha alpha genotype (882 +/- 37 vs. 672 +/- 38 mOsm/kg H2O) (P less than 0.05); patients with the -alpha/alpha alpha genotype had greater concentrating ability than individuals with a normal alpha-globin gene arrangement. There was an inverse linear correlation between urinary osmolality after dDAVP and the percentage HbS in all patients studied (r = -0.654; P less than 0.05). A linear correlation also existed for urine concentrating ability and the calculated polymerization tendencies for an oxygen saturation of 0.4 and O (r = -0.62 and 0.69, respectively). We conclude that the severity of hyposthenuria in HbAS is heterogeneous. It is determined by the amount of HbS polymer, that in turn is dependent upon the percentage HbS, which is itself related to the alpha-globin genotype.


Systematic Review of Normal Subjects Harbouring BCR-ABL1 Fusion Gene.
The treatment of chronic myeloid leukaemia (CML) requires quantitative polymerase chain reaction (qPCR) to monitor BCR-ABL1 in International Scale (IS). Some normal subjects were found to harbour BCR-ABL1. We performed a systematic review on normal subjects harbouring BCR-ABL1. A literature search was done on July 16, 2017 using EBSCOhost Research Databases interface and Western Pacific Region Index Medicus. Two authors selected the studies, extracted the data, and evaluated the quality of studies using the modified Appraisal Tool for Cross-Sectional Studies independently. The outcomes were prevalence, level of BCR-ABL1IS, proportion, and time of progression to CML. The initial search returned 4,770 studies. Eleven studies, all having used convenient sampling, were included, with total of 1,360 subjects. Ten studies used qualitative PCR and one used qPCR (not IS). The mean prevalence of M-BCR was 5.9, 15.5, and 15.9% in cord blood/newborns/infants (CB/NB/I) (n = 170), children (n = 90), and adults (n = 454), respectively, while m-BCR was 15, 26.9, and 23.1% in CB/NB/I (n = 786), children (n = 67), and adults (n = 208), respectively. No study reported the proportion and time of progression to CML. Nine studies were graded as moderate quality, one study as poor quality, and one study as unacceptable. The result of the studies could neither be inferred to the general normal population nor compared. Follow-up data were scarce.


Fruit and vegetable consumption and all-cause mortality: a dose-response analysis.
The association between fruit and vegetable (FV) consumption and overall mortality has seldom been investigated in large cohort studies. Findings from the few available studies are inconsistent. The objective was to examine the dose-response relation between FV consumption and mortality, in terms of both time and rate, in a large prospective cohort of Swedish men and women. FV consumption was assessed through a self-administrated questionnaire in a population-based cohort of 71,706 participants (38,221 men and 33,485 women) aged 45-83 y. We performed a dose-response analysis to evaluate 10th survival percentile differences (PDs) by using Laplace regression and estimated HRs by using Cox regression. During 13 y of follow-up, 11,439 deaths (6803 men and 4636 women) occurred in the cohort. In comparison with 5 servings FV/d, a lower consumption was progressively associated with shorter survival and higher mortality rates. Those who never consumed FV lived 3 y shorter (PD: -37 mo; 95% CI: -58, -16 mo) and had a 53% higher mortality rate (HR: 1.53; 95% CI: 1.19, 1.99) than did those who consumed 5 servings FV/d. Consideration of fruit and vegetables separately showed that those who never consumed fruit lived 19 mo shorter (PD: -19 mo; 95% CI: -29, -10 mo) than did those who ate 1 fruit/d. Participants who consumed 3 vegetables/d lived 32 mo longer than did those who never consumed vegetables (PD: 32 mo; 96% CI: 13, 51 mo). FV consumption <5 servings/d is associated with progressively shorter survival and higher mortality rates. The Swedish Mammography Cohort and the Cohort of Swedish Men were registered at clinicaltrials.gov as NCT01127698 and NCT01127711, respectively.


Induction of apoptosis by the Vpr protein of human immunodeficiency virus type 1 occurs independently of G(2) arrest of the cell cycle.
The HIV-1 accessory gene product Vpr can inhibit cell proliferation via cell cycle arrest at the G(2) phase, and it can induce apoptosis after G(2) arrest. We found recently that C81, a carboxy-terminally truncated form of Vpr, induced apoptosis via G(1) arrest but did not induce G(2) arrest of the cell cycle. Thus, it seemed possible that expression of Vpr in cells might cause apoptosis independently of the ability of Vpr to induce G(2) arrest. We demonstrate here that Vpr-induced apoptosis occurs by a mechanism that does not necessarily require induction of G(2) arrest. First, it was found that the extent of apoptosis reached a maximum even when few cells were arrested at the G(2) phase of the cell cycle and was reduced in inverse proportion to the increased induction of G(2) arrest. Thus, the extent of induction of G(2) arrest was not correlated with the extent of Vpr-induced apoptosis. Furthermore, we replaced the Ile/Leu residues in the leucine zipper-like domain of Vpr with Ala or Pro and used cells that expressed the mutant protein to demonstrate that Vpr caused apoptosis in a manner that was independent of G(2) arrest. Finally, replacement of Ile/Leu by Pro at positions 60, 67, 74, and 81 within the leucine zipper-like domain of wild-type Vpr and C81 revealed that the Ile/Leu residues at positions 60, 67, and 74 in the leucine zipper-like domain were indispensable for induction of apoptosis induced by Vpr and by C81 and confirmed, in addition, that both processes might be regulated by the same pathway. C81 appears to be a useful tool for elucidation of the mechanism of apoptosis induced by expression of Vpr protein.


[Laparoscopic treatment of common bile duct lithiasis].
With the advances of videolaparoscopic surgery, this approach had become the treatment of choice for cholelithiasis. However, about 5% to 10% may present common bile duct lithiasis. Most surgeons have still difficulties to deal with this situation and do prefer resolve with open surgery or with further endoscopic approach. We present a case of a 60-year-old man, with 18 months history of right upper quadrant pain, weight loss and jaundice. He was referred with diagnostic of pancreatic cancer. Laboratory investigation showed increased bilirubin (10 mg/dL), alkaline phosphatase and GGT. Abdominal ultrasound showed atrophic gallbladder with dilated intra and extrahepatic biliary tree. Computerized tomography scan disclosed enlarged biliary tree with 3 cm stone in the distal common bile duct. The patient underwent a laparoscopic cholecystectomy followed by choledochotomy and retrieval of the large stone. A latero-lateral choledochoduodenum anastomosis was then performed to decompress the biliary tree. The patient had an uneventful recovery being discharged at the 6th postoperative day. Laparoscopic management of choledocholithiasis is feasible in many patients, specially those with dilated biliary tree. The retrieval of stones may be followed by biliary drainage with T-tube. In some elderly patients with chronically dilated common bile duct, as in the present case, a choledochoduodenal anastomosis is the procedure of choice.


