CoMA - an intuitive and user-friendly pipeline for amplicon-sequencing data analysis.
In recent years, there has been a veritable boost in next-generation sequencing (NGS) of gene amplicons in biological and medical studies. Huge amounts of data are produced and need to be analyzed adequately. Various online and offline analysis tools are available; however, most of them require extensive expertise in computer science or bioinformatics, and often a Linux-based operating system. Here, we introduce "CoMA-Comparative Microbiome Analysis" as a free and intuitive analysis pipeline for amplicon-sequencing data, compatible with any common operating system. Moreover, the tool offers various useful services including data pre-processing, quality checking, clustering to operational taxonomic units (OTUs), taxonomic assignment, data post-processing, data visualization, and statistical appraisal. The workflow results in highly esthetic and publication-ready graphics, as well as output files in standardized formats (e.g. tab-delimited OTU-table, BIOM, NEWICK tree) that can be used for more sophisticated analyses. The CoMA output was validated by a benchmark test, using three mock communities with different sample characteristics (primer set, amplicon length, diversity). The performance was compared with that of Mothur, QIIME and QIIME2-DADA2, popular packages for NGS data analysis. Furthermore, the functionality of CoMA is demonstrated on a practical example, investigating microbial communities from three different soils (grassland, forest, swamp). All tools performed well in the benchmark test and were able to reveal the majority of all genera in the mock communities. Also for the soil samples, the results of CoMA were congruent to those of the other pipelines, in particular when looking at the key microbial players.


Impact of bone deformities and labral and cartilage lesions on early functional results of arthroscopic treatment of femoroacetabular impingement.
Femoroacetabular impingement (FAI) is a frequent cause of inguinal pain. Treatment failure rates range between 2.9% and 13.2%. The aim of the present study was to assess the impact of preoperative bone deformities (BD), labral lesions (LL) and cartilage lesions (CL) on clinical results of arthroscopic treatment of FAI. A prospective operational study included patients undergoing hip arthroscopy for FAI. All patients had full radiographic work-up and clinical assessment on Non-Arthritic Hip Score (NAHS), preoperatively and at 1year. Hips with Tönnis grade>1, coxa profunda [VCE (vertical center edge angle)>35°] or borderline dysplasia (VCE<25°) were excluded. The Czerny classification was used for the labrum and the Beck classification for the cartilage. The aim of the study was to assess the impact of preoperative BD, LL and CL on clinical results of arthroscopic treatment of FAI. The study hypothesis was that type of lesion does not influence early functional results at 1year, whatever the technique used for the labrum. One hundred and ninety-seven patients were included. Mean preoperative NAHS was 59.1±17.5. There were 145 patients with labral suture (73.6%), 42 with labral debridement (21.3%) and 10 with conservative treatment (5.1%). At 1year, mean NAHS was 88.1±15.3: i.e., a significant improvement (p<2.2×10-16). Improvement was also significant in the debridement, non-operative and suture subgroups. BD showed significant correction in the overall population (alpha angle 48.2° postoperatively versus 66.7° preoperatively; crossing sign in 14.5% versus 62.9% of cases). There were no significant differences in functional scores according to extension or type of labral or cartilage lesion. At follow-up, 3 patients (1.5%) required repeat arthroscopy. The present study showed that early functional results of arthroscopic treatment of FAI were unaffected by the severity of bone deformity (alpha and VCE angles), or extension or type of labral or cartilage lesion. Regardless of BD, LL and CL, 1-year clinical progression was satisfactory when all bone deformities were treated by the arthroscopic procedure. IV; prospective non-comparative study.


Effects of polyunsaturated fatty acids supplementation on reproductive parameters associated with the performance of suckled beef cows.
To evaluate the effects of a polyunsaturated fatty acids (PUFA) supplement on reproductive parameters of suckled beef cows, two experiments were conducted. In Experiment (Exp.) 1, 60 primiparous cows were randomly assigned to one of two treatments: CTRL - 1.36 kg/day of corn gluten feed (CGF) and MEGR - 1.36 kg/day of CGF and 0.23 kg/day of calcium salts of soybean oil. Supplementation occurred from 30 days before fixed-time artificial insemination (TAI) until 7 days post-TAI. The expression of interferon-stimulated genes (ISG) was measured on days 18 and 21. Pregnancy rates were diagnosed on days 30 and 100. Treatment altered plasma fatty acid profile (P<0.05), however, did not change cow BW (P=0.52) or body condition score (BCS) (P=0.52). Treatment did not alter (P=0.12) pregnancy rates to TAI or final pregnancy rates (P=0.56). Treatments did not impact messenger RNA (mRNA) expression of the ISG OAS1 or MX2 on days 18 (P=0.67; P=0.96, respectively) or 21 (P=0.72; P=0.17, respectively). Length of gestation was greater (P=0.02) for MEGR, however, treatments did not alter calf birth weight (P=0.20). In Exp. two, 66 multiparous cows were assigned to one of two treatments: MEG - 0.65 kg/day of CGF+0.23 kg/day of calcium salts of palm oil and MEGR - 0.65 kg/day of CGF+0.23 kg/day of Ca salts of soybean oil. Cows were supplemented from 30 days prepartum to 30 days postpartum. On day 35 after TAI, pregnancy status, embryo crown-to-rump length (CRL), and plasma concentrations of pregnancy-specific protein-B (PSPB) were evaluated. Treatment altered plasma fatty acid profile (P<0.05). In addition, cows from the MEG treatment had greater BW (P<0.01) and BCS (P<0.01) than those in the MEGR treatment, as well as heavier calves at weaning (P=0.03). Treatment did not affect resumption of estrous cycle (P=0.29). There were no differences in pregnancy rates to TAI (P=0.87) or final pregnancy rates (P=0.29). No differences between treatments were detected on CRL (P=0.24) and plasma concentrations of PSPB (P=0.46). Birth weight (P=0.12) and calving distribution (P=0.52) were not altered. We concluded that PUFA supplementation altered plasma fatty acid profile, however, did not impact the remaining reproductive parameters evaluated.


Dengue Fever in mainland China.
Dengue is an acute emerging infectious disease transmitted by Aedes mosquitoes and has become a serious global public health problem. In mainland China, a number of large dengue outbreaks with serious consequences have been reported as early as 1978. In the three decades from 1978 to 2008, a total of 655,324 cases were reported, resulting in 610 deaths. Since the 1990s, dengue epidemics have spread gradually from Guangdong, Hainan, and Guangxi provinces in the southern coastal regions to the relatively northern and western regions including Fujian, Zhejiang, and Yunnan provinces. As the major transmission vectors of dengue viruses, the biological behavior and vectorial capacity of Aedes mosquitoes have undergone significant changes in the last two decades in mainland China, most likely the result of urbanization and global climate changes. In this review, we summarize the geographic and temporal distributions, the serotype and genotype distributions of dengue viruses in mainland China, and analyze the current status of surveillance and control of vectors for dengue transmission.


Hypophosphatasia: a developmental anomaly of alkaline phosphatase?
This report deals with quantitative and qualitative investigations of alkaline phosphatase in two unrelated infants with the severe infantile form of hypophosphatasia. Both affected infants had no detectable leukocyte alkaline phosphatase activities and both sets of parents and one sibling tended to have low but variable leukocyte enzyme activities. Normal duodenal juice alkaline phosphatase activity was present in the one patient in whom it was measured and a wide range of variation in enzymic activity was observed in the stools. There was no significant difference in the stool enzyme activity between both patients with hypophosphatasia (42.01 +/- 9.77 U) and control infants (40.55 +/- 6.29 U). However, the heterozygous parents had values significantly lower than the control adults (2.10 +/- 0.47 as compared with 19.10 +/- 4.44 U). Intestinal bacteria did not contribute significantly to the stool alkaline phosphatase activity. Enzyme activity was present in the bile of one of the patients and nearly absent in that of the other. Three "inducers" of alkaline phosphatase were given to both patients (phenobarbital, vitamin A, and corticosteroid). No clinical improvement or rise in serum alkaline phosphatase activity was observed during the trial of therapy with these agents. However, a significant increase in the activity of serum acid phosphatase was demonstrated during the course of vitamin A administration, suggesting an in vivo action of vitamin A on the lysosomes through decreasing the stability of the membrane and releasing acid phosphatase to the serum. Quantitative determination of tissue alkaline phosphatases from autopsy tissues was highly variable: no activity was found in bone, lungs, or spleen of either infant; there was a discrepancy in liver and kidney alkaline phosphatase values (zero in one patient and present in the other) and activity was present in the intestinal mucosa of both. Qualitative analysis of kidney, liver, and intestinal alkaline phosphatase revealed some differences between the patients and control subjects in heat inactivation and phenylalanine inhibition (Table 3). Starch gel electrophoresis of the liver preparation of one patient disclosed a single band which had greater mobility than that of six control subjects matched for age. Liver extracts from a premature and from full term newborns showed two bands. The single band of the patient's liver enzyme corresponded to the newborn's fast moving component. In addition, the intestinal enzyme prepared from the same patient had an extra band when compared with age-matched control subjects.


