Binding and internalization of interleukin 1 by T cells. Direct evidence for high- and low-affinity classes of interleukin 1 receptor.
In this report we describe, on the basis of direct IL-1 binding assays and IL-1 internalization studies, the existence of two classes of IL-1-R on a variety of T cell types. Cells of the EL4-6.1 thymoma express large numbers (approximately 20,000 per cell) of IL-1-R that have a Kd of approximately 300 pM for IL-1. Even though these receptors make up 98-99% of the total IL-1-R per cell, they appear to be nonfunctional, based on their inability to endocytose IL-1. A minor class of IL-1-R (200-400/cell) has an approximately 100-fold higher affinity for IL-1 (Kd, approximately 5 pM) and can rapidly internalize the ligand upon binding. All of the biological activity of IL-1 can be shown to occur via binding to high-affinity IL-1-R since the IL-1 concentration giving half-maximum biological activity in EL4-6.1 cells corresponds precisely to the Kd of this class of receptor. Other cell types, including normal T cells, also express both high- and low-affinity IL-1-R, but the absolute number of receptors per cell is considerably less.


Molecular characterization of Marek's disease herpesvirus B antigen.
The Marek's disease herpesvirus (MDHV) B antigen (MDHV-B) was identified and molecularly characterized as a set of three glycoproteins of 100,000, 60,000, and 49,000 apparent molecular weight (gp100, gp60, and gp49, respectively) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) after immunoprecipitation from [35S]methionine-labeled infected cells by specific rabbit antiserum directed against MDHV-B (R alpha B), as previously determined by immunodiffusion. Further identification was accomplished by blocking this immunoprecipitation with highly purified MDHV-B. The same set of three polypeptides was also immunoprecipitated from [35S]methionine- and 14C-labeled infected cells with two other sera shown to have anti-B activity, i.e., rabbit anti-MDHV-infected-cell plasma membrane (R alpha PM) and immune chicken serum from birds naturally infected with MDHV. The three herpesvirus of turkeys (HVT) B-antigen (HVT-B) glycoproteins immunoprecipitated with all three sera containing anti-B activity were also shown to be identical in size to those of MDHV-B by immunoprecipitation and SDS-PAGE. These data serve to clarify the molecular identification of the polypeptides found in common between MDHV and HVT by linking them to MDHV-B, previously identified only by immunodiffusion, and to a similarly sized set of immunologically related common glycoproteins called gp100, gp60, and gp49, detected with monoclonal antibody by other workers. Tunicamycin inhibition of N-linked glycosylation resulted in either nonglycosylated or O-linked glycosylated putative precursors of MDHV-B and HVT-B with apparent molecular weights of 88,000, called pr88, and 44,000, tentatively called pr44, both immunoprecipitable with all three sera. However, the relationships of these two polypeptides to each other and to the overall precursor-processing relationship of the MDHV-B complex remains to be elucidated. The three fully glycosylated B-antigen polypeptides were not connected by disulfide linkage. Collectively, the data presented here and by others support the conclusion that all three glycoproteins now identified as gp100, gp60, and gp49 have MDHV-B determinants. Finally, detection of the same three polypeptides with well-absorbed R alpha PM, which was directed against purified infected-cell plasma membranes, suggests that at least one component of the B-antigen complex has a plasma membrane location in the infected cell.(ABSTRACT TRUNCATED AT 400 WORDS)


The Staphylococci phages family: an overview.
Due to their crucial role in pathogenesis and virulence, phages of Staphylococcus aureus have been extensively studied. Most of them encode and disseminate potent staphylococcal virulence factors. In addition, their movements contribute to the extraordinary versatility and adaptability of this prominent pathogen by improving genome plasticity. In addition to S. aureus, phages from coagulase-negative Staphylococci (CoNS) are gaining increasing interest. Some of these species, such as S. epidermidis, cause nosocomial infections and are therefore problematic for public health. This review provides an overview of the staphylococcal phages family extended to CoNS phages. At the morphological level, all these phages characterized so far belong to the Caudovirales order and are mainly temperate Siphoviridae. At the molecular level, comparative genomics revealed an extensive mosaicism, with genes organized into functional modules that are frequently exchanged between phages. Evolutionary relationships within this family, as well as with other families, have been highlighted. All these aspects are of crucial importance for our understanding of evolution and emergence of pathogens among bacterial species such as Staphylococci.


Adherence to Immunoprophylaxis Regimens for Respiratory Syncytial Virus Infection in Insured and Medicaid Populations.
Immunoprophylaxis is the only pharmaceutical intervention for mitigating respiratory syncytial virus (RSV) infection. Patient level data on adherence to American Academy of Pediatrics (AAP) immunoprophylaxis recommendations are limited. This study characterizes adherence to AAP guidelines in privately insured and Medicaid populations. We performed a retrospective birth cohort study of 211 174 privately insured children in Northern California; and 458 837 publicly insured children in Tennessee born between January 1, 1996 and December 31, 2008. Adherence to the AAP guideline was defined for eligible infants as the number of doses of RSV immunoprophylaxis administered over the number recommended for 4 mutually exclusive eligibility groups: chronic lung disease, prematurity <29 weeks, prematurity <32 weeks, and other eligibility. We identified 3456 California (Kaiser Permanente Northern California [KPNC]) and 12 251 Tennessee (Tennessee Medicaid [TennCare]) infants meeting AAP eligibility criteria. Immunoprophylaxis administration increased over the study period, from 15% for all eligible groups in 1998 to 54% in 2007. Adherence was highest among babies with chronic lung disease (KPNC 67% and TennCare 55%). Nonadherence (0% adherence) was greatest among infants of African American mothers (adjusted odds ratio [AOR] = 1.32; 95% confidence interval [CI] = .98-1.78); those with mothers with less than a high school education (AOR = 1.58; CI = 1.09-2.30) in KPNC; and in infants of Hispanic mothers in TennCare (AOR = 1.65; CI = 1.24-2.20). In KPNC, 0.11% of ineligible term infants and 5% of ineligible premature infants received immunoprophylaxis; the corresponding proportions in TennCare were 1% and 11%. Overall adherence with AAP guidelines has increased over time. Considerable overuse and underuse of immunoprophylaxis are evident with identifiable risk groups to target for improvement.