Characterization of the cell kinetics and growth properties of cystic fibrosis diploid fibroblasts in vitro.
The population growth kinetics of human diploid skin fibroblasts derived from cystic fibrosis homozygotes and heterozygotes and from normal subjects were investigated. Our data suggest the following: 1. Population doubling times increase with time in culture, with no significant differences observed among the three genotypes tested, when data were compared at the same subculture times or phases of growth. 2. The fraction of dividing cells in a population decreased with the duration in which the cells were in culture. No significant differences were obtained for cells derived from the three genotypes. 3. Cell cycle times were very similar (18-20 hr) when comparing the normal and cystic fibrosis lines or when comparing cystic fibrosis lines in phases 1 and 2 of growth. 4. No significant variations in population doubling times or growth fractions could be attributed to age or sex of the biopsy donor. 5. Variability in growth fractions and doubling times was minimal through the eighth subculture period but was very great in older cultures (tenth subculture). 6. Changes in growth fractions and doubling times appear to be due to the possibility of "aging" of human diploid fibroblasts in culture rather than to the presence or absence of genes for cystic fibrosis. 7. It is strongly indicated that differences in cell kinetic parameters cannot be used as the basis for differentiation between cells derived from normal or cystic fibrosis genotypes.


Overview perspective of bacterial resistance.
The rapidly escalating prevalence of antimicrobial resistance is a global concern. This reduced susceptibility to currently available antimicrobial agents coupled with the progressive shortage of newly approved compounds is a worrisome situation. Major problems are encountered for a growing number of Gram-positive (i.e., Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp.) and Gram-negative pathogens (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae). We provide an overview of bacterial resistance focusing on the most common pathogens responsible for infection in both the community and healthcare settings. In addition, several strategies to curb antimicrobial resistance are also discussed. It is increasingly evident that without the introduction of novel antimicrobial agents, a return to the clinical outcomes associated with the pre-antibiotic era are inevitable.


Betulinic acid is a PPARγ antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis.
PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARγ and PPARα antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARγ sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARγ, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases.


Contributions of electrogenic pumps to resting membrane potentials: the theory of electrogenic potentials.
Pumped and transported components of ionic flux have been added to passive electrodiffusive components. This permits the derivation of equations for the resting membrane potential that take account of electrogenic mechanisms in which the transport mechanism or pump itself produces a net ionic current. Such equations are general in that they apply to non-steady-state conditions in which intracellular ionic concentrations are changing. The equations developed allow calculation of resting membrane potentials in terms of ionic concentrations, membrane permeability to ions, and kinetic relations for pumped ionic fluxes. When applied to skeletal muscle fibers, the equations predict a buffering effect of the Na/K pump on the membrane potential over a wide range in the values [K]i and [Na]i such that a fairly constant membrane potential occurs under conditions in which the passive ionic fluxes themselves would produce increasing degrees of depolarization. A plot of the membrane potential versus log [K]o with an electrogenic Na pump present gives a curve with slopes both greater than and less than 58 mV per 10-fold concentration change. Over a middle range of [K]o values, the slope is 58 mV. The slope of Em versus log [K]o curves is, therefore, not a very sensitive test for the presence of an electrogenic pump. For the same internal ionic concentrations, less electrogenic increment in membrane potential is observed the higher the value of [K]o, and the more depolarized the membrane. This is due to a rectification present in the pump current-voltage curve, which requires that more pump current be present to produce a given membrane hyperpolarization at depolarized values of the potential than at hyperpolarized values of the potential. A gain in Na and a loss of K by the fibers affects the rectification curve in such a way that less pump current is required to produce the same degree of hyperpolarization. This mechanism ensures that adequate internal negativity will be maintained at high values of [Na]i and [K]o where saturation of the pumping rates might be expected. In the non-steady state of Na extrusion, the condition for which these equations were developed, it is clearly possible for the Na pump to generate potentials considerably higher than those generated under steady-state conditions. For steady-state conditions, both skeletal muscle and squid giant axon Na pumps generate additional internal negativity amounting to a few millivolts.(ABSTRACT TRUNCATED AT 400 WORDS)


Ambiguity and uncertainty: the ongoing concerns of male partners of women treated for breast cancer.
As the prevalence of breast cancer increases, survival improves and short stay or outpatient care become the norm, greater numbers of men will be involved in providing care and support for their partners at home. This qualitative study explored the experiences of 26 male partners of women who had completed treatment for breast cancer. A questionnaire was developed in order to collect background information and to provide a pool for further qualitative sampling. One hundred and five questionnaires were distributed, 79 returned and 26 one-to-one interviews were conducted. While negotiating a role in their wives' breast cancer experience the men attempted to find a balance between the ambiguity and uncertainty they experienced and their need to maintain normality. They described feeling 'in limbo' when expectations of being able to move on following their wives treatment were not fulfilled. An understanding of the 'liminal' experience of being a male partner of a woman with breast cancer may help health care professionals to address the ongoing difficulties men encounter. This is important as it is often the male partners who are called upon to provide continued care and support beyond the recognised treatment period.


Preoperative embolization versus local hemostatic agents in surgery of hypervascular spinal tumors.
Currently, there is no consensus about how to reduce the intraoperative risk of hemorrhage in spinal decompression surgery of hypervascular spinal tumors, such as aggressive hemangioma, multiple myeloma, plasmacytoma, metastasis of renal cell carcinoma. A retrospective study of 110 patients, operated in our institute was held in the period between 2003 and 2013. There were 69 male and 41 female patients with extradural hypervascular spinal tumor. The study included 61 patients with metastasis of renal cell carcinoma, 27 with multiple myeloma, 15 with plasmacytoma and 7 with aggressive hemangioma. The first group included 57 patients who underwent preoperative tumor embolization. The second group consisted of 53 patients, which were treated surgically using intraoperative local hemostatic agents. We performed 2 types of treatment options: palliative decompression and total spondylectomy. The first group was divided into two subgroups: 30 patients with palliative decompression (1PD) and 27 with total spondylectomy (1TS). In the second group there were: 28 patients with palliative decompression (2PD) and 25 with total spondylectomy (2TS). The parameters under evaluation were the blood loss volume, drainage loss, operation time, hemoglobin level, possible complications and time of hospital stay. The average intraoperative blood loss for all embolized patients was slightly less than in subgroups with local hemostatic agents. No significant difference in blood loss volume was found between groups 1PD and 2PD (p > 0.05). In groups 1TS and 2TS, we did get significant difference (p < 0.05). Statistically significant difference in the average drainage loss was found between two methods of hemostasis in both subgroups (p < 0.05). The operation time was not significantly different between groups. Postoperative hemoglobin level reduce is almost equal in both groups of patients. Postoperative complications were also nearly equal in the groups. The average hospital stay was significantly less (p < 0.05) in groups with 2PD and 2TS. The research proves that for patients with hypervascular spinal tumors, who underwent palliative decompression, there is no significant difference between two methods of reducing blood loss. Therefore, we do not see reasons to use expensive and risky procedure of embolization for such patients. While for patients with total spondylectomy preoperative embolization is efficient to reduce intraoperative bleeding.


Role of feedforward geniculate inputs in the generation of orientation selectivity in the cat's primary visual cortex.
Neurones of the mammalian primary visual cortex have the remarkable property of being selective for the orientation of visual contours. It has been controversial whether the selectivity arises from intracortical mechanisms, from the pattern of afferent connectivity from lateral geniculate nucleus (LGN) to cortical cells or from the sharpening of a bias that is already present in the responses of many geniculate cells. To investigate this, we employed a variation of an electrical stimulation protocol in the LGN that has been claimed to suppress intra cortical inputs and isolate the raw geniculocortical input to a striate cortical cell. Such stimulation led to a sharpening of the orientation sensitivity of geniculate cells themselves and some broadening of cortical orientation selectivity. These findings are consistent with the idea that non-specific inhibition of the signals from LGN cells which exhibit an orientation bias can generate the sharp orientation selectivity of primary visual cortical cells. This obviates the need for an excitatory convergence from geniculate cells whose receptive fields are arranged along a row in visual space as in the classical model and provides a framework for orientation sensitivity originating in the retina and getting sharpened through inhibition at higher levels of the visual pathway.