Antioxidant activity of pomegranate juice reduces emphysematous changes and injury secondary to cigarette smoke in an animal model and human alveolar cells.
Cigarette smoke (CS) increases oxidative stress (OS) in the lungs. Pomegranate juice (PJ) possesses potent antioxidant activities, attributed to its polyphenols. This study investigates the effects of PJ on the damaging effects of CS in an animal model and on cultured human alveolar cells (A549). Male C57BL/6J mice were divided into the following groups: Control, CS, CS + PJ, and PJ. Acute CS exposure was for 3 days, while chronic exposure was for 1 and 3 months (5 days of exposure/week). PJ groups received daily 80 μmol/kg via bottle, while other groups received distilled water. At the end of the experiments, different parameters were studied: 1) expression levels of inflammatory markers, 2) apoptosis, 3) OS, and 4) histopathological changes. In vitro, A549 cells were pretreated for 48 hours with either PJ (0.5 μM) or vehicle. Cells were then exposed to increasing concentrations of CS extracted from collected filters. Cell viability was assessed by counting of live and dead cells with trypan blue staining. Acutely, a significant increase in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression, apoptosis, and OS was noted in CS when compared to Control. PJ significantly attenuated the expression of inflammatory mediators, apoptosis, and OS. Chronically (at 1 and 3 months), increased expression of TNF-α was observed, and lung sections demonstrated emphysematous changes when compared to Control. PJ supplementation to CS animals attenuated the increased expression of TNF-α and normalized lung cytoarchitecture. At the cellular level, CS extract reduced cellular proliferation and triggered cellular death. Pretreatment with PJ attenuated the damaging effects of CS extract on cultured human alveolar cells. The expression of inflammatory mediators associated with CS exposure and the emphysematous changes noted with chronic CS exposure were reduced with PJ supplementation. In vitro, PJ attenuated the damaging effects of CS extract on cultured human alveolar cells.


Environmental and Dietary Risk Factors for Colonic Diverticulosis and Diverticulitis.
Colonic diverticulosis (CD) is among the most common conditions of the large bowel. Several factors have been associated with an increased risk of CD and its complications, including advanced age, obesity, physical inactivity, and a low-fiber diet. Available data is conflicting and a comprehensive analysis of different bowel, dietary and environmental habits linked with CD is lacking. We aimed to investigate the relationship between potential risk factors and CD prevalence using full data from a colonoscopy-based cross-sectional study in Europe. The study was conducted at three tertiary referral centers in Germany and Lithuania. It included consecutive adult patients referred for routine colonoscopy who completed a detailed questionnaire on our considered multiple risk factors for diverticulosis and diverticulitis, including dietary and environmental factors, and bowel habits. The study included 1,333 patients, 696 women and 635 men. Colonic diverticulosis was diagnosed in 858 (64%) of patients. Multivariate analysis revealed that age (OR: 1.08, 95%CI: 1.06-1.10, p<0.001) and obesity (OR: 1.05, 95%CI: 1.02-1.09, p=0.004) were associated with CD. We also revealed new risk factors for CD: increased frequency of bowel movements (OR: 0.10, 95%CI: 0.03-0.33, p<0.001) and feeling of incomplete bowel emptying (OR: 2.05, 95%CI: 1.47-2.87, p<0.001). Older participants had reduced odds (OR: 0.921, 95 CI: 0.89-0.95, p<0.05) of diverticulitis compared to younger subjects. Feeling of incomplete bowel emptying after defecation was associated with increased odds (OR: 2.769, 95% CI 1.35-5.7, p<0.006) for diverticulitis. Moreover, participants with a higher educational status had increased odds (OR: 2.453, 95%CI: 1.31-4.59, p=0.005) for diverticulitis compared to the lower education group. Study shows that older age, obesity, frequency of bowel movements, and feeling of incomplete bowel emptying are associated with the risk of CD. Furthermore, older age, feeling of incomplete bowel emptying, and higher education were associated with the risk of diverticulitis among CD patients.


Areal spread of the effect of cloud seeding at the whitetop experiment.
With reference to arguments that weather modification technology is sufficiently advanced for the federal government to finance cloud-seeding operations as a means of alleviating water shortages, an analysis of the Whitetop rain stimulation experiment was performed. The average 24-hour precipitation in six concentric regions up to 180 miles from the center of the target on 102 days of cloud seeding was less than that on the 96 experimental days without seeding. For distances less than 30 miles, the apparent loss of rain due to seeding was 32 percent. With the increase in distance, this apparent loss decreased to a minimum of 9 percent for gages between 120 and 150 miles from the center. However, the 48 gages at distances between 150 and 180 miles showed a 22 percent apparent loss of rain due to seeding. The estimated average loss of rain within the whole region of about 100,000 square miles was 21 percent of what would have fallen without seeding. When a 5-year experiment, expected to produce a 5 to 10-percent increase, shows a 20-percent decrease in rainfall, the relevant technology does not appear reliable enough for practical use.


Direct maternal deaths attributable to HIV in the era of antiretroviral therapy: evidence from three population-based HIV cohorts with verbal autopsy.
To assess whether HIV is associated with an increased risk of mortality from direct maternal complications. Population-based cohort study using data from three demographic surveillance sites in Eastern and Southern Africa. We use verbal autopsy data, with cause of death assigned using the InSilicoVA algorithm, to describe the association between HIV and direct maternal deaths amongst women aged 20-49 years. We report direct maternal mortality rates by HIV status, and crude and adjusted rate ratios comparing HIV-infected and uninfected women, by study site and by ART availability. We pool the study-specific rate ratios using random-effects meta-analysis. There was strong evidence that HIV increased the rate of direct maternal mortality across all the study sites in the period ART was widely available, with the rate ratios varying from 4.5 in Karonga, Malawi [95% confidence interval (CI) 1.6-12.6] to 5.2 in Kisesa, Tanzania (95% CI 1.7-16.1) and 5.9 in uMkhanyakude, South Africa (95% CI 2.3-15.2) after adjusting for sociodemographic confounders. Combining these adjusted results across the study sites, we estimated that HIV-infected women have 5.2 times the rate of direct maternal mortality compared with HIV-uninfected women (95% CI 2.9-9.5). HIV-infected women face higher rates of mortality from direct maternal causes, which suggests that we need to improve access to quality maternity care for these women. These findings also have implications for the surveillance of HIV/AIDS-related mortality, as not all excess mortality attributable to HIV will be explicitly attributed to HIV/AIDS on the basis of a verbal autopsy interview.


Health & nutritional status of HIV infected children in Hyderabad, India.
Information on nutritional status of HIV infected children from India is lacking and is required before taking up nutritional supplementation trials. Thus, the aim of the present study was to assess the growth and morbidity status of HIV infected children over a period of one year in a city in southern India. This was an observational study carried out between July 2009 and February 2011, at two orphanages in Hyderabad, India. Seventy seven HIV-positive children aged between 1 and half and 15 years, both on and not on antiretroviral therapy (ART) were included. Nutritional status was assessed longitudinally for one year by weight gain, linear growth and body composition. Serum samples were analyzed for haemoglobin, micronutrients, CD4 and CD8 counts. Dietary intakes were assessed by institutional diet survey and morbidity data were recorded every day for 12 months. Mean energy intakes were less than recommended dietary allowance (RDA) in all age groups. Iron and folate intakes were less than 50 per cent of RDA; 46 (59.7%) children were stunted, 36 (46.8%) were underweight and 15 (19.5%) had low BMI for age. Anaemia was observed in 35 (45.5%) children. Micronutrient deficiencies such as vitamin D (40/77; 51.9%), vitamin A (11/77; 14.3%), folate (37/77; 48.1%), iron (38/77; 49.3%) were widely prevalent. HIV viral load was higher in children not on ART and those with morbidity. Respiratory (36.6%) and dermatological illnesses (18.8%) were the commonest presentations. Acute, chronic malnutrition and micronutrient deficiencies were common in HIV infected children, especially in those not on ART and having morbidity. With severe malnutrition being an alarming consequence of HIV, prophylactic nutritive care should be considered for integration into HIV care strategies besides initiation of ART to improve the nutritional status and quality of life of these children.


Will hospital closures mean physician unemployment in Ontario?
Dr. Duncan Sinclair, the former dean of medicine who heads the commission charged with restructuring Ontario's health care system, said something dramatic was needed to revamp the system. He wasn't kidding. His commission recently called for the closure of 3 hospitals in Ottawa and 10 more in Toronto. In a wideranging interview with Charlotte Gray he talks about the commission's goals and their potential impact on physicians.


3-D visualization of acute RF ablation lesions using MRI for the simultaneous determination of the patterns of necrosis and edema.
Catheter ablation using RF energy is a common treatment for atrial arrhythmias. Although this treatment provides a potential cure, currently, there remains a high proportion of patients returning for repeat ablations. Electrophysiologists have little information to verify that a lesion has been created in the myocardium. Temporary electrical block can be created from edema, which will subside. MRI can visualize acute and chronic ablation lesions using delayed-enhancement techniques. However, the ablation patterns cannot be determined from 2-D images alone. Using the combination of T(2)-weighted and delayed-enhancement MRI, ablation lesions can be characterized in terms of necrosis and edema. A novel 3-D visualization technique is presented that projects the image intensity due the lesions onto a 3-D cardiac surface, allowing the complete, simultaneous visualization of the delayed-enhancement and T(2)-weighted ablation patterns. Results show successful visualization of ablation patterns in 18 patients, and an application of this technique is presented in which electroanatomical mapping systems can be validated by overlaying the acquired ablation points onto the cardiac surfaces and assessing the correlation with the lesion maps.