The Implementation and Evaluation of a Media Literacy Intervention About PAES Use in Sport Science Students.
With respect to both competitive and amateur/fitness sports, media may strongly influence young people's opinions and behaviors concerning the use of PAES (Performance and Appearance Enhancing Substances). The present investigation addressed this topic by focusing on sport sciences students' beliefs concerning the possible role of media related to the implementation and evaluation of a PAES-focus media literacy intervention conducted with sport science students. This study relied on a sample of 521 students (attrition rate 10.3%) (45.1% female, mean age = 22.6, SD = 2.20), which provided baseline data on students' levels of media literacy concerning the use of PAES (i.e. "descriptive sample"), and a sample of 248 students, who participated in and provided data on the media literacy intervention. This latter sample included a group of 128 students (44.5% female, mean age = 23.03, SD = 3.76) who actively participated in the intervention (i.e. "intervention group"), and a group of 120 students who did not (i.e. "control group", 53.3% female, mean age = 22.25, SD = 2.47). All students filled out media literacy questionnaires targeting students' awareness of media influence, their views about the realism of media content, their sense of confidence in dealing with media messages, and their positive attitudes toward PAES use. Analyses of questionnaire data showed that students are relatively aware of media influence on people's views and behaviors with respect to PAES use. At the same time, students also believed that young people do not consider media as "realistic sources" of information; nonetheless, they also did not consider themselves entirely capable of dealing effectively with media messages. With respect to the intervention, students overall appreciated and greatly welcomed the educational program on media literacy, and the analyses of intervention data across intervention and control groups showed that key media literacy variables changed over time, attesting to the overall effectiveness of the intervention.


Solid-Phase Extraction and Simultaneous Determination of Tetracycline Residues in Edible Cattle Tissues Using an HPLC-FL Method.
In this assay, edible cattle tissues from local markets of Ardabil, a Province of Iran, were examined for residues of tetracycline antibiotics (tetracycline, oxytetracycline and chlortetracycline). In total, 110 samples of triceps, gluteal muscle, diaphragm, kidney and liver were randomly obtained from the local markets of the city of Ardabil. Solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) methods were used to extract and analyze tetracycline antibiotic (TC) residues, respectively. The mean amount of total TC residues in all tested samples was 226.3 ± 112.5 ng/g and the mean amount of the total TC residues in triceps, gluteal muscle, diaphragm, kidney and liver samples were 176.3 ± 46.8, 405.3 ± 219.6, 96.8 ± 26.9, 672.4 ± 192.0 and 651.3 ± 210.1 ng/g, respectively. Additionally, 25.8% of muscle samples, 31.8% of liver samples and 22.7% of kidney samples contained amounts of TC residues beyond the maximum residue limit (MRLs). To reduce the TC residues found in edible cattle tissues, regulatory authorities should ensure that the cattle would undergo the proper withdrawal period from TCs before the slaughtering.


Assessing the Impacts of Drought on Grassland Net Primary Production at the Global Scale.
Quantitatively assessing the impacts of drought on grassland has significant implications to understand the degradation mechanism and prevention degraded grassland. In this study, we analyzed the relationship between grassland drought and grassland Net Primary Productivity (NPP) based on the self-calibrated Palmer Drought Severity Index (scPDSI) from 1982 to 2008. The results showed that the global grassland scPDSI value had a slightly increasing trend with the rate of 0.0119 per year (R2 = 0.195), indicating that the global grassland drought lighter to some extent during study period. Moreover, the correlation coefficient between annual grassland NPP and scPDSI was from -0.83 to 0.92. The grassland NPP decreased under mild drought from 1992 to 1996. Additionally, the correlation coefficient between scPDSI and NPP for each grassland type was: Closed Shrublands > Non-woody grassland > Savannas > Open Shrublands > Woody Savannas, indicating that drought had difference influences on the different grassland types. Our results might provide the underlying insights needed to be guide for the effects of extreme weather events on grassland NPP.