Initiation and maturation of I-Z-I bodies in the growth tips of transfected myotubes.
While over a dozen I-Z-I proteins are expressed in postmitotic myoblasts and myotubes it is unclear how, when, or where these first assemble into transitory I-Z-I bodies (thin filament/Z-band precursors) and, a short time later, into definitive I-Z-I bands. By double-staining the growth tips of transfected myotubes expressing (a) MYC-tagged s-alpha-actinins (MYC/s-alpha-actinins) or (b) green fluorescent protein-tagged titin cap (GFP/T-cap) with antibodies against MYC and I-Z-I band proteins, we found that the de novo assembly of I-Z-I bodies and their maturation into I-Z-I bands involved relatively concurrent, cooperative binding and reconfiguration of, at a minimum, 5 integral Z-band molecules. These included s-alpha-actinin, nebulin, titin, T-cap and alpha-actin. Resolution of the approximately 1.0 microm polarized alpha-actin/nebulin/tropomyosin/troponin thin filament complexes occurred subsequent to the maturation of Z-bands into a dense tetragonal configuration. Of particular interest is finding that mutant MYC/s-alpha-actinin peptides (a) lacking spectrin-like repeats 1-4, or consisting of spectrin-like repeats 1-4 only, as well as (b) mutants/fragments lacking titin or alpha-actin binding sites, were promptly and exclusively incorporated into de novo assembling I-Z-I bodies and definitive I-Z-I bands as was exogenous full length MYC/s-alpha-actinin or GFP/T-cap.


[Influence of nutritional status on the organism's response to infectious disease].
The nutritional status of a patient determines to a great extent his/her susceptibility and capacity in responding to infections. Protein and caloric malnutrition as well as many selective mineral and vitamin deficiencies deteriorate the immune and inflammatory metabolic response, increasing the frequency of infections and worsening their evolution and prognosis. Furthermore, recurrent infections can deteriorate nutritional status, with both problems forming a vicious circle that needs to be recognized for adequate treatment. This problem is not as foreign to us as we might think, given that many hospitalized patients as well as those with chronic diseases suffer from serious nutritional deficiencies. If we also take into account the proposition that the nutritional status of a patient can affect his/her response to treatment with antibiotics and vaccines, we realize then that not enough attention has been paid to this important public health risk factor to date.


Sputum screening by quantitative microscopy: a reexamination of a portion of the National Cancer Institute Cooperative Early Lung Cancer Study.
To investigate the hypothesis that image cytometry of sputum specimens can detect squamous carcinoma without requiring visually abnormal cells. The sensitivity and specificity of image cytometry were evaluated in a case-control study. Seventy-three sputum slides from the Mayo portion of the National Cancer Institute Cooperative Early Lung Cancer Study were restained by a modified Feulgen method. We examined 40 slides from 9 patients in whom squamous carcinoma developed and 33 slides from 11 patients in whom no cancer developed during a follow-up of at least 5 years. Images of normal epithelial nuclei were collected by using an automated image cytometer. Discriminant analysis was used to determine differences in DNA distribution of normal nuclei in sputum specimens from noncancer patients versus normal nuclei in sputum samples from patients in whom carcinoma developed. By using features based on DNA distribution, 74% correct classification of nuclei was possible without human review of the material and without the use of visually abnormal nuclei. A receiver operating characteristic curve demonstrated sensitivities and specificities, including 40% sensitivity and 90% specificity. Although this study was limited to 20-year-old slides and squamous cell carcinoma, automated image cytometry detected a substantial proportion of patients with squamous cell cancer without using visually abnormal nuclei.


Activity-dependent regulation of 'on' and 'off' responses in cat visual cortical receptive fields.
1. A supervised learning procedure was applied to individual cat area 17 neurons to test the possible role of neuronal co-activity in controlling the plasticity of the spatial 'on-off' organization of visual cortical receptive fields (RFs). 2. Differential pairing between visual input evoked in a fixed position of the RF and preset levels of postsynaptic firing (imposed iontophoretically) were used alternately to boost the 'on' (or 'off') response to a 'high' level of firing (S+ pairing), and to reduce the opponent response (respectively 'off' or 'on') in the same position to a 'low' level (S- pairing). This associative procedure was repeated 50-100 times at a low temporal frequency (0.1-0.15 s-1). 3. Long-lasting modifications of the ratio of 'on-off' responses, measured in the paired position or integrated across the whole RF, were found in 44 % of the conditioned neurons (17/39), and in most cases this favoured the S+ paired characteristic. The amplitude change was on average half of that imposed during pairing. Comparable proportions of modified cells were obtained in 'simple' (13/27) and 'complex' (4/12) RFs, both in adult cats (4/11) and in kittens within the critical period (13/28). 4. The spatial selectivity of the pairing effects was studied by pseudorandomly stimulating both paired and spatially distinct unpaired positions within the RF. Most modifications were observed in the paired position (for 88 % of successful pairings). 5. In some cells (n = 13), a fixed delay pairing procedure was applied, in which the temporal phase of the onset of the current pulse was shifted by a few hundred milliseconds from the presentation or offset of the visual stimulus. Consecutive effects were observed in 4/13 cells, which retained the temporal pattern of activity imposed during pairing for 5-40 min. They were expressed in the paired region only. 6. The demonstration of long-lasting adaptive changes in the ratio of 'on' and 'off' responses, expressed in localized subregions of the RF, leads us to suggest that simple and complex RF organizations might be two stable functional states derived from a common connectivity scheme.


Knocking Out the Gene RLS1 Induces Hypersensitivity to Oxidative Stress and Premature Leaf Senescence in Rice.
Improving a plant's level of tolerance to oxidative stress can frequently also enhance its tolerance to several other abiotic stresses. Here, a screen of a japonica type rice T-DNA insertion mutant library identified a highly oxidative stress-sensitive mutant. The line exhibited premature leaf senescence, starting at the three-leaf stage, and the symptoms were particularly severe from the five-leaf stage onwards. The leaves progressively lost chlorophyll, suffered protein degradation and were compromised with respect to their photosynthetic activity; their leaf mesophyll and bulliform cells became shrunken, and several senescence-associated genes (SAGs), senescence-associated transcription factor genes (SATFs) and autophagy-related genes (ATGs) were progressively up-regulated. The product of the gene inactivated by the mutation, identified via positional cloning, was putatively a ubiquitin-conjugating enzyme. The gene was denoted here as RLS1 (reactive oxygen species-sensitive leaf senescence1). The phenotype of plants in which RLS1 was knocked down using RNA interference was comparable to that of the rls1 mutant. A comparative analysis of the knock-out line and the wild type leaves showed that the former accumulated more hydrogen peroxide and more malondialdehyde, expressed a heightened level of superoxide dismutase activity and a decreased level of catalase activity, and exhibited an altered transcriptional profile with respect to several SAGs, SATFs and ATGs, and that these effects were magnified when the plants were exposed to oxidative stress. The product of RLS1 is presumed to be a critical component of the rice oxidative stress response and is involved in ROS (reactive oxygen species)-mediated leaf senescence.