Increase in average foveal thickness after internal limiting membrane peeling.
To report the findings in three cases in which the average foveal thickness was increased after a thin epiretinal membrane (ERM) was removed by vitrectomy with internal limiting membrane (ILM) peeling. The foveal contour was normal preoperatively in all eyes. All cases underwent successful phacovitrectomy with ILM peeling for a thin ERM. The optical coherence tomography (OCT) images were examined before and after the surgery. The changes in the average foveal (1 mm) thickness and the foveal areas within 500 μm from the foveal center were measured. The postoperative changes in the inner and outer retinal areas determined from the cross-sectional OCT images were analyzed. The average foveal thickness and the inner and outer foveal areas increased significantly after the surgery in each of the three cases. The percentage increase in the average foveal thickness relative to the baseline thickness was 26% in Case 1, 29% in Case 2, and 31% in Case 3. The percentage increase in the foveal inner retinal area was 71% in Case 1, 113% in Case 2, and 110% in Case 3, and the percentage increase in foveal outer retinal area was 8% in Case 1, 13% in Case 2, and 18% in Case 3. The increase in the average foveal thickness and the inner and outer foveal areas suggests that a centripetal movement of the inner and outer retinal layers toward the foveal center probably occurred due to the ILM peeling.


Lack of cosegregation of the subgroup II antigens on genes 2 and 6 in porcine rotaviruses.
The rotavirus subgroup I and II specificities associated with gene 2 and 6 products (vp2 and vp6, respectively) were shown not to cosegregate in a number of porcine rotavirus strains. The porcine OSU rotavirus strain and OSU-vp7-like strains were all found to possess a subgroup II-specific region on vp2 and a subgroup I-specific region on vp6. Of interest is the observation that the subgroup II-specific epitope on vp2 appears to be present only in human and porcine rotavirus strains, suggesting a possible human-pig ancestral lineage for gene 2.


Social Media Bytes: Daily Associations Between Social Media Use and Everyday Memory Failures Across the Adult Life Span.
The prevalence of social media use in daily life is increasing; however, little is known about its cognitive costs and/or benefits. Social media use may help to offload memory to an external resource as well as to facilitate social relations, which could bolster or hinder everyday memory. Further, the relationship between social media use and memory may be moderated by age such that associations-whether positive or negative-could be exacerbated among older adults due to age-related declines. Using an 8-day daily diary study from the Midlife in the United States Refresher cohort (n = 782, 25-75 years), multilevel models examined the impact of daily social media use, age, and their interaction on same-day and next-day memory failures. The concurrent model revealed that on days when social media use was high, individuals reported more memory failures. The lagged model further revealed that higher previous-day social media use was associated with more memory failures on the subsequent day, controlling for previous-day memory failures. These effects were not moderated by age. Post hoc analyses revealed no evidence of reverse-causation as previous-day memory failures did not predict next-day social media use. Although past research has consistently shown that social engagement is a protective resource for memory, social media use may be a risk factor for memory failures for adults of any age. These findings highlight the growing importance of understanding the implications of social media use.


Highly Ordered 3D Microstructure-Based Electronic Skin Capable of Differentiating Pressure, Temperature, and Proximity.
Electronic skin are devices that mimic the functionalities of human skin, which require high sensitivity, large dynamic range, high spatial uniformity, low-cost and large-area processability, and the capacity to differentiate various external inputs. We herein introduce a versatile droplet-based microfluidic-assisted emulsion self-assembly process to generate three-dimensional microstructure-based high-performance capacitive and piezoresistive pressure sensors for electronic skin applications. Our technique can generate uniformly sized micropores that are self-assembled in an orderly close-packed manner over a large area, which results in high spatial uniformity. The size of the micropores can easily be tuned from 100 to 500 μm, through which sensitivity and dynamic range were controlled as high as 0.86 kPa-1 and up to 100 kPa. Our device can be printed on curvilinear surfaces and be molded into various shapes. We furthermore demonstrate that by simultaneously utilizing capacitive and piezoresistive pressure sensors, we can distinguish between pressure and temperature, or between pressure and proximity. These demonstrations make our process and sensors highly useful for a wide variety of electronic skin applications.


Quinoline, quinazoline and acridone alkaloids.
This review covers the isolation, structure determination, synthesis and biological activity of quinoline, quinazoline and acridone alkaloids from plant, microbial and animal sources; 115 references are cited.


Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14.
Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.


[Treatment of chronic diseases of the liver with catergen].
Fifty-seven patients with chronic liver diseases of different etiology were treated with catergen ((+)-cyanidanol 3) given in a dose of 1.5 g (3 tablets) a day throughout 3 months. The findings were compared with those derived in the control groups of patients (82) who received vitamins or essentiale. It was shown that catergen significantly improved some biochemical characteristics of the blood and indicators of the antipyrine test in patients with compensated liver cirrhosis of the viral and alcoholic etiology. In patients with alcoholic cirrhosis, catergen, like essentiale, exerted an inhibitory effect on lipid peroxidation in the liver. There were no significant differences in the biochemical characteristics of the blood in patients with chronic alcoholic hepatitis treated with catergen and control group patients. In patients with primary biliary cirrhosis, catergen exerted an insignificant symptomatic effect but in single cases. The side dyspeptic effects which demanded the drug withdrawal were only recorded in 2 patients. It is concluded that catergen may be used in the treatment of virus- and alcohol-induced chronic liver diseases of moderate activity.


Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer.
This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.


Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: a controlled, population-based study.
Although hyperinsulinemia seems to be an essential feature of polycystic ovary syndrome, the frequency of gynecologic disorders related to polycystic ovary syndrome at a population level in women with evident metabolic syndrome is not known. We conducted a cross-sectional, population-based study. Participants (N = 204) were recruited from a random sample of women in 5 age groups (range, 35-54 years) living in a defined area. Metabolic syndrome was considered to be present if 3 of the following 8 criteria were fulfilled: (1) first-degree relative with type II diabetes, (2) body mass index > or = 30 kg/m2, (3) waist/hip ratio > or = 0.88, (4) blood pressure > or = 160/95 mm Hg or drug treatment for hypertension, (5) fasting serum triglyceride level > or = 1.70 mmol/L, (6) high-density lipoprotein cholesterol value < 1.20 mmol/L, (7) abnormal glucose metabolism, and (8) fasting insulin value > or = 13.0 mU/L. The frequency of metabolic syndrome was 106 (19.5%) of 543 cases. The control group consisted of 62 overweight women without central obesity or metabolic syndrome and 53 healthy lean women (body mass index < 27 kg/m2. The group with metabolic syndrome differed from the other women according to most of the selection criteria and also had the highest free testosterone concentration. However, there were no differences between the groups regarding parity, infertility problems, or obstetric outcome. However, oligomenorrhea appeared to be more common in women with metabolic syndrome, especially in those with more severe symptoms (46.2%), than in obese (25.4%) and lean (15.1%) control subjects. Polycystic-like ovaries were detected by vaginal ultrasonography with similar frequency (13.1%, 15.3%, and 13.2% in women with metabolic syndrome, obese women, and lean women, respectively). Surprisingly few women with metabolic syndrome had symptoms suggestive of polycystic ovary syndrome, in comparison with obese and lean women. Our results suggest that at the population level polycystic ovary syndrome only accounts for a distinct subgroup of a much wider problem, metabolic syndrome.


Bacterial DNA containing methylated CpG motifs retains immunostimulatory activity in synergy with modified lipopolysaccharides.
We previously described the immunostimulatory activity of CIA07, a combination of bacterial DNA fragments and modified LPS, and demonstrated that CIA07 has antitumor activity in a mouse bladder cancer model. In this study, we investigated whether methylation of the CpG motifs on the bacterial DNA fragments affects the immunostimulatory potential of CIA07. E. coli DNA fragments were methylated with CpG methylase, and then combined with modified LPS for experiments. Our results revealed that methylated CIA07 (mCIA07) and unmethylated CIA07 were equally active in inducing cytokine secretion from human whole blood cells. In addition, both methylated DNA fragments and mCIA07 retained the ability to activate expression and nuclear translocation of NF-kappaB in RAW 264.7 cells. Finally, methylated DNA fragments and mCIA07 exhibited an antitumor activity comparable to those of their unmethylated counterparts in our mouse bladder cancer model. These data demonstrate that CpG methylation of E. coli DNA does not abrogate the immunostimulatory activity of DNA fragments or CIA07, suggesting that the synergistic activity by bacterial DNA in combination with LPS may be independent of the methylation status of CpG motifs.


Junctional membrane uncoupling. Permeability transformations at a cell membrane junction.
The permeability of the membrane surfaces where cells are in contact (junctional membranes) in Chironomus salivary glands depends on Ca(++) and Mg(++). When the concentration of these ions at the junctional membranes is raised sufficiently, these normally highly permeable membranes seal off; their permeability falls one to three orders, as they approach the nonjunctional membranes in conductance. This permeability transformation is achieved in three ways: (a) by iontophoresis of Ca(++) into the cell; (b) by entry of Ca(++) and/or Mg(++) from the extracellular fluid into the cell through leaks in the cell surface membrane (e.g., injury); or (c) by entry of these ions through leaks arising, probably primarily in the perijunctional insulation, due to trypsin digestion, anisotonicity, alkalinity, or chelation. Ca(++) and Mg(++) appear to have three roles in the junctional coupling processes: (a) in the permeability of the junctional membranes; (b) in the permeability of the perijunctional insulation; and (c) a role long known- in the mechanical stability of the cell junction. The two latter roles may well be closely interdependent, but the first is clearly independent of the others.


The Latin American Cancer Research Information Project (LACRIP): an evaluation of its development in Mexico.
In 1979 the National Cancer Institute, the Pan American Health Organization, and the Latin American Information and Documentation Center (Brazil) jointly sponsored the Latin American Cancer Information Project. This paper reports the objectives, development, and utilization of this service as it is administered by the National Health Information Documentation Center in Mexico. Evaluation of the project provides insight into problems of information dissemination in countries that are experiencing great economic instability.