Effect of physical exercise on seizure occurrence in a model of temporal lobe epilepsy in rats.
Although the favorable effect of physical fitness on general health is unquestionable, physical exercise and fitness programs in patients with epilepsy are still a matter of controversy. Little objective evidence regarding the effect of exercise on seizure frequency and severity has been reported. One sought to clarify the relationship between exercise and epilepsy in an animal model of temporal lobe epilepsy (the pilocarpine model of epilepsy). To evaluate the effect of an aerobic physical program on seizure frequency, 29 epileptic animals were continuously monitored during 24 h for 135 days after the first spontaneous recurrent seizure (SRS) and divided into three groups. The first group (N = 14) was submitted to an aerobic exercise program (training group). The second group (N = 7) was maintained in the treadmill for the same time as the training group without being submitted to physical exercise (sham group). The third group (N = 8) served as control. The behavioral observation was divided in three periods of 45 days. The first period was used to determine the number of seizures before physical training program. The second period was utilized to determine the number of seizures during the physical training program. The third period was used to analyze the frequency of seizures after the physical training program. The mean frequency of seizures in the control and sham groups increased significantly from period 1 to period 2 and from period 1 to period 3. However, in the training group, the frequency of seizures did not change significantly between the three periods of 45 days of observation. When the same periods of the three groups were analyzed together, a significant reduction in seizure frequency was observed comparing the training group with the control and sham groups during the period of physical training. The data presented in this study suggest that physical exercise is not a seizure-inducing factor in this experimental model of epilepsy.


Further information on the leprosy pproblem in the world.
Information was obtained for the period 1966-70 concerning the number of registered cases, the number of cases that were inactive and released from control, the number of inpatients and of institutions for inpatient care, the proportion of lepromatous, tuberculoid, and indeterminate patients, and the frequency of disabilities.Comparison of the data from different countries was made difficult by non-uniform use of epidemiological terminology. In the circumstances, it would be hazardous to make an appraisal of the leprosy programmes in many of the countries, and it is difficult to determine correctly the trend of the endemics in these countries. The data collected suggest that the total number of estimated cases has not changed substantially in the last 5 years.


Interference of kallikrein 1b26 (klk1b26) translation by microRNA specifically expressed in female mouse submandibular glands: an additional mechanism for sexual dimorphism of klk1b26 protein in the glands.
Mouse kallikrein 1b26 (klk1b26) protein is more abundant in male submandibular glands (SMGs) than in female ones. This sexual dimorphism has been thought to be due to increased mRNA synthesis stimulated by androgen. However, the klk1b26 protein level in female SMG is far less than that expected from the mRNA level, suggesting an additional mechanism for down-regulation of klk1b26 expression in female SMGs. We examined the effects of small non-coding RNAs in mouse SMGs on in vitro translation of klk1b26 using a reticulocyte lysate system and reverse transcription (RT)-PCR for klk1b26 mRNA. Statistical analyses were performed with a computer package (Microsoft Excel). The microRNA (miRNA) preparation from female SMGs, but not male SMGs, interfered with the in vitro translation of the klk1b26 protein and inhibited the RT-PCR for klk1b26 mRNA with forward primers targeting its 5'-terminal region (between the 15th and 40th nucleotide from the 5'-terminal). The miRNA preparation from castrated mouse SMGs showed the inhibitory effect on the klk1b26 translation, but that from a 5α-dihydrotestosterone-treated female mouse SMGs did not. Synthetic miRNAs (miR-325 and miR-1497a), which have partial complementarity with klk1b26 mRNA at its 5'-terminal region (15th to 40th nucleotide position from the 5'-terminal), also interfered with the in vitro klk1b26 translation. When the female miRNA preparation was incubated with a 30-nucleotide-long single-strand oligoDNA (named [15th-44th]ssDNA, whose sequence corresponded to the 15th to 44th position from the 5'-terminal of klk1b26 mRNA) prior to the addition into the in vitro translation system, the inhibitory effect of the miRNA preparation on klk1b26 translation disappeared, while [15th-44th]ssDNA itself had no effect on the translation. Preincubation of the miRNA preparation with another single-strand DNA ([169th-198th]ssDNA, whose sequence corresponded with 169th to 198th position of klk1b26 mRNA) did not show the inhibitory effect. The small non-coding RNA, most probably miRNA, specifically expressed in female mouse SMGs interfered with klk1b26 protein synthesis in the in vitro translation system. Therefore sexual dimorphism observed in klk1b26 expression in mouse SMGs is due at least in part to the female-specific small non-coding RNA in SMGs.


Lead screening practices of pediatric residents.
As part of their training, pediatric residents provide primary care services to young children, including youngsters who may have elevated blood lead levels. We set out to (1) determine the percentage of pediatric residents who screen children for elevated blood lead levels according to the guidelines of the Centers for Disease Control and Prevention and the American Academy of Pediatrics; (2) assess the likelihood of lead screening by residents based on demographic and practice-setting characteristics; and (3) compare the attitudes of residents who report that they are universal screeners, selective screeners, or nonscreeners. Confidential, cross-sectional survey of a nationally representative sample of pediatric residents conducted as part of the American Academy of Pediatrics 28th Periodic Survey of Fellows. One hundred forty-three responding pediatric residents (51% response rate). Seventy-five percent of pediatric residents reported screening all patients aged 9 to 36 months for elevated blood lead levels, 21% reported screening some, and 4% reported screening none. Pediatric residents who cared for patients in urban settings were more likely to report screening patients for elevated blood lead levels than were pediatric residents who cared for patients in suburban or rural settings (100% vs 73%; P < .001) and pediatric residents in the Northeast were more likely to report screening universally than were residents in the rest of the country (93% vs 63%; P < .001). Overall, pediatric residents who reported screening patients universally were more likely to believe that the benefits of screening outweigh the costs than were residents who reported screening patients selectively (67% vs 17%; P < .001). Most pediatric residents reported that they screened patients for elevated blood lead levels, either universally or selectively. Nevertheless, the screening practices of pediatric resident and their opinions concerning the relative benefits and costs of lead screening largely reflect the areas of the country and the practice settings in which they had their primary care experiences.