Fiber Orientation and Concentration in an Injection-Molded Ethylene-Propylene Copolymer Reinforced by Hemp.
This paper characterizes and analyzes the microstructures of injection-molded polypropylene parts reinforced with 20 wt% of hemp fibers in order to understand the process induced variations in thermomechanical properties. In-thickness fiber orientation and fiber content were determined by X-ray tomography along the flow. The fiber content along the flow path was also determined by direct fiber content measurements after matrix dissolution, showing an increase of 2%/100 mm for a 2.2 mm-thick plate due to fiber migration during the filling stage. A typical shell/core structure for fiber orientation in injection molding was observed, but with a very clear transition between the layer solidified under high shear rates and the core in which the fiber content was reduced by more than 50%. The orientation of hemp fibers is lower than the one of glass fibers, especially in thickness direction. However, the overall fiber orientation in the injection direction induces significant anisotropic thermomechanical properties, which cannot be explained by simple micromechanical models that consider isotropic mechanical properties for hemp fibers. These phenomena must be taken into account in process simulation codes for injection molding to better predict thermomechanical properties as well as part shrinkage and warpage to design molds.


Rod and cone ERGs and their oscillatory potentials.
Normal human ERGs were recorded from a dark-adapted subject using white and colored test flashes. Oscillatory potentials (OPs) were studied after high-pass digital filtering. When blue and red responses were compared at equivalent photopic intensities, OPs were visible at much lower intensities for the blue flashes. As the intensity was reduced from maximum, the first (negative) wave for red flashes maintained a latency of 20-25 msec before being lost in noise, whereas the first wave for blue flashes increased its latency progressively from 25 to 60 msec. These differences between photopically matched red and blue responses are interpreted to be due to rod-generated responses. When blue, orange, and white responses were compared at equivalent scotopic intensities, the latency of the largest negative wave was found to be similar for all three colors. The authors interpret this wave to be the beginning of the rod-generated OPs, so that the preceding waves (particularly evident for orange flashes) are cone-generated OPs, and they propose that the existence of separate rod and cone OPs should be borne in mind when investigating clinical changes in OPs.


Early decrease in serum amphiregulin or vascular endothelial growth factor levels predicts sorafenib efficacy in hepatocellular carcinoma.
Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, identifying secreted biomarkers that predict sorafenib efficacy in all HCC patients remains challenging. It was recently reported that sorafenib interferes with protein homeostasis and inhibits global translation in tumour cells. A likely consequence of this inhibition would be the interruption of autocrine loops. The aim of the present study was to investigate the effect of sorafenib on two growth factors implicated in autocrine loops and HCC tumour invasion: amphiregulin (AREG) and vascular endothelial growth factor (VEGF). ELISA, quantitative polymerase chain reaction analysis, western blotting and a cytokine array were performed on HCC cell lines and the prognostic role of these two biomarkers in HCC patients was evaluated. Serum AREG and VEGF levels were assayed by ELISA in 55 patients with advanced HCC treated with sorafenib. It was observed that sorafenib decreased AREG, VEGF and cytokine expression at the transcriptional and post‑transcriptional levels. All HCC patients in our cohort had detectable concentrations of AREG and VEGF both at baseline and after sorafenib treatment. The decreased serum levels of AREG and VEGF after 15 days of sorafenib treatment were significantly associated with better overall and progression‑free survival. The results of the multivariate analysis demonstrated that a decrease in AREG was an independent prognostic indicator of overall survival (hazard ratio, 0.208; 95% confidence interval, 0.173‑0.673; P=0.0003). These results suggest that sorafenib inhibits auto-crine loops and that early decrease in serum AREG or VEGF levels predicts sorafenib efficacy in HCC patients.


Nanoparticles in drug delivery: mechanism of action, formulation and clinical application towards reduction in drug-associated nephrotoxicity.
Over the past few decades, nanoparticles (NPs) have gained immeasurable interest in the field of drug delivery. Various NP formulations have been disseminated in drug development in an attempt to increase efficacy, safety and tolerability of incorporated drugs. In this context, NP formulations that increase solubility, control release, and/or affect the in vivo disposition of drugs, were developed to improve the pharmacokinetic and pharmacodynamic properties of encapsulated drugs. In this article, important properties related to NP function such as particle size, surface charge and shape are disseminated. Also, the current understanding of how NP characteristics affect particle uptake and targeted delivery is elucidated. Selected NP systems currently used in delivery of drugs in biological systems and their production methods are discussed as well. Emphasis is placed on current NP formulations that are shown to reduce drug-induced adverse renal complications. Formulation designs utilizing NP-encapsulated drugs offer alternative pharmacotherapy options with improved safety profiles for current and emerging drugs. NPs have been shown to increase the therapeutic index of several entrapped drugs mostly by decreasing drug localization and side effects on organs. Recent studies on NP-encapsulated chemotherapeutic and antibiotic medications show enhanced therapeutic outcomes by altering drug degradation, increasing systemic circulation and/or enhancing cell specific targeting. They may also reduce the distribution of encapsulated drugs into the kidneys and attenuate drug-associated adverse renal complications. The usefulness of NP formulation in reducing the nephrotoxicity of nonsteroidal anti-inflammatory drugs is an under explored territory that deserves more attention.


In vitro antibacterial capacity and cytocompatibility of SiO2-CaO-P2O5 meso-macroporous glass scaffolds enriched with ZnO.
Zn2+ ions exhibit osteogenic, angiogenic and antimicrobial properties. For this reason, they are often added in small amounts to bioceramics being investigated for bone tissue engineering. In this paper, the cytocompatibility and antibacterial properties of 80% SiO2-15% CaO-5% P2O5 (mol%) mesoporous bioactive glass (MBG) scaffolds substituted with 4.0% and 7.0% of ZnO were studied and compared with the Zn-free scaffold. Cell proliferation, morphology, differentiation and cytotoxic effects of Zn2+ ions released from the samples were examined by culturing human osteoblast-like cells (HOS) osteoblasts both in the presence of sample extracts and on the scaffold surface. The bacterial inhibition capacity of the scaffolds was explored by using Gram-positive Stapylococcus aureus bacteria, responsible for numerous infections in orthopedic surgery, to simulate a severe infection. Our results show that the Zn-MBG scaffolds possess a hierarchical meso-macropore structure suitable for osteoblast growth. Furthermore, the amount of Zn2+ released from the scaffold with 4.0% ZnO was found to be more favorable for HOS cell development than that released from the scaffold including 7.0% ZnO. Zn2+ released to the medium from both scaffolds exhibited antibacterial properties against S. aureus. Thus, the cytocompatibility and the antibacterial ability exhibited by the MBG scaffold containing 4.0% ZnO make it a suitable candidate for bone regeneration applications.


Tracking discourse complexity preceding Alzheimer's disease diagnosis: a case study comparing the press conferences of Presidents Ronald Reagan and George Herbert Walker Bush.
Changes in some lexical features of language have been associated with the onset and progression of Alzheimer's disease. Here we describe a method to extract key features from discourse transcripts, which we evaluated on non-scripted news conferences from President Ronald Reagan, who was diagnosed with Alzheimer's disease in 1994, and President George Herbert Walker Bush, who has no known diagnosis of Alzheimer's disease. Key word counts previously associated with cognitive decline in Alzheimer's disease were extracted and regression analyses were conducted. President Reagan showed a significant reduction in the number of unique words over time and a significant increase in conversational fillers and non-specific nouns over time. There was no significant trend in these features for President Bush.