The role of immature granulocyte in the early prediction of acute perforated and nonperforated appendicitis in children.
Acute appendicitis (AA) is the most common reason for pediatric abdominal surgery in the world. Despite ad-vances in science and technology, diagnosing AA is still difficult today, and complications are common as a result. The early prediction of complicated appendicitis is of great importance for the surgical planning, further treatments, and predicting the course of disease. The immature granulocyte (IG) is a new and more effective marker in predicting the severity of inflammation than traditional markers. Our aim is to determine the effectiveness of IG% in the diagnosis and severity of AA. Eighty-eight patients diagnosed with AA and a control group of fifty-eight healthy children were included in this prospec-tive study. Patients with pathologically confirmed AA were divided into two subgroups: acute simple appendicitis (ASA) and acute perforated appendicitis (APA). The demographic characteristics, white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), IG%, and C-reactive protein (CRP) values were analyzed. Receiver operating characteristics (ROC) anal-ysis was used to compare the diagnostic accuracies and predictive performances. Patients with AA had higher IG%, WBC count, NLR, and MPV value than control group (p=0.28, p=0.22, p<0.001, p=0.001, respectively). Only IG% showed statistically significant difference from other inflammatory markers evaluated in ASA and APA patients (p<0.001). ROC analysis showed that IG% is a good predictor for the presence of APA at an optimal cut-off for IG being 0.2% (sensitivity 81.8%, specificity 85.2%, area under the ROC curve 0.83). In the present study, we demonstrated that AA patients with higher IG levels might be more likely to develop perforation. The IG values combined with a physical examination, imaging studies, and other laboratory tests may help clinicians to identify high-risk AA patients in the pediatric emergency department.


Humibacter soli sp. nov., isolated from soil.
A novel actinobacterial strain, designated R1-20T, was isolated during a study of the bacterial diversity of the soil at a white heron nesting site. The isolate was non-motile, Gram-stain-positive and short rod-shaped. Colonies were dull white and convex with entire margin during the early stages of growth, and gradually became yellow. 16S rRNA gene sequence analysis indicated that the isolate belongs to the genus Humibacter of the family Microbacteriaceae, as sequence similarity with its nearest neighbours was 97.16 % with Humibacter antriD7-27Tand 96.44 % with Humibacter albusDSM 18994T. However, the combination of cultural and physiological as well as chemotaxonomic properties clearly distinguished strain R1-20T from other Humibacter species. The DNA G+C content of strain R1-20T was 65.5 mol%, and the major respiratory isoprenoid quinone was menaquinone MK-11. The acyl group of the peptidoglycan was of acetyl type, and the diagnostic diamino acid was 2,4-diaminobutyric acid. Glutamic acid, alanine and glycine were also present in the cell wall. The major fatty acids of strain R1-20T were anteiso-C17 : 0, iso-C16 : 0 and anteiso-C15 : 0. On the basis of phylogenetic, phenotypic and chemotaxonomic analysis, strain R1-20T merits recognition as a representative of a novel species of the genus Humibacter, for which the name Humibacter soli sp. nov. is proposed. The type strain is R1-20T (=KCTC 39614T=JCM 31015T).


Successful treatment of focal renal artery fibromuscular dysplasia by balloon dilatation demonstrated via fractional flow reserve.
We present a rare case of fibromuscular dysplasia (FMD) manifesting in the mid segment of right renal artery, which led to the development of refractory hypertension. The patient received balloon angioplasty to a severe lesion on the middle of right renal artery and subsequently had normalisation of blood pressures. Fractional flow reserve (FFR) detection of the renal artery before and after balloon dilatation was 0.71 and 0.98, respectively. The patient showed renal artery stenosis (RAS) with distal tumour-like dilatation, and multiple tortuosity and stenosis in carotid artery and coronary artery. At follow-up 2 months later, her blood pressures had normalised.


Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants.
Homocystinuria (HCU), an inherited metabolic disorder caused by lack of cystathionine beta-synthase (CBS) activity, is chiefly caused by misfolding of single amino acid residue missense pathogenic variants. Previous studies showed that chemical, pharmacological chaperones or proteasome inhibitors could rescue function of multiple pathogenic CBS variants; however, the underlying mechanisms remain poorly understood. Using Chinese hamster DON fibroblasts devoid of CBS and stably overexpressing human WT or mutant CBS, we showed that expression of pathogenic CBS variant mostly dysregulates gene expression of small heat shock proteins HSPB3 and HSPB8 and members of HSP40 family. Endoplasmic reticulum stress sensor BiP was found upregulated with CBS I278T variant associated with proteasomes suggesting proteotoxic stress and degradation of misfolded CBS. Co-expression of the main effector HSP70 or master regulator HSF1 rescued steady-state levels of CBS I278T and R125Q variants with partial functional rescue of the latter. Pharmacological proteostasis modulators partially rescued expression and activity of CBS R125Q likely due to reduced proteotoxic stress as indicated by decreased BiP levels and promotion of refolding as indicated by induction of HSP70. In conclusion, targeted manipulation of cellular proteostasis may represent a viable therapeutic approach for the permissive pathogenic CBS variants causing HCU.


ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6 specific nanobody restricts M. tuberculosis growth in macrophages.
Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6's mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.


[Antagonistic activity of lactobacilli of the colon].
Study of antagonistic activity of lactobacilli of the colon against members of its autochthonous bacterial flora and agents of some acute infectious and chronic diseases of the gastrointestinal tract. Antagonistic activity of 19 lactobacilli cultures against 28 cultures of bacteria belonging to various groups and fungi was evaluated within the framework of specially developed two-stage cultivation technique in the conditions of a combined system. The results of the study were evaluated according to a semi-quantitative scale that allows to put one or the other value of the zone of growth delay of the studied strain culture in compliance with the one or the other (low, moderate, high) level of antagonistic activity of the lactobacillus culture. Lactobacilli of the colon showed selective antagonistic activity against pathogenic enterobacteriae: pronounced against Salmonella enterica Serovar Enteritidis, Shigella flexneri 2b, Yersinia spp., and trace against Salmonella enterica Serovar Typhimurium. The level of antagonistic activity of lactobacilli against a wide range of members of autochthonous bacterial flora varied in a wide range, without revealing connection neither to its belonging to species, nor to its population level, nor to the belonging to group of the antagonistic effect objects. On the other hand a connection was traced with beloriging to a certain microbiota: being quite active against members of its own microbiota, lactobacilli often showed significantly lower level of antagonistic activity against cultures with the same species name isolated from other microbiota. In light of the results obtained, level of lactobacilli population may hardly be viewed as the only criteria of their full participation in the process of stabilizing microecological welfare of the colon, that allows to make a complete representation of the level of dysbiotic disorder in the mentioned biotope. With in the framework of rational bacteriological diagnostics of the level of dysbiotic disorders in the colon, evaluation of population level of lactobacilli should be evaluated along with the degree of their antagonistic activity against other components of the same microbiota.


Integrative analysis of single nucleotide polymorphisms and gene expression efficiently distinguishes samples from closely related ethnic populations.
Ancestry informative markers (AIMs) are a type of genetic marker that is informative for tracing the ancestral ethnicity of individuals. Application of AIMs has gained substantial attention in population genetics, forensic sciences, and medical genetics. Single nucleotide polymorphisms (SNPs), the materials of AIMs, are useful for classifying individuals from distinct continental origins but cannot discriminate individuals with subtle genetic differences from closely related ancestral lineages. Proof-of-principle studies have shown that gene expression (GE) also is a heritable human variation that exhibits differential intensity distributions among ethnic groups. GE supplies ethnic information supplemental to SNPs; this motivated us to integrate SNP and GE markers to construct AIM panels with a reduced number of required markers and provide high accuracy in ancestry inference. Few studies in the literature have considered GE in this aspect, and none have integrated SNP and GE markers to aid classification of samples from closely related ethnic populations. We integrated a forward variable selection procedure into flexible discriminant analysis to identify key SNP and/or GE markers with the highest cross-validation prediction accuracy. By analyzing genome-wide SNP and/or GE markers in 210 independent samples from four ethnic groups in the HapMap II Project, we found that average testing accuracies for a majority of classification analyses were quite high, except for SNP-only analyses that were performed to discern study samples containing individuals from two close Asian populations. The average testing accuracies ranged from 0.53 to 0.79 for SNP-only analyses and increased to around 0.90 when GE markers were integrated together with SNP markers for the classification of samples from closely related Asian populations. Compared to GE-only analyses, integrative analyses of SNP and GE markers showed comparable testing accuracies and a reduced number of selected markers in AIM panels. Integrative analysis of SNP and GE markers provides high-accuracy and/or cost-effective classification results for assigning samples from closely related or distantly related ancestral lineages to their original ancestral populations. User-friendly BIASLESS (Biomarkers Identification and Samples Subdivision) software was developed as an efficient tool for selecting key SNP and/or GE markers and then building models for sample subdivision. BIASLESS was programmed in R and R-GUI and is available online at http://www.stat.sinica.edu.tw/hsinchou/genetics/prediction/BIASLESS.htm.


A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression.
A large body of evidence indicates that major affective disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum depression. This review provides a critical appraisal of available evidence linking IO&NS pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites, lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression.