Improved Optical Flow Estimation Method for Deepfake Videos.
Creating deepfake multimedia, and especially deepfake videos, has become much easier these days due to the availability of deepfake tools and the virtually unlimited numbers of face images found online. Research and industry communities have dedicated time and resources to develop detection methods to expose these fake videos. Although these detection methods have been developed over the past few years, synthesis methods have also made progress, allowing for the production of deepfake videos that are harder and harder to differentiate from real videos. This research paper proposes an improved optical flow estimation-based method to detect and expose the discrepancies between video frames. Augmentation and modification are experimented upon to try to improve the system's overall accuracy. Furthermore, the system is trained on graphics processing units (GPUs) and tensor processing units (TPUs) to explore the effects and benefits of each type of hardware in deepfake detection. TPUs were found to have shorter training times compared to GPUs. VGG-16 is the best performing model when used as a backbone for the system, as it achieved around 82.0% detection accuracy when trained on GPUs and 71.34% accuracy on TPUs.


Metallothionein-IIA promotes neurite growth via the megalin receptor.
Metallothionein (MT)-I/II has been shown to be neuroprotective and neuroregenerative in a model of rat cortical brain injury. Here we examine expression patterns of MT-I/II and its putative receptor megalin in rat retina. At neonatal stages, MT-I/II was present in retinal ganglion cells (RGCs) but not glial or amacrine cells; megalin was present throughout the retina. Whilst MT-I/II was absent from adult RGC in normal animals and after optic nerve transection, the constitutive megalin expression in RGCs was lost following optic nerve transection. In vitro MT-IIA treatment stimulated neuritic growth: more RGCs grew neurites longer than 25 microm (P < 0.05) in dissociated retinal cultures and neurite extension increased in retinal explants (P < 0.05). MT-IIA treatment of mixed retinal cultures increased megalin expression in RGCs, and pre-treating cells with anti-megalin antibodies prevented MT-IIA-stimulated neurite extension. Our results indicate that MT-IIA stimulates neurite outgrowth in RGCs and may do so via the megalin receptor; we propose that neurite extension is triggered via signal transduction pathways activated by the NPxY motifs of megalin's cytoplasmic tail.


The effect of diabetes mellitus on chronic rhinosinusitis and sinus surgery outcome.
Patients with diabetes mellitus (DM) are known to be prone to infection. However, the association between diabetes and chronic rhinosinusitis (CRS) has not been well studied. We sought to determine the effects of DM on CRS culture results and quality of life (QOL) after functional endoscopic sinus surgery (FESS). We conducted a retrospective cohort study. Adult CRS patients undergoing FESS were recruited from October 1, 2007 to December 31, 2011. Patient demographics, comorbidities, medication use, and Lund-Mackay CT scores were collected prior to FESS. Intraoperative culture was obtained. Preoperative and 1-month, 3-month, and 6-month postoperative QOL was measured by scores on the 22-item Sinonasal Outcome Test (SNOT-22). A mixed effects model was performed for analysis. Among the 376 CRS patients included, 19 patients (5.05%) had DM. Compared to non-DM patients, DM patients were significantly more likely to have Pseudomonas aeruginosa (26.32% vs 7.56%; p = 0.004) and Gram-negative rods (26.32% vs 8.96%; p = 0.013), but there was no significant difference in the prevalence of Staphylococcus aureus; DM patients were also significantly more likely to have nasal polyps and gastroesophageal reflux disease. Additionally, DM patients had significantly less improvement of postoperative SNOT-22 scores from baseline to 6-month follow-up than non-DM patients (adjusted mean = 11.14, 95% CI (0.14, 22.15), p = 0.047) after adjusting for all the other risk factors for CRS. DM patients may be prone to Gram-negative bacterial sinus infections, and have significantly worse short-term postoperative QOL. Special postoperative care may need to be considered in CRS patients with DM.


Greenland and Svalbard glaciers host unknown basidiomycetes: the yeast Camptobasidium arcticum sp. nov. and the dimorphic Psychromyces glacialis gen. and sp. nov.
Sampling campaigns in Greenland and Svalbard were executed to explore fungal diversity in cold habitats. Three very abundant groups of strains were discovered, consisting either of recently described or of yet-undescribed psychrophilic and oligotrophic yeasts and dimorphic fungi, accounting for around 50 % of the total cultivable diversity of basidiomycetes in our studies. The occurrence of these taxa has also been demonstrated by culture-independent methods. Based on phylogenetic analyses of ribosomal gene cluster sequences (D1/D2 domains of 28S (LSU), 18S (SSU), ITS with 5.8S rDNA) and sequences of protein-coding genes for elongation factor one alpha (TEF), cytochrome b (CYTB) and two subunits of the RNA polymerase II (RPB1 and RPB2) obtained from pure cultures, the isolated taxa presented in this study belong to Basidiomycota, subphylum Pucciniomycotina, class Microbotryomycetes, family Camptobasidiaceae. The dataset of the sequences supported the recognition of three species: Camptobasidium gelus, Camptobasidium arcticum sp. nov. (ex-type strain EXF-12713) and Psychromyces glacialis gen. and sp. nov. (ex-type strain EXF-13111). Camptobasidium gelus was found in the Svalbard and Greenland samples, while representatives of the here proposed new species, C. arcticum, were found only in the Greenland Ice Sheet. Psychromyces gen. nov. was erected for the dimorphic/filamentous isolates found in Svalbard and Greenland glacial environments. The taxon, for which the invalid name 'Rhodotorula svalbardensis' has been used, belongs to this genus. Based on ribosomal genes, Camptobasidium arcticum and Psychromyces glacialis are related, phylogenetically most closely related to the genera Glaciozyma and Cryolevonia. Seven genes phylogeny restricted to taxa with available sequences, supported the placement of Psychromyces to Camptobasidiaceae.