Visuospatial memory and neuroimaging correlates in mild cognitive impairment.
Spatial abilities decline in normal aging and decrease faster and earlier in Alzheimer's disease (AD), but these deficits are under investigated. The main goals of this study were to assess visuospatial memory abilities in mild cognitive impairment (MCI), in order to verify whether these tasks might be valid as the standard cognitive test to differentiate MCI individuals from normal controls and to investigate the brain structural correlates of visuospatial deficits. Twenty MCI patients and fourteen healthy elderly controls underwent an experimental visuospatial battery, which also included self-rating spatial questionnaires, and structural MRI brain imaging. Compared to healthy elderly controls, MCI patients scored significantly worse in almost all visuospatial tasks. ROC analysis showed that visuospatial tasks had an elevated discriminant power between groups (AUC >0.90). Voxel-based morphometry analysis, compared to controls, disclosed a higher level of atrophy in frontal and medio-temporal regions and a different pattern of correlation between grey matter values and visuospatial performance, with wider distributed areas of the occipital and middle temporal cortex in the map and route learning. This study indicates that visuospatial memory tests are valid tools in completing the diagnostic evaluation of MCI.


Proton MRS imaging in the follow-up of patients with suspected low-grade gliomas.
We compared the value of changes in proton magnetic resonance spectroscopic imaging ((1)H-MRSI) with changes in clinical status and/or contrast-enhanced magnetic resonance imaging (MRI) in the monitoring of patients with suspected low-grade glioma (LGG). From June 1, 1999 till May 31, 2002, we included consecutive, neurologically intact adult patients suspected of having an LGG, demonstrating non-enhancing supratentorial lesions without edema or mass effect on MRI, and in whom all treatment (including a diagnostic biopsy) was deferred. Till January 1, 2003, patients were surveyed clinically and radiologically (contrast-enhanced MRI and (1)H-MRSI). Patients who showed progression on clinical examination and/or MRI were denoted as progressive disease. Other patients were denoted as stable disease. A decrease in NAA/CHO ratio of > or =20% compared to the baseline value was considered as indicative for progression on (1)H-MRSI. We included 14 patients with suspected LGG. Seven patients demonstrated progressive disease during the follow-up period, preceded or accompanied by concomitant (1)H-MRSI changes in five patients. Four of these five patients were operated on within the follow-up interval. The histological diagnosis demonstrated high-grade glioma in three and LGG in one patient. In the other two patients with progressive disease, no progression was found on (1)H-MRSI. The other seven patients demonstrated stable disease, but four of them showed progression on (1)H-MRSI. Our data do not show convincing evidence that (1)H-MRSI contributes to adequate monitoring and follow-up of patients with suspected LGG. Future research should preferably include pathological data at the time of (1)H-MRSI changes.


Preparative isolation of the two forms of pig pancreatic pro-(carboxypeptidase A) and their monomeric carboxypeptidases A.
A method is reported for the preparative isolation of the two forms of pro-(carboxypeptidase A) from pig pancreas: the monomer and the binary complex with pro-(proteinase E). This method, which is mainly based on chromatography on DEAE-Sepharose at pH 5.7, allows these proenzymes to be prepared more quickly and in safer conditions than with other reported methods. Undegraded and homogeneous carboxypeptidase A1 and A2 species (peptidyl-L-amino acid hydrolase, EC 22.214.171.124), in monomeric forms with high specific activity, are also obtained in high yield by controlled trypsin activation of either of the pro-(carboxypeptidases A) followed by chromatography on DEAE-Sepharose at pH 5.8 under dissociating conditions (7 M-urea).


Characterization of irradiated starches by using FT-Raman and FTIR spectroscopy.
Fourier transform infrared (FTIR) and Fourier transform Raman (FT-Raman) methods were used for rapid characterization and classification of selected irradiated starch samples. Biochemical changes due to irradiation were detected using the two vibrational spectroscopic techniques, and canonical variate analysis (CVA) was applied to the spectral data for discriminating starch samples based on the extent of irradiation. The O-H (3000-3600 cm(-1)) stretch, C-H (2800-3000 cm(-1)) stretch, the skeletal mode vibration of the glycosidic linkage (900-950 cm(-1)) in both Raman and infrared spectra, and the infrared band of water adsorbed in the amorphous parts of starches (1550-1750 cm(-1)) were employed in classification analysis of irradiated starches. Spectral data related to water adsorbed in the noncrystalline regions of starches provided a better classification of irradiated starches with 5 partial least-squares (PLS) factors in the multivariate model.


Interaction of species A rotavirus VP4 with the cellular proteins vimentin and actin related protein 2 discovered by a proximity interactome assay.
Rotavirus (RV) is an important zoonosis virus, which can cause severe diarrhea and extra-intestinal infection. To date, some proteins or carbohydrates have been shown to participate in the attachment or internalization of RV, including HGBAs, Hsc70, and integrins. This study attempted to indicate whether there were other proteins that would participate in the entry of RV; thus, the RV VP4-interacting proteins were identified by proximity labeling. After analysis and verification, it was found that VIM and ACTR2 could significantly promote the proliferation of RV in intestinal cells. Through further viral binding assays after knockdown, antibody blocking, and recombinant protein overexpression, it was revealed that both VIM and ACTR2 could promote RV replication.


A method for teaching techniques of office surgery.
A method of instruction in basic wound repair and the teaching of suturing skills such as might be used in the office or Emergency Room is described which has been used effectively in family practice resident training. The method utilizes pigs' feet with four specific exercises and objectives accomplished: (1) stellate or Y-shaped laceration; (2) semi-circular, bevelled, flap-type laceration; (3) elliptical, excisional biopsy with "dog ear" correction; and (4) Z-plasty revision. Diagrams are provided, explicitly demonstrating proper techniques of the above exercises. A brief comment on skill evaluation concludes the paper.


Inhibition of puerperal lactation. A double blind study of bromocriptine and placebo.
Bromocriptine and placebo were randomly allocated for three weeks to 52 postpartum patients requiring lactation suppression. Bromocriptine significantly lowered plasma prolactin levels and suppressed breast milk, breast pain and engorgement quicker than placebo. No side-effects were noted and rebound lactation did not occur. Menstruation appeared to re-start sooner when Bromocriptine was given.


Random walk behavior of migrating cortical interneurons in the marginal zone: time-lapse analysis in flat-mount cortex.
Migrating neurons are thought to travel from their origin near the ventricle to distant territories along stereotypical pathways by detecting environmental cues in the extracellular milieu. Here, we report a novel mode of neuronal migration that challenges this view. We performed long-term, time-lapse imaging of medial ganglionic eminence (MGE)-derived cortical interneurons tangentially migrating in the marginal zone (MZ) in flat-mount cortices. We find that they exhibit a diverse range of behaviors in terms of the rate and direction of migration. Curiously, a predominant population of these neurons repeatedly changes its direction of migration in an unpredictable manner. Trajectories of migration vary from one neuron to another. The migration of individual cells lasts for long periods, sometimes up to 2 d. Theoretical analyses reveal that these behaviors can be modeled by a random walk. Furthermore, MZ cells migrate from the cortical subventricular zone to the cortical plate, transiently accumulating in the MZ. These results suggest that MGE-derived cortical interneurons, once arriving at the MZ, are released from regulation by guidance cues and initiate random walk movement, which potentially contributes to their dispersion throughout the cortex.