[Characteristics of regulatory system in children exposed to the environmental chemical factors].
In children residing in areas with a high content of a number of aromatic hydrocarbons in ambient air and organochlorine compounds in drinking water there were studied the blood levels of these compounds, as well as the assessment of the indices of the immune and neuroendocrine systems was performed. The higher blood content of phenol and formaldehyde has been established and there was identified an array of organochlorine and aromatic compounds not detected in the control group children. In the blood of the children of a study group there was found an imbalance of indices of cellular components of innate and adaptive immunity, pro- and anti-inflammatory cytokines, as well as increased concentrations of free thyroxine and serotonin in the blood serum, which indicates to a change in the functions of regulatory systems in children exposed to organochlorine and aromatic compounds.


Estimation of delay to diagnosis and incidence in HIV using indirect evidence of infection dates.
Minimisation of the delay to diagnosis is critical to achieving optimal outcomes for HIV patients and to limiting the potential for further onward infections. However, investigation of diagnosis delay is hampered by the fact that in most newly diagnosed patients the exact timing of infection cannot be determined and so inferences must be drawn from biomarker data. We develop a Bayesian statistical model to evaluate delay-to-diagnosis distributions in HIV patients without known infection date, based on viral sequence genetic diversity and longitudinal viral load and CD4 count data. The delay to diagnosis is treated as a random variable for each patient and their biomarker data are modelled relative to the true time elapsed since infection, with this dependence used to obtain a posterior distribution for the delay to diagnosis. Data from a national seroconverter cohort with infection date known to within ± 6 months, linked to a database of viral sequences, are used to calibrate the model parameters. An exponential survival model is implemented that allows general inferences regarding diagnosis delay and pooling of information across groups of patients. If diagnoses are only observed within a given window period, then it is necessary to also model incidence as a function of time; we suggest a pragmatic approach to this problem when dealing with data from an established epidemic. The model developed is used to investigate delay-to-diagnosis distributions in men who have sex with men diagnosed with HIV in London in the period 2009-2013 with unknown date of infection. Cross-validation and simulation analyses indicate that the models developed provide more accurate information regarding the timing of infection than does CD4 count-based estimation. Delay-to-diagnosis distributions were estimated in the London cohort, and substantial differences were observed according to ethnicity. The combination of all available biomarker data with pooled estimation of the distribution of diagnosis-delays allows for more precise prediction of the true timing of infection in individual patients, and the models developed also provide useful population-level information.


Fluorimetric assay of the neurotensin-degrading metalloendopeptidase, endopeptidase 24.16.
Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp (Mcc = 3-carboxy-7-methoxycoumarin; Dnp = dinitrophenyl), a quenched fluorimetric substrate originally designed as a probe to measure Pz-peptidase (also called endopeptidase 24.15), was examined as a putative substrate of the neurotensin-degrading neutral metalloendopeptidase, endopeptidase 24.16. During the purification of endopeptidase 24.16 the neurotensin(1-10) and neurotensin(11-13) formation due to this enzyme was coeluted with Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp-hydrolysing activity. By both fluorimetric and h.p.l.c. analyses, we observed that the latter activity was dose-dependently and completely abolished by neurotensin with an IC50 value (2.6 microM) that closely corresponds to the affinity of purified endopeptidase 24.16 for neurotensin (Km = 2.5 microM). Furthermore, Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp hydrolysis was inhibited by a series of dipeptides with a rank of order of potencies that parallels that observed in competition experiments of tritiated neurotensin hydrolysis by brain and intestinal endopeptidase 24.16. Altogether, these data clearly demonstrate that, in addition to Pz-peptidase, Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp also behaves as a substrate of endopeptidase 24.16, with a Km of about 26 microM. In addition, we show that, even in crude membrane preparations, Mcc-Pro-Leu-Gly-Pro-D-Lys-Dnp behaves as a useful tool to monitor and accurately quantify endopeptidase 24.16.


Transcranial Electrical Motor Evoked Potential in Predicting Positive Functional Outcome of Patients after Decompressive Spine Surgery: Review on Challenges and Recommendations towards Objective Interpretation.
Spine surgeries impose risk to the spine's surrounding anatomical and physiological structures especially the spinal cord and the nerve roots. Intraoperative neuromonitoring (IONM) is a technology developed to monitor the integrity of the spinal cord and the nerve roots via the surgery. Transcranial motor evoked potential (TcMEP) (one of the IONM modalities) is adopted to monitor the integrity of the motor pathway of the spinal cord and the motor nerve roots. Recent research suggested that the IONM is conducive as a prognostic tool towards the patient's functional outcome. This paper summarizes the researches of IONM being adopted as a prognostic tool. In addition, this paper highlights the problems associated with the signal parameters as the improvement criteria in the previous researches. Lastly, we review the challenges of TcMEP to achieve a prognostic tool focusing on the factors that could interfere with the generation of a stable TcMEP response. The final section will discuss recommendations for IONM technology to achieve an objective prognostic tool.


Treatment of pelvic osteolysis associated with a stable acetabular component inserted without cement as part of a total hip replacement.
Thirty-five patients who had had a primary total hip replacement with a porous-coated acetabular component inserted without cement had a revision procedure to treat pelvic osteolysis. The mean age at the time of the revision operation was forty-nine years (range, twenty-nine to eighty-five years). Forty-six distinct pelvic osteolytic lesions were noted radiographically around the thirty-five cups. These lesions ranged in size from 0.5 by 0.5 centimeter to 6.3 by 2.7 centimeters (mean, 2.6 by 1.7 centimeters). Fourteen of the thirty-five patients had no or only slight occasional pain at the time of diagnosis of the pelvic osteolysis, fifteen patients had pain attributed to a loose femoral component, one had pain related to a spontaneous fracture of the greater trochanter, and one had pain related to recurrent subluxation. The remaining four patients had pain in the groin despite radiographically stable implants. All of the metal-backed porous-coated acetabular components were stable according to the preoperative radiographs, and the stability was confirmed at the time of the revision. The metal shell was left in place and the acetabular liner was exchanged in all thirty-five patients. The osteolytic lesions were debrided, and thirty-four of the forty-six lesions were filled with allograft bone chips. The patients were evaluated a minimum of two years (range, two to five years; mean, 3.3 years) after the revision operation, and all thirty-five sockets were found to be radiographically stable. The bone grafts appeared to have consolidated, and none of the osteolytic defects had progressed. One-third of the lesions were no longer visible on radiographs, regardless of whether or not they had been filled with bone graft. The remaining lesions had decreased in size. It appears that, in the short-term, exchange of the liner and debridement of the granuloma, with or without use of allograft bone chips in the osteolytic defect, is a reasonable alternative to revision of the socket provided that the metal shell is solidly fixed at the time of the revision operation. If the metal shell has been markedly damaged by the femoral head, the locking mechanism for the polyethylene liner is not intact, or a satisfactory replacement liner is not available, then revision of the porous-coated acetabular component is indicated. These results must be considered preliminary. Since osteolysis may take several years to redevelop after a revision, additional follow-up is required.


Microbial, Physicochemical, and Sensory Characteristics of Quality Grade 2 Beef Enhanced by Injection of Pineapple Concentrate and Honey.
This study investigated the effect of injecting pineapple concentrate and honey into low marbled beef in order to enhance its sensory qualities, particularly tenderness and flavor, without compromising its fresh appearance. Beef loin was injected with a solution of 6.0% pineapple concentrate, 2.5% honey, 0.5% monosodium L-glutamate, 0.5% phosphate, and 0.3% salt (w/w) to 120% (w/w) of initial meat weight and stored for 14 d. Non-injected beef loin served as a control. Total aerobic bacterial counts, surface meat color, shear force, reducing sugar content, and sensory evaluation of the beef were analyzed at 0.5, 7, and 14 d of storage. Injection did not affect the total aerobic bacterial counts or color of the beef. However, injection increased the stability of meat color, compared with that of the control, during storage. The shear force value was significantly lower in the injected beef than that in the control. The injected beef had a significantly higher reducing sugar content compared with that of the control. In sensory evaluation, tenderness, juiciness, flavor, and overall acceptance of the injected beef were significantly higher than those of the control at 0.5 d. In conclusion, injection of pineapple concentrate and honey can improve the sensory qualities of low marbled beef, during short storage periods, without changing the fresh appearance of the beef.


A multimodal, longitudinal investigation of alcohol's emotional rewards and drinking over time in young adults.
Theories of alcohol use disorder (AUD) have long suggested that alcohol's emotional rewards play a key role in reinforcing problematic drinking. Studies employing survey methods, in which participants recall and aggregate their experiences with alcohol in a single questionnaire, indicate that self-reported expectancies and motivations surrounding alcohol's emotional rewards predict problematic drinking trajectories over time. The current study is the first to combine laboratory alcohol-administration, ambulatory methods, and longitudinal follow-ups to assess whether alcohol's ability to enhance positive mood and reduce negative mood predicts later drinking problems. Sixty young heavy social drinkers (50% female) participated in laboratory-based alcohol-administration, attending both alcohol (target blood alcohol concentration [BAC] .08%) and no-alcohol laboratory sessions. Forty-eight of these participants also wore transdermal alcohol monitors and completed mood surveys outside the laboratory for 7 days. Participants reported on their drinking at 18-month follow-up (90% compliance). Controlling for baseline drinking, greater negative mood reduction from alcohol at baseline predicted more drinking problems at follow-up, an effect that emerged as consistent across methods capturing alcohol's emotional rewards in the laboratory, b = -.24, p = .02, as well as via ambulatory methods, b = -3.14, p = .01. Greater positive mood enhancement from alcohol, captured via laboratory methods, also predicted drinking problems, b = .16, p = .03, and binge drinking, b = 3.22, p = .02, at follow-up. Models examining drinking frequency/quantity were nonsignificant. Results provide support for emotional reward as a potential factor in the development of problematic drinking. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Dual roles of vascular-derived reactive oxygen species--with a special reference to hydrogen peroxide and cyclophilin A.
Reactive oxygen species (ROS) have been considered to play a major role in the pathogenesis of cardiovascular diseases. However, this notion needs to be revised since recent evidence indicates that vascular-derived hydrogen peroxide (H2O2) serves as an important signaling molecule in the cardiovascular system at its low physiological concentrations. At low concentrations, H2O2 can act as a second messenger, transducing the oxidative signal into biological responses through post-translational protein modification. These structural changes ultimately lead to altered cellular function. Intracellular redox status is closely regulated by the balance between oxidant and antioxidant systems and their imbalance can cause oxidative or reductive stress, leading to cellular damage and dysregulation. For example, excessive H2O2 deteriorates vascular functions and promotes vascular disease through multiple pathways. Furthermore, cyclophilin A (CyPA) has been shown to be secreted from vascular smooth muscle cells and to augment the destructive effects of ROS, linking it to the development of many cardiovascular diseases. Thus, it is important to understand the H2O2 signaling and the roles of downstream effectors such as CyPA in the vascular system in order to develop new therapeutic strategies for cardiovascular diseases. In this review, we will discuss the dual roles of vascular-derived H2O2 in mediating vascular functions (physiological roles) and promoting vascular diseases (pathological roles), with particular emphasis on the function of CyPA. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".