Neural progenitors, neurogenesis and the evolution of the neocortex.
The neocortex is the seat of higher cognitive functions and, in evolutionary terms, is the youngest part of the mammalian brain. Since its origin, the neocortex has expanded in several mammalian lineages, and this is particularly notable in humans. This expansion reflects an increase in the number of neocortical neurons, which is determined during development and primarily reflects the number of neurogenic divisions of distinct classes of neural progenitor cells. Consequently, the evolutionary expansion of the neocortex and the concomitant increase in the numbers of neurons produced during development entail interspecies differences in neural progenitor biology. Here, we review the diversity of neocortical neural progenitors, their interspecies variations and their roles in determining the evolutionary increase in neuron numbers and neocortex size.


Pseudidiomarina taiwanensis gen. nov., sp. nov., a marine bacterium isolated from shallow coastal water of An-Ping Harbour, Taiwan, and emended description of the family Idiomarinaceae.
Two strains of heterotrophic, aerobic, marine bacteria, designated strains PIT1T and PIT2, were isolated from sea-water samples collected at the shallow coastal region of An-Ping Harbour, Tainan, Taiwan. Both strains were Gram-negative. Cells grown in broth cultures were straight rods that were non-motile, lacking flagella. Both strains required NaCl for growth and exhibited optimal growth at 30-35 degrees C, 1-4 % NaCl and pH 8. They grew aerobically and were incapable of anaerobic growth by fermentation of glucose or other carbohydrates. Cellular fatty acids were predominantly iso-branched, with C(15 : 0) iso and C(17 : 0) iso representing the most abundant components. The DNA G+C contents of strains PIT1(T) and PIT2 were 49.3 and 48.6 mol%, respectively. Phylogeny based on 16S rRNA gene sequences, together with data from phenotypic and chemotaxonomic characterization, revealed that the two isolates could be assigned to a novel genus in the family Idiomarinaceae, for which the name Pseudidiomarina gen. nov. is proposed. Pseudidiomarina taiwanensis sp. nov. is the type species of the novel genus (type strain PIT1T = BCRC 17465T = JCM 13360T).


APOA5 -1131T/C polymorphism is associated with coronary artery disease in a Chinese population: a meta-analysis.
Functional studies suggest that the APOA5 -1131T/C polymorphism plays an important role in triglyceride (TG) metabolism, which is an event contributing to the pathogenesis of coronary artery disease (CAD). However, genetic evidence of its effect on CAD is inconsistent. To assess this correlation, we performed a meta-analysis of published data. A comprehensive meta-analysis was performed on nine published studies, with a total sample of 2049 subjects and 2373 controls using a fixed effect model. Under the fixed effect model, the risk of the disease was significantly higher in subjects with CC genotype in comparison with both TT (OR: 1.99; 95% CI: 1.64-2.41) and TC (OR: 1.48; 95% CI: 1.22-1.80) subjects. Compared with TT homozygotes, there was 43% increase in the incidence of CAD (OR: 1.43; 95% CI: 1.26-1.61) of C carriers (CC+TC). There was no heterogeneity for these effect estimates. Our findings support the view that -1131T/C polymorphism of the APOA5 gene is associated with CAD and the C allele might be a genetic risk factor that increases susceptibility to CAD.


Analysis of Medical Device Alerts Issued by the Portuguese Medicines Agency: Scoping the Purpose of New Regulatory Recommendations.
Medical devices are healthcare technologies with a significantly growing market worldwide. This study aims to analyze medical device alerts issued by the Portuguese Medicines Agency, INFARMED, I.P. during 2017, as well as to identify the respective regulatory actions and to suggest additional recommendations. All alerts on medical device alerts publicly available in the website of INFARMED, I.P. were identified and analyzed, including actions taken. Additionally, reports on medical devices from the Portuguese national competent authorities were compared with reports from other European Union member states such as Germany. A total of 32 safety alerts were identified: 18 (56%) related with devices without identified records of commercialization in Portugal, six (19%) related with devices voluntarily withdrawn from the market, such as counterfeit products, and eight (25%) categorized as 'other'. In both Portugal and Germany, 0.28 and 4.53 reports of national competent authorities per million inhabitants were identified, respectively. Diverse regulatory actions were taken, such as six compulsory indications to not acquire or use devices. Considering that the European Union is an open market where citizens should have equal access to medical devices, the Portuguese system of medical device safety alerts seems to be functioning normally. The identified safety alerts seemed relevant, with Portugal registering a proportionally slightly lower number of alerts when compared with higher sales volume markets, which may be explained by an underreporting of this type of problems. Further studies are needed to confirm these preliminary results, although the development of databases comprising data on patients using medical devices is recommended in order to generate automatic email and text message alerts. A limited number of safety alerts on medical devices was identified in Portugal, with few reported cases of counterfeit or falsified devices. The Portuguese Medicines Agency contributes to the citizens' access to quality medical devices, by issuing safety alerts, recommendations and mandatory market withdrawals for unsuitable or unsafe medical devices.