Cholesterol-lowering effect of soy protein in normocholesterolemic and hypercholesterolemic men.
Cardiovascular heart disease is a major health problem in the United States. Elevated blood cholesterol has been shown to significantly increase the risk of cardiovascular heart disease. The National Cholesterol Educational Program (NCEP) Step I diet, which restricts fat and cholesterol intakes, is usually recommended as the initial treatment to lower blood cholesterol. Soy protein has been shown to be hypocholesterolemic, particularly in hypercholesterolemic subjects. However, the hypocholesterolemic effect of soy protein in subjects with a blood total cholesterol concentration <5.17 mmol/L is not clear. To determine whether soy protein could enhance the hypocholesterolemic effect of the NCEP Step I diet, 13 normocholesterolemic and 13 hypercholesterolemic men aged 20-50 y were enrolled in a randomized, 2-part, crossover study. Subjects were fed either an NCEP Step I soy-protein diet or an NCEP Step I animal protein diet for 5 wk. After a washout period of 10-15 wk, the subjects were fed the alternate diet for 5 wk. The hypocholesterolemic effect of soy protein was found to be independent of age, body weight, pretreatment plasma lipid concentrations, and sequence of dietary treatment. Regardless of plasma lipid status, the soy-protein diet was associated with a statistically significant decrease in the plasma concentrations of LDL cholesterol (P = 0.029) as well as the in the ratio of plasma LDL cholesterol to HDL cholesterol (P = 0.005). Our results indicate that soy protein enhances the hypocholesterolemic effect of the NCEP Step I diet in both normocholesterolemic and hypercholesterolemic men.


Infective endocarditis and spondylodiscitis due to posterior nasal packing in a patient with a bioprosthetic aortic valve.
Infective endocarditis (IE) is a severe form of heart valve disease and is associated with a poor prognosis and high risk of mortality. We report the first known case of bioprosthetic aortic valve endocarditis associated with spondylodiscitis as a result of posterior nasal packing coated with antibiotics but without systemic antibiotic prophylaxis.


Acute chest syndrome: sickle cell disease.
Acute chest syndrome (ACS) is a common complication and reason for hospital admission in patients with sickle cell disease (SCD). It is also the most common cause of death in this patient population. Most of the time, the trigger for ACS in an individual patient cannot be identified. However, although infection is the most common identifiable cause for ACS, other important triggers are vaso-occlusive crisis (VOC) and asthma. This comprehensive review will focus on the pathogenesis, clinical characteristics, complications and treatment available to manage ACS. But importantly, this review will highlight new possible etiologies, with the goal of improving oxygenation and, therefore, a reduction in sickling and lung damage in this patient population.


Relapse of Lung Adenocarcinoma Manifested by Spontaneous Tumor Lysis Syndrome.
Tumor lysis syndrome (TLS) is an oncologic emergency characterized by several metabolic derangements, such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. TLS is typically observed in hematologic malignancies, especially after starting the first administration of antineoplastic therapies. TLS in a solid malignancy is very unusual, and exceedingly rare when occurring spontaneously, in the absence of chemotherapy. We report a case of a 76-year-old man with lung adenocarcinoma, which started as a cancer with indolent behavior and small tumor burden but relapsed in 5 months with rapidly proliferating metastatic disease. Spontaneous TLS was the presenting clinical manifestation of the tumor relapse, and it led to the patient's death. To our knowledge, this is the first case of spontaneous TLS in a relapsed adenocarcinoma of the lung reported in the medical literature. The development of the metabolic derangements of TLS should prompt the consideration of tumor relapse during the follow-up of patients with solid malignancies.


Accuracy combining different brands of implants and abutments.
To evaluate the vertical misfit between different brands of dental implants and prosthetic abutments, with or without mechanical torque, and to study their possible combination. Five different brands of implant were used in the study: Biofit (Castemaggiore, Italy), Bioner S.A. (Barcelona, Spain), 3i Biomet (Palm Beach, U.S.A.), BTI (Alava, Spain) and Nobel Biocare (Göteborg, Sweden), with standard 4.1 mm heads and external hexagons, and their respective machined prosthetic abutments. The implant-to-abutment fit/misfit was evaluated at four points (vestibular, lingual/palatine, mesial and distal) between implants and abutments of the same brand and different brands, with or without mechanical torque, using SEM micrographs at 5000X. Image analysis was performed using NIS-Elements software (Nikon Instruments Europe B.V.). Before applying torque, vertical misfit (microgaps) of the different combinations tested varied between 1.6 and 5.4 microns and after applying torque, between 0.9 and 5.9 microns, an overall average of 3.46 ± 2.96 microns. For manual assembly without the use of mechanical torque, the best results were obtained with the combination of the 3i implant and the BTI abutment. The Nobel implant and Nobel abutment, 3i-3i and BTI-BTI and the combination of 3i implant with BTI or Nobel abutment provided the best vertical fit when mechanical torque was applied. The vertical fits obtained were within the limits considered clinically acceptable. The application of mechanical torque improved outcomes. There is compatibility between implants and abutments of different brand and so their combination is a clinical possibility.


Thickness-dependent smectic-A-smectic-C* transition in chiral smectic free-standing liquid-crystal films.
We have conducted heat-capacity measurements near the smectic-A -smectic-C* phase transition in free-standing films of a chiral liquid-crystal compound. The heat-capacity behavior confirms the evolution of the transition in the interior layers from first to second order as a function of film thickness suggested earlier in tilt angle measurements. The asymmetry in the heat-capacity anomaly exhibits an interesting crossover in thinner films. We also observed the phase transitions leading to the crystallization to the tilted crystal-G phase in these films at lower temperatures. The surface ordering strength in these films is found to be much larger than that in other orthogonal-smectic films, which we speculate is due to the molecular tilt.


Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma.
Vascular Endothelial Growth Factor (VEGF) promotes angiogenesis in many different tumor types. VEGF levels may affect tumor growth, metastatic potential, and response to radiotherapy. This study assesses the prognostic value of VEGF protein levels in a cohort of patients with oral and oropharyngeal squamous cell carcinomas. The relationships between clinical outcome and the covariables of tumor-node-metastasis stage, disease stage (I to IV), grade, margin status, race, sex, and age were also determined. Chart review identified 77 patients with oral or oropharyngeal squamous cell carcinoma treated with gross total surgical resection and postoperative radiation between 1981 and 1992. Sufficient follow-up data and tumor tissue were available in 56 patients (73%). VEGF protein levels were determined using immunohistochemistry. The association between VEGF status, covariables, and outcome was assessed in a bivariate and multivariate model using two-sided statistical tests. Twenty-three tumors (41%) were positive for VEGF expression. VEGF-positive tumors were more likely to recur locally (relative risk [RR] = 3.08; 95% confidence interval [CI], 1.03 to 9.24) and distantly (RR = 4.62; 95% CI, 1.41 to 15.10). In bivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.66; 95% CI, 1.27 to 5.56) and overall survival (RR = 3.21; 95% CI, 1.63 to 6.32). In multivariate analysis, VEGF positivity was the most significant predictor of poor disease-free survival (RR = 2.75; 95% CI, 1.30 to 5.79) and overall survival (RR = 3.53; 95% CI, 1.75 to 7.13). In this cohort, VEGF positivity was the most significant predictor of poor prognosis. VEGF status may prove to be an important prognostic factor in head and neck cancer.