Secretion of Phospholipase Dδ Functions as a Regulatory Mechanism in Plant Innate Immunity.
Plant phospholipase Ds (PLDs), essential regulators of phospholipid signaling, function in multiple signal transduction cascades; however, the mechanisms regulating PLDs in response to pathogens remain unclear. Here, we found that Arabidopsis (Arabidopsis thaliana) PLDδ accumulated in cells at the entry sites of the barley powdery mildew fungus, Blumeria graminis f. sp hordei Using fluorescence recovery after photobleaching and single-molecule analysis, we observed higher PLDδ density in the plasma membrane after chitin treatment; PLDδ also underwent rapid exocytosis. Fluorescence resonance energy transfer with fluorescence lifetime imaging microscopy showed that the interaction between PLDδ and the microdomain marker AtREMORIN1.3 (AtREM1.3) increased in response to chitin, indicating that exocytosis facilitates rapid, efficient sorting of PLDδ into microdomains upon pathogen stimulus. We further unveiled a trade-off between brefeldin A (BFA)-resistant and -sensitive pathways in secretion of PLDδ under diverse conditions. Upon pathogen attack, PLDδ secretion involved syntaxin-associated VAMP721/722-mediated exocytosis sensitive to BFA. Analysis of phosphatidic acid (PA), hydrogen peroxide, and jasmonic acid (JA) levels and expression of related genes indicated that the relocalization of PLDδ is crucial for its activation to produce PA and initiate reactive oxygen species and JA signaling pathways. Together, our findings revealed that the translocation of PLDδ to papillae is modulated by exocytosis, thus triggering PA-mediated signaling in plant innate immunity.plantcell;31/12/3015/FX1F1fx1.


Reviewing concomitant medications for participants in oncology clinical trials.
The importance and key components of clinical medication reviews for participants in oncology clinical trials are described, and drug- drug interactions (DDIs) associated with new oncology drug classes are discussed. Use of investigational drugs is a mainstay of adult oncology clinical trials and has led to discovery of new oncology drug classes, including immunotherapy agents and oral targeted therapies, as well as novel chemotherapy delivery methods. As sponsor-supplied DDI information on investigational drugs and drug classes is typically limited and often inconsistent, a clinical medication review to assess the potential for DDIs is recommended for all patients enrolling in oncology clinical trials. A simplified approach to performing such reviews includes (1) evaluating the trial protocol for DDI risks, (2) meeting with the patient face-to-face to perform the review, (3) making medication-related recommendations based on the findings of the patient encounter, and (4) documenting review findings in the medical record. Pharmacists can create a personalized "concomitant-medication review guide" listing key medication-use information in table format to assist other clinicians in preventing and assessing DDIs during a patient's clinical trial participation. Each investigational drug and new drug class in oncology has a unique DDI profile. It is essential that patients be screened for DDI risks prior to clinical trial participation and that pharmacists and clinical investigators have clear guidelines for managing DDIs. Performing a clinical medication review is one approach to simplifying this process and ensuring patient safety.


Overactive bladder syndrome is associated with detrusor overactivity and abnormal voiding pattern in nulliparous women.
Pregnancy and childbirth are frequently associated with overactive bladder syndrome (OAB). However, the role of parous effects in OAB among nulliparous (NP) women remains controversial. This study investigated abnormal voiding patterns and detrusor overactivity (DO) among NP women with OAB in comparison with parous women. From August 2011 to December 2018, 906 patients met the inclusion criteria for participation and were divided into three groups: 221 patients in the NP group, 571 patients in the normal spontaneous delivery (NSD) group, and 114 patients in the cesarean section (CS) group. Urodynamic study examinations were performed, and the presence of DO, abnormal voiding patterns, and maximum urethral closure pressure (MUCP) was recorded. Data were analyzed using analysis of variance, χ2 tests, and independent t tests. Compared with parous women in the NSD and CS groups, patients in the NP group had a significantly higher prevalence of abnormal voiding patterns, DO, and MUCP. Furthermore, abnormal voiding patterns were significantly associated with DO and MUCP, respectively, especially in the NP group. We hypothesized that hypertonicity or poor relaxation of the pelvic muscle in NP women may cause functional BOO, which is related to their OAB.


[Acetaminophen poisonings hospitalized at the Pomeranian Center of Toxicology in 2010-2015].
Acetaminophen is a widely available analgesic and antipyretic medication. Although it is advertised as safe, it is responsible for more than 50% of drug-induced hepatotoxicity cases and the most common cause of acute liver failure in developed countries. Until 2000 the frequency of acetaminophen overdoses in Poland was relatively low, but a significant increase has been seen in recent years. The aim of the study was to perform a demographic analysis of the acetaminophen overdose cases hospitalized at the Pomeranian Center of Toxicology (PCT) in Gdańsk, Poland, in 2010-2015. The Pomeranian Center of Toxicology in Gdańsk is the Regional Clinical Toxicology Center for a population of more than 3.5 million people from the Pomeranian and the Warmian-Masurian Voivodeships. All the patients hospitalized at PCT in 2010-2015 were analyzed. Cases in which the primary or secondary diagnosis was encoded as T39.1, according to the International Classification of Diseases ICD-10, were selected. Statistical analysis was performed using the χ2 and McNemara tests. In the reference period, 7754 poisoned patients were hospitalized, including 4163 men and 3591 women. There were 667 cases of acetaminophen overdose (231 men and 436 women). There was a significant increase in the percentage of acetaminophen overdoses in 2010-2015 (6.5% and 10.8%, p < 0.01). In the group aged < 18 years, there were 217 cases of acetaminophen overdose (37 men and 180 women). The share or acetaminophen overdose cases in this group (17.2%) was significantly higher than among patients aged ≥ 18 years (6.9%, p < 0.01). The male to female ratio in the group aged ≥ 18 years was 0.75, and in the group aged < 18 years it was 0.21 (p < 0.01). There was a significant increase in the number of acetaminophen overdose cases hospitalized at the Pomeranian Center of Toxicology in 2010-2015. The share of acetaminophen overdoses was significantly higher in the group aged < 18 years than in the adult group. In both age groups, acetaminophen overdose was more frequent in women. Med Pr. 2019;70(6):733-8.


Role of protein phosphorylation in regulating rat submandibular mucin secretion.
The possible involvement of protein phosphorylation during beta-adrenergic receptor stimulation in rat submandibular gland was investigated in vitro using a dispersed cell preparation. (-)-Isoproterenol, a beta-adrenergic agonist, or dibutyryl cAMP stimulation was associated with an enhanced phosphorylation of three protein bands having apparent molecular weights of 34,000, 26,000, and 21,000, respectively. (-)-Propranolol, a beta-adrenergic antagonist, inhibited the phosphorylation of the three proteins during beta-adrenergic stimulation but not during dibutyryl cAMP stimulation. The three proteins were not fragments of a higher-molecular-weight protein. Subcellular fractionation using differential centrifugation, fractionation in an aqueous two-phase polymer system, and discontinuous sucrose gradient ultracentrifugation coupled with marker enzyme analysis indicated that all three proteins were enriched in the same subfractions: a heavy plasma membrane fraction and a fraction containing plasma membrane and Golgi membrane material. The extent of protein phosphorylation for all three proteins increased as a function of time and dose after beta-adrenergic stimulation. After 20 min of maximal beta-adrenergic stimulation, the addition of a beta-adrenergic blocker caused a time-dependent decrease in the 32P content of all three proteins. Pure cholinergic or pure alpha-adrenergic receptor stimulation had no effect on the 32P content of the three proteins. These data are consistent with a role for cAMP-mediated protein phosphorylation during mucin secretion from rat submandibular cells.