Use of disease embedding technique to predict the risk of progression to end-stage renal disease.
The accurate prediction of progression of Chronic Kidney Disease (CKD) to End Stage Renal Disease (ESRD) is of great importance to clinicians and a challenge to researchers as there are many causes and even more comorbidities that are ignored by the traditional prediction models. We examine whether utilizing a novel low-dimensional embedding model disease2disease (D2D) learned from a large-scale electronic health records (EHRs) could well clusters the causes of kidney diseases and comorbidities and further improve prediction of progression of CKD to ESRD compared to traditional risk factors. The study cohort consists of 2,507 hospitalized Stage 3 CKD patients of which 1,375 (54.8%) progressed to ESRD within 3 years. We evaluated the proposed unsupervised learning framework by applying a regularized logistic regression model and a cox proportional hazard model respectively, and compared the accuracies with the ones obtained by four alternative models. The results demonstrate that the learned low-dimensional disease representations from EHRs can capture the relationship between vast arrays of diseases, and can outperform traditional risk factors in a CKD progression prediction model. These results can be used both by clinicians in patient care and researchers to develop new prediction methods.


Biomechanics of rigid tibial nail insertion sites.
The use of a very proximal insertion site for rigid intramedullary nailing was evaluated in a biomechanical study. The purpose of this study was to compare the bursting strains generated in a proximal tibia fracture fragment during rigid nailing, using the recommended insertion sites versus a more proximal site just anterior to the tibial plateau in the midline. Proximal one-third tibia fractures were created in 12 pairs of fresh cadaver specimens. Strain gauges were applied to the medial and lateral cortices of the proximal fragments. Lottes nails, Grosse-Kempf nails, and unreamed Russell-Taylor nails were inserted in four successive pairs of specimens. In each pair, one side used the recommended starting point, and the other side used the proximal insertion site. The strain was recorded at successive 2- to 4-cm depth intervals during nail insertion. In the Lottes group, much larger bursting strains were generated in the lateral cortex when using a distal starting point (P < 0.05). In the unreamed Russell-Taylor group, the anteromedial surface strains were significantly increased using a distal starting point (P < 0.05). The Grosse-Kempf group showed no significant difference in strains associated with any insertion point during tibial intramedullary nailing.


An investigation of the antileishmanial properties of semi-synthetic saponins.
Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive efforts have recently been made to discover new leads from small molecule synthetic compound libraries held by industry; however, the number of new chemical entities identified and entering development as anti-leishmanials has been very low. This has led to increased interest in the possibility of discovering naturally derived compounds with potent antileishmanial activity which may be developed towards clinical applications. Plant-derived triterpenoid and steroidal saponins have long been considered as anti-microbials and here we describe an investigation of a library of 137 natural (9) and semi-synthetic saponins (128) for activity against Leishmania mexicana, a causative agent of cutaneous leishmaniasis. The triterpenoid sapogenin, hederagenin, readily obtained in large quantities from Hedera helix (common ivy), was converted into a range of 128 derivatives. These semi-synthetic compounds, as well as saponins isolated from ivy, were examined with a phenotypic screening approach to identify potent and selective anti-leishmanial hits. This led to the identification of 12 compounds, including the natural saponin gypsogenin, demonstrating high potency (ED50 < 10.5 μM) against axenic L. mexicana amastigotes, the mammalian pathogenic form. One of these, hederagenin disuccinate, was sufficiently non-toxic to the macrophage host cell to facilitate further analyses, selectivity index (SI) > 10. Whilst this was not active in an infected cell model, the anti-leishmanial properties of hederagenin-derivatives have been demonstrated, and the possibility of improving the selectivity of natural hederagenin through chemical modification has been established.


Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis.
Cross-linking of Fas (CD95) induces apoptosis, a response that has been reported to depend upon the Ras activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activating enzyme Jun kinase (JNK), downstream effectors of Ras or Ras-like small GTP-binding proteins, we evaluated the role of these molecules in Fas-mediated apoptosis. Although cross-linking of Fas on Jurkat T cells did result in JNK activation, increased activity was observed relatively late, being detectable only after 60 min of stimulation. Expression of a dominant negative form of SEK1 that blocked Fas-mediated induction of JNK activity had no effect on Fas-mediated apoptosis. Furthermore, maximally effective concentrations of anti-Fas did not cause JNK activation if apoptosis was blocked by a cysteine protease inhibitor, suggesting that under these conditions, activation of JNK may be secondary to the stress of apoptosis rather than a direct result of Fas engagement. Despite the activation of JNK, there was no induction of AP-1 activity as determined by gel shift assay or induction of an AP-1-responsive reporter. The lack of a requirement for AP-1 induction in Fas-mediated death was further substantiated with Jurkat cells that were stably transfected with a dominant negative cJun, TAM-67. While TAM-67 effectively prevented AP-1-dependent transcription of both the interleukin-2 and cJun genes, it had no effect on Fas-induced cell death, even at limiting levels of Fas signaling. Thus, induction of JNK activity in Jurkat cells by ligation of Fas at levels sufficient to cause cell death is likely a result, rather than a cause, of the apoptotic response, and AP-1 function is not required for Fas-induced apoptosis.