Immune Defense in Hypoxic Waters: Impacts of CO2 Acidification.
AbstractPeriodic episodes of low oxygen (hypoxia) and elevated CO2 (hypercapnia) accompanied by low pH occur naturally in estuarine environments. Under the influence of climate change, the geographic range and intensity of hypoxia and hypercapnic hypoxia are predicted to increase, potentially jeopardizing the survival of economically and ecologically important organisms that use estuaries as habitat and nursery grounds. In this review we synthesize data from published studies that evaluate the impact of hypoxia and hypercapnic hypoxia on the ability of crustaceans and bivalve molluscs to defend themselves against potential microbial pathogens. Available data indicate that hypoxia generally has suppressive effects on host immunity against bacterial pathogens as measured by in vitro and in vivo assays. Few studies have documented the effects of hypercapnic hypoxia on crustaceans or bivalve immune defense, with a range of outcomes suggesting that added CO2 might have additive, negative, or no interactions with the effects of hypoxia alone. This synthesis points to the need for more partial pressure of O2 × low pH factorial design experiments and recommends the development of new host∶pathogen challenge models incorporating natural transmission of a wide range of viruses, bacteria, and parasites, along with novel in vivo tracking systems that better quantify how pathogens interact with their hosts in real time under laboratory and field conditions.


[Physicochemical properties of Teschen disease virus RNA].
The specific infectivity of virion RNA of teschen disease virus in a sensitive PP cell culture was 4-5 lg TCD50/ml per 1 microgram RNA. When virion RNA was inoculated into cell cultures insusceptible to the native virus, the virus replicated to a titre of 2.0-3.5 lg TCD50/ml. The molecular weight of virion RNA determined by two independent methods was 2.7 x 10(6) daltons. Tm calculated from the curve of virion RNA melting temperature was 57 degrees C. The double-stranded replicative form of RNA recovered from virus-infected PP cells was shown to have sucrose gradient sedimentation coefficient of 20 S. The specific infectivity was 2-3 lg TCD50/ml per 1 microgram of RNA.


Exploring Suicidal Ideation Using an Innovative Mobile App-Strength Within Me: The Usability and Acceptability of Setting up a Trial Involving Mobile Technology and Mental Health Service Users.
Suicide is a growing global public health problem that has resulted in an increase in the demand for psychological services to address mental health issues. It is expected that 1 in 6 people on a waiting list for mental health services will attempt suicide. Although suicidal ideation has been shown to be linked to a higher risk of death by suicide, not everybody openly discloses their suicidal thoughts or plans to friends and family or seeks professional help before suicide. Therefore, new methods are needed to track suicide risk in real time together with a better understanding of the ways in which people communicate or express their suicidality. Considering the dynamic nature and challenges in understanding suicide ideation and suicide risk, mobile apps could be better suited to prevent suicide as they have the ability to collect real-time data. This study aims to report the practicalities and acceptability of setting up and trialing digital technologies within an inpatient mental health setting in the United Kingdom and highlight their implications for future studies. Service users were recruited from 6 inpatient wards in the north west of England. Service users who were eligible to participate and provided consent were given an iPhone and Fitbit for 7 days and were asked to interact with a novel phone app, Strength Within Me (SWiM). Interaction with the app involved journaling (recording daily activities, how this made them feel, and rating their mood) and the option to create safety plans for emotions causing difficulties (identifying strategies that helped with these emotions). Participants also had the option to allow the study to access their personal Facebook account to monitor their social media use and activity. In addition, clinical data (ie, assessments conducted by trained researchers targeting suicidality, depression, and sleep) were also collected. Overall, 43.0% (80/186 response rate) of eligible participants were recruited for the study. Of the total sample, 67 participants engaged in journaling, with the average number of entries per user being 8.2 (SD 8.7). Overall, only 24 participants created safety plans and the most common difficult emotion to be selected was feeling sad (n=21). This study reports on the engagement with the SWiM app, the technical difficulties the research team faced, the importance of building key relationships, and the implications of using Facebook as a source to detect suicidality. To develop interventions that can be delivered in a timely manner, prediction of suicidality must be given priority. This paper has raised important issues and highlighted lessons learned from implementing a novel mobile app to detect the risk of suicidality for service users in an inpatient setting.


Association of the polyadenylate segment of messenger RNA with other polynucleotide sequences in mouse sarcoma 180 polyribosomes.
Limited digestion of polysomal RNA with pancreatic ribonuclease releases a structure consisting of poly(A) associated with other polyribonucleotide sequences. This complex can be purified by oligo(dT)-cellulose chromatography. Heating for formamide treatment causes the dissociation of fragments free of poly(A) from the poly(A)-containing components. The two types of fragments tend to reassociate under annealing conditions, and this association is prevented by poly(U). Control experiments indicate that this structure is not an artifact generated during the manipulations. The same structure can be obtained by limited RNase digestion of polyribosomes, followed by deproteinization. The results suggest that the mRNA in polyribosomes may have a defined configuration caused by the interaction of the poly(A) sequence with another segment of the RNA.


Characterization of aqueous alcohol solutions in bottles with THz reflection spectroscopy.
We demonstrate a method based on self-referenced THz time-domain spectroscopy for inspection of aqueous liquids, and in particular alcohol solutions, inside closed containers. We demonstrate that it is possible to determine the alcohol content of an aqueous solution, and that liquids can be classified as either harmless or inflammable. The method operates in reflection mode with the result that liquids opaque to THz radiation can be characterized with little influence of the bottle shape. The method works with plastic bottles as well as glass bottles, with absorption of THz radiation by the plastic or the glass being the limiting factor. The reflection mode allows for automatic control of the validity of the measurement. The method will be useful in liquid scanning systems at security checkpoints.


Ameliorating effect of Citrus aurantium extracts and nobiletin on β‑amyloid (1‑42)‑induced memory impairment in mice.
The aim of the present study was to evaluate the neuroprotective effect of Citrus aurantium extract (CAE) and nobiletin against amyloid β 1‑42 (Aβ 1‑42)‑induced spatial learning and memory impairment in mice. After injecting Aβ 1‑42 (5 µl/2.5 min, intracerebroventricular injection), amnesic mice were orally administered CAE and nobiletin for 28 days. Memory, spatial and cognitive ability were measured using passive avoidance and a Morris water maze task. Acetylcholinesterase (AchE) activity was investigated in the hippocampus and cortex using commercial kits and the analysis of Bax, Bcl‑2, and cleaved caspase‑3 protein expression by western blot assays was used to confirm the anti‑apoptotic mechanism of CAE and nobiletin. The present study confirmed impairments in learning and memory in the Aβ‑induced neurodegenerative mice with increased AchE activity in the brain. However, the daily administration of CAE and nobiletin reduced the spatial learning deficits and increased the AchE activity in the cortex and hippocampus. Furthermore, CAE and nobiletin significantly downregulated the Bax and cleaved caspase‑3 protein expression and upregulated the Bcl‑2 and Bcl‑2/Bax expression in the cortex and hippocampus of Aβ‑treated mice. These results suggest that CAE and nobiletin exert a neuroprotective effect by regulating anti‑apoptotic mechanisms, including reduced AchE activity in the cortex and hippocampus of the cognitive deficit mouse model.