Prevalence of intestinal parasites in preschool children in the region of Uberlândia, State of Minas Gerais, Brazil.
Children are an important high-risk group for helminth and protozoa infections. Daycare centers are environments where children have proven to be more susceptible to acquiring intestinal parasites. Thus, the purpose of this study was to verify the prevalence of intestinal parasites in children who attended the two daycare centers maintained by the local government of Uberlândia, State of Minas Gerais, Brazil. Fecal samples were collected from 133 children (73 children at the Public Preschool for Early Childhood Education, PPECE A, and 60 at the PPECE B) following identification according to sex and age and agreement to participate by parents or guardians who signed the free, informed consent form. The samples were examined by the Lutz method. Coproparasitological tests performed on 133 children showed that 29.3% of them were parasitized for enteroparasites or commensals, 6.7% of the children presented polyparasitism. Among the protozoa, Giardia lamblia were the most prevalent and Hymenolepis nana were the most frequent among the helminths. Thus, analysis of the results showed that intestinal parasites still represent a public health problem, especially among children and in areas where the socioeconomic and educational conditions are less favorable.


Intertorsional interactions revealing absolute configurations: the V6 internal rotation heavy-top case of benzotrifluoride.
The microwave spectroscopic signatures of multiple torsional states of the CF(3) internal rotation in benzotrifluoride (alpha,alpha,alpha-trifluorotoluene) are reported. Individual rotational transitions are observed in a total of eight different torsional states, a quite challenging task for heavy tops even with Fourier transform microwave techniques. Accidental mixings of m = 0 and m = 3 torsional states as well as m = 1 and m = 2 torsional states, which can complicate the assignment of the spectra severely, are observed. These accidental mixings are probably systematic for molecules with heavy tops exhibiting an almost free internal rotation, and give an opportunity to determine the sign in the (1/2) V(6) (1+/-cos6tau) potential function hindering internal rotation and in consequence the orientation of the CF(3) top versus C(6)H(5) frame. A recently developed torsion-rotation program reproduces all line positions within an experimental accuracy of about 2.0 kHz. The V(6) barrier is determined to be 3.229949(32) cm(-1). The corresponding torsional spacings are determined with the seven-digit accuracy underlying the supersonic-jet Fourier transform microwave technique.


Microtubule associated protein 2 in bipolar depression: Impact of pregnenolone.
Pregnenolone, and related neurosteroids, may have antidepressant properties. Preclinical research proposes that microtubule associated protein 2 (MAP2) binding may be a mechanism for antidepressant properties of pregnenolone. Thus, MAP2 might be a novel target for antidepressant therapy. This clinical study is the first to examine serum MAP2 levels in people with bipolar depression and controls, and whether pregnenolone treatment is associated with a change in MAP2 levels. Blood samples from a previously published clinical trial of pregnenolone for adult bipolar depression were analyzed at baseline and week 6 of treatment with pregnenolone or placebo for serum MAP2 levels using Western Blot. MAP2 levels from healthy controls were also obtained. MAP2 levels in the bipolar depressed patients (n=11) tended to be higher than in controls (n=4) (p=0.062). MAP2 levels decreased non-significantly from baseline to week 6 in placebo (n=5) and pregnenolone-treated patients (n=6). MAP2 level changes correlated positively with change in self-reported depressive symptom scores in the pregnenolone group (r=0.771, p=0.072) but not in the placebo group (r=0.000, p=1.000). This study, exploring relationships between MAP-2 in humans with mood disorders, is limited by the small sample size. Thus, the findings must be viewed with great caution. These findings suggest possible differences in serum MAP-2 levels between bipolar depressed persons and controls and a relationship between changes in depressive symptoms and MAP-2 levels during pregnenolone therapy. Findings suggest additional research is needed on MAP-2 in mood disorders.


Childhood onset of diabetes mellitus. Report on hospital cases.
Onset of diabetes mellitus (DM) during childhood and adolescence is still relatively uncommon in Indonesia compared to many other countries in Europe and the American continent. Two surveys done in two big cities in Indonesia (Semarang, 1974 and Surabaya, 1977) showed a prevalence of 0.2-0.26% in the age group of 6-20 years. In our clinic we have seen 28 patients with DM from 1973-1988. All were insulin dependent. The youngest was 1 year, the oldest 15 years of age. The peak age group was 6-10 years. Male/female ratio was 1:3. Fifteen children experienced ketoacidosis of whom 6 had it more than once. Two children had major thalassemia, both died. Six other patients died due to severe infections and inadequate treatment. One girl of 5 years had Grave's disease. Most of the patients belonged to the low socio-economic group for whom adequate treatment was not always possible.


Teaching veterinary anesthesia and surgery: the impact of instructor availability on anesthesia, operative, and recovery times in dogs undergoing ovariohysterectomy or castration.
Veterinary students learning to perform elective ovariohysterectomy (OVH) and castration procedures have traditionally been taught by a few instructors supervising many student groups simultaneously. This study, using a historical control group, explored the impacts of having a dedicated instructor with each student group for anesthetic induction and an entire surgical procedure. Our hypothesis was that preparation, surgical, and anesthesia times would be shorter and, consequently, post-operative recovery times would be shorter with a dedicated instructor compared to traditional methods. Anesthesia records of dogs undergoing elective surgery by third-year veterinary students were reviewed over 3 consecutive years. Traditional instruction was used in year 1 (Y1), and a dedicated instructor per student group was used in year 2 (Y2) and year 3 (Y3). Anesthesia time, surgical time, recovery time, and pre- and post-operative rectal temperature were analyzed, and a stepwise regression model was developed for factors influencing recovery time. Of 206 records reviewed (Y1, 33; Y2, 98; Y3, 75), there were 101 OVH procedures and 105 castration procedures. Preparation, surgery, and anesthesia times were longer in animals undergoing surgery in Y1, when the traditional instruction method was used. Recovery time was not influenced by instructor assignment. Using dedicated instructors to teach OVH and castration to third-year veterinary students decreased overall anesthesia time by 36 to 49 minutes for OVH and 29 to 32 minutes for castration. A teaching model of dedicated instructors requires excellent coordination between surgeons and anesthesiologists to ensure that a similar number of animals can undergo procedures in the time allotted for teaching.


Proteomics of nucleocytoplasmic partitioning.
The partitioning of the proteome between nucleus and cytoplasm affects nearly every aspect of eukaryotic biology. Despite this central role, we still have a poor understanding of which proteins localize in the nucleus and how this varies in different cell types and conditions. Recent advances in quantitative proteomics and high-throughput imaging are starting to close this knowledge gap. Studies on protein interaction are beginning to reveal the spectrum of cargos of nuclear import and export receptors. We anticipate that it will soon be possible to predict each protein's nucleocytoplasmic localization based on its importin/exportin interactions and its estimated diffusion rate through the nuclear pore. This insight is likely to provide us with a fundamental understanding of how cells use nucleocytoplasmic partitioning to encode and relay information.


A novel strategy for allogeneic stem cell transplantation: perfusion method plus intra-bone marrow injection of stem cells.
Using long bones of cynomolgus monkeys, we have recently developed a new "Perfusion Method (PM)" for harvesting bone marrow cells (BMCs) while minimizing the contamination of BMCs with T cells from the peripheral blood. When thus collected BMCs, which contain not only pluripotent hemopoietic stem cells (P-HSCs) but also mesenchymal stem cells (MSCs), are directly injected into the bone marrow cavity of recipients (intra-bone marrow BMT: "IBM-BMT"), the donor-derived hemopoietic cells quickly recover even when the radiation doses used as the conditioning regimen are reduced. Recipient mice, rats, and even monkeys show neither graft-vs-host disease (GVHD) nor graft failure. In this article, we discuss why this new method (PM+IBM-BMT) may become a valuable strategy for allogeneic stem cell (both P-HSC and MSC) transplantation.


[Atypical spinal amyotrophy in adults].
The authors describe the clinical pleomorphism of atypical spinal amyotrophy of adults (ASAA) characterized by lesions of the anterior horn structures of the cervical part of the spinal cord as well as by the spreading of the process along the entire length of the spinal cord and to the bulbar part of the spine. This is supported by the electrophysiological and morphological data. The disease begins at the 3d and 4th decades of life and progresses to the lethal outcome due to cardiopulmonary insufficiency. Inheritance occurs by the autosomal dominant type with the high penetrance and by the autosomal recessive type stemming from the long-term inbreeding. ASAA described is identical to the late spinal amyotrophy depicted by S. N. Davidenkov according to the data obtained by Browning, Bernhardt and Strümpel. The appearance of an isolated form of ASAA in Saratov Province may be related to the migration of the population 200 years ago from western Europe to the central land along the Volga.


1alpha,25-Dihydroxyvitamin D3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells.
Prostate specific membrane antigen (PSMA) expression correlates with prostate cancer grade and is increased in hormone-refractory prostate cancer. The increased expression of PSMA following androgen deprivation therapy may be a consequence of the down-regulation of PSMA expression by androgen. Moreover, 1alpha,25-dihydroxyvitamin D3 (1,25-VD) has been shown to suppress prostate cancer progression as well as cell motility and invasion. Since PSMA is positively correlated with both of these characteristics, we hypothesized that 1,25-VD would regulate PSMA expression. LNCaP prostate cancer cells were treated with 1,25-VD, followed by analysis of cell surface PSMA expression. The PSMA enhancer, located within the third intron of the PSMA gene, was cloned into a reporter vector and regulation by 1,25-VD was investigated. The role of the androgen receptor (AR) in 1,25-VD mediated suppression of PSMA expression was examined using Casodex and AR specific siRNA. Surface expression of PSMA was significantly decreased in a dose-dependent manner by 10 nM 1,25-VD or greater. Regulation by 1,25-VD occurred at the level of the PSMA enhancer. Over-expression of the vitamin D receptor (VDR) also decreased expression of PSMA. Additionally, suppression of AR translation using siRNA technology blocked the suppressive effect of 1,25-VD on PSMA expression, however inhibition of PSMA expression by 1,25-VD occurred in the absence of androgens. Suppression of PSMA by 1,25-VD occurs at the level of the PSMA enhancer and is elevated by over-expression of the VDR. This regulation involves the AR, but is not dependent on the presence of androgens.