Endotoxin Tolerance in Abdominal Aortic Aneurysm Macrophages, In Vitro: A Case-Control Study.
Macrophages are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). This study examined the environmentally conditioned responses of AAA macrophages to inflammatory stimuli. Plasma- and blood-derived monocytes were separated from the whole blood of patients with AAA (30-45 mm diameter; n = 33) and sex-matched control participants (n = 44). Increased concentrations of pro-inflammatory and pro-oxidant biomarkers were detected in the plasma of AAA patients, consistent with systemic inflammation and oxidative stress. However, in monocyte-derived macrophages, a suppressed cytokine response was observed in AAA compared to the control following stimulation with lipopolysaccharide (LPS) (tumor necrosis factor alpha (TNF-α) 26.9 ± 3.3 vs. 15.5 ± 3.2 ng/mL, p < 0.05; IL-6 3.2 ± 0.6 vs. 1.4 ± 0.3 ng/mL, p < 0.01). LPS-stimulated production of 8-isoprostane, a biomarker of oxidative stress, was also markedly lower in AAA compared to control participants. These findings are consistent with developed tolerance in human AAA macrophages. As Toll-like receptor 4 (TLR4) has been implicated in tolerance, macrophages were examined for changes in TLR4 expression and distribution. Although TLR4 mRNA and protein expression were unaltered in AAA, cytosolic internalization of receptors and lipid rafts was found. These findings suggest the inflamed, pro-oxidant AAA microenvironment favors macrophages with an endotoxin-tolerant-like phenotype characterized by a diminished capacity to produce pro-inflammatory mediators that enhance the immune response.


Surgical management of infants with congenital lobar emphysema and concomitant congenital heart disease.
Congenital lobar emphysema (CLE) is an uncommon cause of infantile respiratory distress. It is diagnosed on the basis of evidence of lobar overaeration, mediastinal shift, and compression of the adjacent lobe. Concomitant congenital heart disease (CHD) and CLE is not uncommon. In the literature a 12% to 20% concomitance rate is given. The optimal treatment of respiratory symptoms associated with CLE and CHD is not clear; however, there has been a great deal of progress in the treatment of CLE and CHD. The aim of this study was to evaluate a clinical experience with and long-term follow-up of the surgical treatment of 13 patients with concomitant CLE and CHD. We reviewed the cases of 13 patients with concomitant CLE and CHD. The medical records were evaluated with reference to age, type of CHD, pulmonary artery pressure, clinical symptoms, and results of surgical management. One patient died. This patient had ventricular septal defect (VSD) and left upper lobe emphysema in the postoperative period. The remaining patients undergoing follow-up were clinically well at the final evaluation. Postoperative thoracic computed tomography revealed complete spontaneous regression of emphysema 3 months after division of ductus arteriosus in 1 patient. Pulmonary hypertensive episode was seen in 3 patients after the early postoperative period. Five of the patients were discharged with bronchodilator treatment after surgery. Six patients needed positive inotropic support. Among the patients with pulmonary hypertension and those with VSD who had undergone cardiopulmonary bypass, we found a greater need for inotropic support, a higher risk of postoperative infection, and a longer intubation period. Echocardiography in the late postoperative revealed decreased pulmonary artery diameter and pressure; myocardial performance was normal. Results of blood gas analyses revealed increased oxygen saturation and decreased partial pressure of carbon dioxide. Normal exercise activity was found in all patients. The presence of CHD, especially in infants with unusual respiratory distress symptoms, should be kept in mind, and echocardiography and/or cardiac catheterization should be considered in the diagnosis. In patients with high pulmonary artery pressure, palliative or corrective surgery for CHD in addition to lobectomy can be considered. We believe that for lesions without high pulmonary artery pressure, such as small atrial septal defect and patent foramen ovale, clinical follow-up is sufficient treatment after lobectomy. If the cause of CLE is compression of large ductus arteriosus, only division of the patent ductus arteriosus may be considered before lobectomy and clinical and radiologic follow-up. The cardiac lesion should be assessed as to severity and ease of management. A corrective procedure can be carried out at lobectomy. Because of the technical ease with which the cardiac operation can be performed at the time of lobectomy, we suggest that in addition to lobectomy, operative treatment of cardiac lesions be performed.


Varicella and herpes zoster vaccine development: lessons learned.
Before vaccination, varicella zoster virus (VZV), which is endemic worldwide, led to almost universal infection. This neurotropic virus persists lifelong by establishing latency in sensory ganglia, where its reactivation is controlled by VZV-specific T-cell immunity. Lifetime risk of VZV reactivation (zoster) is around 30%. Vaccine development was galvanised by the economic and societal burden of VZV, including debilitating zoster complications that largely affect older individuals. Areas covered: We describe the story of development, licensing and implementation of live attenuated vaccines against varicella and zoster. We consider the complex backdrop of VZV virology, pathogenesis and immune responses in the absence of suitable animal models and examine the changing epidemiology of VZV disease. We review the vaccines' efficacy, safety, effectiveness and coverage using evidence from trials, observational studies from large routine health datasets and clinical post-marketing surveillance studies and outline newer developments in subunit and inactivated vaccines. Expert commentary: Safe and effective, varicella and zoster vaccines have already made major inroads into reducing the burden of VZV disease globally. As these live vaccines have the potential to reactivate and cause clinical disease, developing alternatives that do not establish latency is an attractive prospect but will require better understanding of latency mechanisms.