Improving drug safety in hospitals: a retrospective study on the potential of adverse drug events coded in routine data.
Adverse drug events (ADEs) that occur during hospitalization are an ongoing medical concern. Systematic strategies for ADE identification are lacking. The aim of this study was to evaluate the potential to identify adverse drug events caused by medication errors (preventable ADEs, pADEs), and previously unknown adverse drug reactions (ADRs or non-preventable ADEs, npADEs) in inpatients by combining diagnosis codes in routine data with a chart review. Diagnoses of inpatients are routinely coded using the International Classification of Diseases, 10th Revision (ICD-10). A total of 2326 cases were sampled from routine data of four hospitals using a set of ICD-10 German Modification ADE codes. Following a chart review, cases were evaluated in a standardized process with regard to drug relation and preventability of events. By chart review, 1302 cases were classified as hospital-acquired and included in the evaluation. This yielded 1285 cases indicating an ADE. 96.8% of ADEs (1244 ADEs) were classified as known npADEs, only three cases as suspected previously unknown npADEs, one case as event after drug abuse. A total of 37 ADEs were classified as preventable (2.9% of all ADEs) by identifying a medication error as probable cause. The prevalence of pADEs varied considerably between included ADE codes, with hemorrhagic diathesis due to coumarins and localized skin eruptions showing the highest rates (8.7 and 9.1%, respectively). Most frequent medication errors were non-compliance to a known allergy, and improper dose. When focusing on specific ADE codes, routine data can be used as markers for npADEs and medication errors, thus providing a meaningful complement to existing drug surveillance systems. However, the prevalence of medication errors is lower than in former studies on the frequency of pADEs.


Charge transport through redox active [H7P8W48O184]33- polyoxometalates self-assembled onto gold surfaces and gold nanodots.
Polyoxometalates (POMs) are redox-active molecular oxides, which attract growing interest for their integration into nano-devices, such as high-density data storage non-volatile memories. In this work, we investigated the electrostatic deposition of the negatively charged [H7P8W48O184]33- POM onto positively charged 8-amino-1-octanethiol self-assembled monolayers (SAMs) preformed onto gold substrates or onto an array of gold nanodots. The ring-shaped [H7P8W48O184]33- POM was selected as an example of large POMs with high charge storage capacity. To avoid the formation of POM aggregates onto the substrates, which would introduce variability in the local electrical properties, special attention has to be paid to the preformed SAM seeding layer, which should itself be deprived of aggregates. Where necessary, rinsing steps were found to be crucial to eliminate these aggregates and to provide uniformly covered substrates for subsequent POM deposition and electrical characterizations. This especially holds for commercially available gold/glass substrates while these rinsing steps were not essential in the case of template stripped gold of very low roughness. Charge transport through the related molecular junctions and nanodot molecule junctions (NMJs) has been probed by conducting-AFM. We analyzed the current-voltage curves with different models: electron tunneling though the SAMs (Simmons model), transition voltage spectroscopy (TVS) method or molecular single energy level mediated transport (Landauer equation) and we discussed the energetics of the molecular junctions. We concluded to an energy level alignment of the alkyl spacer and POM lowest occupied molecular orbitals (LUMOs), probably due to dipolar effects.


Identification and characterization of enzymes involved in the biosynthesis of pyrimidine nucleoside antibiotics.
Covering: up to September 2020 Hundreds of nucleoside-based natural products have been isolated from various microorganisms, several of which have been utilized in agriculture as pesticides and herbicides, in medicine as therapeutics for cancer and infectious disease, and as molecular probes to study biological processes. Natural products consisting of structural modifications of each of the canonical nucleosides have been discovered, ranging from simple modifications such as single-step alkylations or acylations to highly elaborate modifications that dramatically alter the nucleoside scaffold and require multiple enzyme-catalyzed reactions. A vast amount of genomic information has been uncovered the past two decades, which has subsequently allowed the first opportunity to interrogate the chemically intriguing enzymatic transformations for the latter type of modifications. This review highlights (i) the discovery and potential applications of structurally complex pyrimidine nucleoside antibiotics for which genetic information is known, (ii) the established reactions that convert the canonical pyrimidine into a new nucleoside scaffold, and (iii) the important tailoring reactions that impart further structural complexity to these molecules.


Exercise, fitness, and neurocognitive function in older adults: the "selective improvement" and "cardiovascular fitness" hypotheses.
Although basic research has uncovered biological mechanisms by which exercise could maintain and enhance adult brain health, experimental human studies with older adults have produced equivocal results. This randomized clinical trial aimed to investigate the hypotheses that (a) the effects of exercise training on the performance of neurocognitive tasks in older adults is selective, influencing mainly tasks with a substantial executive control component and (b) performance in neurocognitive tasks is related to cardiorespiratory fitness. Fifty-seven older adults (65-79 years) participated in aerobic or strength-and-flexibility exercise training for 10 months. Neurocognitive tasks were selected to reflect a range from little (e.g., simple reaction time) to substantial (i.e., Stroop Word-Color conflict) executive control. Performance in tasks requiring little executive control was unaffected by participating in aerobic exercise. Improvements in Stroop Word-Color task performance were found only for the aerobic exercise group. Changes in aerobic fitness were unrelated to changes in neurocognitive function. Aerobic exercise in older adults can have a beneficial effect on the performance of speeded tasks that rely heavily on executive control. Improvements in aerobic fitness do not appear to be a prerequisite for this beneficial effect.


Explicating factors that explain condom use intention among in-school adolescents in Botswana: a structural equation modelling approach.
Knowledge with respect to adolescents' intentions to engage in protective sexual behaviours is still deficient in numerous countries around the world, particularly in Sub-Saharan Africa (SSA) where HIV prevalence is the highest. Increasing cross-sectional research suggests that the theory of planned behaviour (TPB) is robust in predicting condom use intentions. This study used secondary, baseline data from a study involving 794 in-school adolescents. A structural equation model was applied to the data. Latent variables were used to validate the applicability of the TPB in HIV/AIDS prevention among adolescents in the Botswana context. The predictors of interest were all derived from the TPB. The results revealed that the TPB predictors, apart from affective and instrumental attitude, were predictive of condom use intention among Batswana adolescents. The independent variables explained 57% of the variance in the model. These results suggest that the TPB is recommended as a framework to establish the predictors of condom use intention among Batswana in-school adolescents. Policy makers working on developing HIV education programmes or interventions targeted at adolescents should improve the intention to use condoms via promotion of positive instrumental attitudes, subjective norms and perceived behavioural control beliefs of condom use.


Identification and characterization of Thermus thermophilus HB8 RuvA protein, the subunit of the RuvAB protein complex that promotes branch migration of Holliday junctions.
The Escherichia coli ruvA and ruvB genes constitute an SOS-regulated operon. The products of these genes form a protein complex that promotes branch migration of the Holliday junction, an intermediate of homologous recombination. RuvA protein binds specifically to the Holliday junction and recruits RuvB protein to the junction. RuvB is an ATP-driven motor protein involved in branch migration. We previously cloned the ruvB gene of the thermophilic bacterium Thermus thermophilus HB8 (Tth) and found that, in contrast to the operon structure in most mesothermic bacteria, the ruvA gene is absent from the vicinity of ruvB. In this work, we cloned the ruvA gene from T. thermophilus HB8 and analyzed its nucleotide sequence. Tth RuvA is a protein of 20,414 Da consisting of 191 amino acid residues, and is 37% identical in amino acid sequence to E. coli RuvA. Tth ruvA complemented the DNA repair defect of E. coli deltaruvA mutants. The purified Tth RuvA protein stimulated Tth RuvB activities, such as hydrolysis of ATP and promotion of branch migration of the Holliday junction, in a manner similar to the RuvA-RuvB interactions observed in E. coli. In addition, Tth RuvA stimulated the E. coli RuvB activities in vitro, which was well consistent with the results of in vivo hetero-complementation experiments.