Combination of Cinobufacini and Doxorubicin Increases Apoptosis of Hepatocellular Carcinoma Cells through the Fas- and Mitochondria-Mediated Pathways.
Cinobufacini, a traditional Chinese medicine, has been used widely for cancer treatment, such as hepatocellular carcinoma (HCC), sarcoma, and leukemia. Previous studies done by our lab indicated that cinobufacini could suppress HCC cells through mitochondria-mediated and Fas-mediated apoptotic pathways. Here, we use a combination of cinobufacini and doxorubicin to inhibit the growth of HCC cells. The combination group induced more significant apoptosis by affecting proteins and RNA of apoptosis-related elements, such as Bcl-2, Bax, Bid, and cytochrome c. Furthermore, cinobufacini, as a mixture of a number of components, had stronger apoptosis-inducing activity than particular individual components or a simple mixture of a few components. Overall, these results suggested that the combination of cinobufacini and doxorubicin may provide a new strategy for inhibiting the proliferation of HCC cells.


FDA regulation of new devices-expedited review.
The expedited review and approval of new medical devices by the US Food and Drug Administration (FDA) is described within the context of ethical issues in the regulation of new technologies. Current statutory provisions governing approval of medical devices, and the way in which the FDA has implemented these provisions are examined. Administrative efforts by the FDA to increase both the quality and efficiency of the new-product review process are then discussed.


Medicaid reimbursement for screening and brief intervention for substance misuse.
Effective January 2008, state Medicaid plans may reimburse for screening and brief intervention for alcohol and drug misuse. This study assessed state Medicaid activity to implement Healthcare Common Procedure Code System codes and pay for screening and brief intervention. State and District of Columbia Medicaid representatives (N=44) participated in semistructured telephone interviews (N=37) or provided e-mail correspondence (N=7) about implementation of reimbursement codes. Confirmatory Web searches of Medicaid fee schedules supplemented findings and provided information for the remaining seven states. More than half the states (N=28) list designated screening and brief intervention codes in their state Medicaid fee schedules; 19 of those states are capable of reimbursing for the codes. Qualitative analysis examined the challenges in choosing codes, assigning reimbursement rates, and working within constrained Medicaid budgets. Implementation of billing codes appears to be an insufficient policy mechanism to promote utilization of screening and brief intervention for treating substance use.


The heme oxygenase system: its role in liver inflammation.
Heme Oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron and bilirubin. To date, three heme oxygenase isozymes have been identified: HO-1, HO-2 and HO-3. While HO-1 is structurally different from its counterparts, HO-2 and HO-3 are very similar (90% homology), with HO-3 being a poor heme catalyst. Of the three isozymes, HO-1 is believed to be the only inducible form. Constitutively expressed HO-2 has been identified in several organs including kidney and vascular smooth muscle, with the most abundant sources (and activity) being in the liver, brain, spleen and testes. Within the normal liver, HO-2 is constitutively expressed within hepatocytes, Kupffer cells, endothelial cells and Ito cells. Until recently, products of the HO reaction were regarded as potentially toxic waste destined only for excretion. However, this view is changing as evidence suggests that HO activity plays an important protective role against cellular stress during inflammatory diseases. Biliverdin is reduced to bilirubin, which has been shown to possess potent antioxidative properties. CO, which is produced in equimolar concentrations to biliverdin and ferrous iron during heme oxidation by HO, may function as a second messenger stimulating soluble guanylate cyclase (sGC) and regulating vascular tone in combination with the free radical gas NO. CO may also possess anti-inflammatory properties such as the capacity to inhibit platelet aggregation, or the expression of pro-inflammatory cytokines. Recently, it has been shown that CO regulates bile formation and bile flow. We review the functional role of HO in liver and the potential application of HO-1 in therapeutic approaches to the treatment of inflammation.


Characterization of an SNR gene locus in Saccharomyces cerevisiae that specifies both dispensible and essential small nuclear RNAs.
A genetic locus is described that specifies two Saccharomyces cerevisiae small nuclear RNAs (snRNAs). The genes specifying the two snRNAs are separated by only 67 base pairs and are transcribed in the same direction. The product RNAs contain 128 and 190 nucleotides and are designated snR128 and snR190, respectively. These RNAs resemble snRNAs of other eucaryotes in nuclear localization and possession of a 5' trimethylguanosine cap. Neither snRNA is related in sequence to previously described vertebrate or yeast snRNAs. Both RNAs exhibit properties consistent with nucleolar organization and hydrogen bonding to pre-rRNA species, suggesting possible roles in ribosome biogenesis. The snR128 species cosediments with deproteinized 27S pre-rRNA, whereas snR190 is associated with a 20S intermediate. Gene disruption in vitro followed by replacement of the chromosomal alleles reveals that SNR128 is essential, whereas SNR190 is not.


Mokken scaling of the Caring Dimensions Inventory (CDI-25).
To validate a Turkish version of the Caring Dimensions Inventory in a group of Turkish nursing students. There are no studies about how nurses or nursing students perceive caring in nursing in Turkey. There is also no valid and reliable instrument in Turkey for evaluating caring in nursing. Descriptive study design. Using a convenience sample of nursing students (n = 266), standard forward-back translation techniques were used with the Caring Dimensions Inventory. An expert panel considered the translations and provided content validation. A final version of the Caring Dimensions Inventory was tested with 10 nursing students, and we found no difficulties with the items in the instrument. Mokken Scaling analysis of the Caring Dimensions Inventory was used. A range of psychosocial and professional/technical items was included in the Mokken scale with 'Providing privacy for a patient' as the most endorsed (mean = 4.66) item and 'Being with a patient during a clinical procedure' being the least endorsed (mean = 3.87). There is a tendency for the most endorsed items to be psychosocial with the professional/technical items being less endorsed, with the exception of the least endorsed item 'Being with a patient during a clinical procedure' which is a psychosocial item. The Turkish version of the Caring Dimensions Inventory is a reliable instrument for measuring nurses' perceptions about caring. The results using the Caring Dimensions Inventory will help to identify how caring in nursing is perceived by nursing students in Turkey. Repeating this study in different groups such as working nurses will help to determine nurses who work in clinical settings perceive caring in nursing.


New water-soluble derivatives of chitin and their based nanoparticles: Antibacterial and catalytic activity.
A facile route towards new chitin derivatives with both catalytical and biological activities is proposed in the course of methodology development aimed at the design of polyfunctional materials on the basis of renewable and accessible natural polysaccharides. Ultrasound-promoted and Cu(I)-catalyzed azido-alkyne click cycloaddition of the propargylic ester of nicotinic acid and its N-methylated analogue to the azido chitin derivative allowed us to obtain previously unknown non-toxic water-soluble derivatives of chitin. The obtained polymers and their based nanoparticles demonstrated a high antibacterial activity in vitro, which is comparable or even superior to that of commercial antibiotics ampicillin and gentamicin. New derivatives of chitin were also shown to be highly efficient and reusable (at least for 10 times) green catalysts for the aldol reaction in water. The catalysts can be easily separated from the reaction mixture by their precipitation with ethanol. The results obtained highlight prospects of further studies on chitin's application in the rational design of novel functional materials with valuable properties.


The Canadian Triage and Acuity Scale: A Canadian perspective on emergency department triage.
The Canadian Triage and Acuity Scale has received widespread acceptance in Canada as a reliable and valid tool for emergency department triage. The importance of accurate triage becomes more apparent as emergency department volumes increase, and resources shrink. The need to ensure that those patients requiring more urgent care receive care first is the basis for all triage scales. Through the Canadian Triage and Acuity Scale National Working Group, the scale became the recommended triage tool for Canadian emergency departments. Work has been done on the interrater reliability of Canadian Triage and Acuity Scale among health care providers. There is a need to further assess the validity of the scale. This scale has now been applied in the out of hospital setting by paramedics and is being used in measurements of emergency physician workload. The future may see an electronic triage tool develop for emergency department use to reduce variability in its application. The Canadian Triage and Acuity Scale has become an integral component of Canadian emergency departments.


The monoamine oxidase inhibition properties of selected structural analogues of methylene blue.
The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50=0.0037μM), Nile blue (IC50=0.0077μM) and 1,9-dimethyl methylene blue (IC50=0.018μM) exhibiting higher potency inhibition compared to MB (IC50=0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.


Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ10 deficiency.
Coenzyme Q10 (CoQ10) or ubiquinone is one of the two electron carriers in the mitochondrial respiratory chain which has an essential role in the process of oxidative phosphorylation. Defects in CoQ10 synthesis are usually associated with the impaired function of CoQ10-dependent complexes I, II and III. The recessively transmitted CoQ10 deficiency has been associated with a number of phenotypically and genetically heterogeneous groups of disorders manifesting at variable age of onset. The infantile, multisystemic presentation is usually caused by mutations in genes directly involved in CoQ10 biosynthesis. To date, mutations in COQ1 (PDSS1 and PDSS2), COQ2, COQ4, COQ6, COQ7, COQ8A/ADCK3, COQ8B/ADCK4, and COQ9 genes have been identified in patients with primary form of CoQ10 deficiency. Here we report novel mutations in the COQ4 gene, which were identified in an infant with profound mitochondrial disease presenting with perinatal seizures, hypertrophic cardiomyopathy and severe muscle CoQ10 deficiency.