[Antioxidant and cerebroprotective action of N-,S-chinazolone derivative under rat brain ischemia].
Under modelling of brain ischemia in rats the antioxidant and cerebroprotective action of new N-,S-chinazolone derivative--compound NC-224 has been established. The compensation of pathobiochemical abnormalities in the system "LPO-antioxidant protection" is observed, indicators of carbohydrate metabolism and energy-supply, and morpho-functional status of brain cells are improved under administration of the compound NC-224. Administration of the compound NC-224 to rats promoted a decrease of the lethality index and signs of neurological deficiency.


Costs and benefits of lifetime exposure to mating rivals in male Drosophila melanogaster.
Theory predicts that males should evolve mechanisms to assess competition and allocate resources accordingly. This requires phenotypic plasticity, to accurately match responses to the environment. Plastic responses in males to sexual competition are diverse and widespread. However, our ability to understand and predict how they evolve is limited because their benefits are rarely measured, and costs are, as yet, entirely unquantified. In the fruit fly Drosophila melanogaster, males that anticipate strong competition for matings or fertilizations subsequently mate for longer and transfer more of two key seminal fluid proteins. This results in significantly elevated reproductive output. In this study, we examined the fitness effects of male responses to rivals across the entire male life span. Males were exposed to rivals or not throughout life while controlling mating opportunities. Males showed significant responses to rivals throughout their lifetimes, associated with significant early-life fitness benefits. However, these disappeared after the third mating. There were also significant costs--males exposed to rivals took significantly fewer mating opportunities in later life and had significantly shorter life spans than controls. The data suggest that there are substantial costs for males of mounting plastic responses to the threat of sexual competition.


Hypoxic Effects on Matrix Metalloproteinases' Expression in the Tumor Microenvironment and Therapeutic Perspectives.
The tumor microenvironment (TME) is characterized by an acidic pH and low oxygen concentrations. Hypoxia induces neoplastic cell evasion of the immune surveillance, rapid DNA repair, metabolic reprogramming, and metastasis, mainly as a response to the hypoxic inducible factors (HIFs). Likewise, cancer cells increase matrix metalloproteinases' (MMPs) expression in response to TME conditions, allowing them to migrate from the primary tumor to different tissues. Since HIFs and MMPs are augmented in the hypoxic TME, it is easy to consider that HIFs participate directly in their expression regulation. However, not all MMPs have a hypoxia response element (HRE)-HIF binding site. Moreover, different transcription factors and signaling pathways activated in hypoxia conditions through HIFs or in a HIF-independent manner participate in MMPs' transcription. The present review focuses on MMPs' expression in normal and hypoxic conditions, considering HIFs and a HIF-independent transcription control. In addition, since the hypoxic TME causes resistance to anticancer conventional therapy, treatment approaches using MMPs as a target alone, or in combination with other therapies, are also discussed.


In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates.
PNU-140690 (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone) is a potent, nonpeptidic inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease currently under clinical evaluation. PNU-140690 and ritonavir were studied in two-drug combinations against the replication of HIV-1 clinical isolates in peripheral blood mononuclear cells. A ritonavir-sensitive (301-1x) and -resistant (301-6x) isolate pair derived from an individual before and after monotherapy with ritonavir were used. These isolates showed no significant difference in sensitivity to PNU-140690, but isolate 301-6x was more than 50-fold less sensitive to ritonavir than isolate 301-1x. Mathematical analysis showed that the combination of various concentrations of PNU-140690 with ritonavir yielded additive to moderately synergistic antiviral effects against the ritonavir-sensitive isolate and stronger synergy against the ritonavir-resistant isolate. The mechanism of synergy was not investigated, but the results suggested that both the virological and the observed in vitro pharmacological effects may have contributed to the observed synergy. Importantly, no significant antagonism was observed with the drug combinations studied. These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protease inhibitor such as ritonavir.


Assessment of the role of plasma nitric oxide levels, T-786C genetic polymorphism, and gene expression levels of endothelial nitric oxide synthase in the development of coronary artery disease.
Reduced bioavailability of nitric oxide (NO) and the T-786C polymorphism of endothelial nitric oxide synthase (eNOS) gene have been reported as risk factors for the development of coronary artery disease (CAD) with conflicting results. We investigated the association of plasma NO levels, T-786C genetic polymorphism, and gene expression levels of eNOS with CAD risk in an Iranian subpopulation. Studied population included 100 patients with angiographically verified CAD and 100 ethnically matched controls. Analysis of T-786C genetic polymorphism and gene expression levels of eNOS was conducted by polymerase chain reaction (PCR) restriction fragment length polymorphism and real-time reverse transcription-PCR methods, respectively. Plasma levels of NO were measured using Griess method. The CC genotype distribution (15% vs. 6%, P = 0.011) and minor C allele frequency (36.5% vs. 21.5%, P = 0.001) of eNOS T-786C polymorphism differed significantly between CAD patients and control. Furthermore, eNOS T-786C polymorphism was more common among smoker than nonsmoker CAD patients (27.7% vs. 7.8%, P = 0.044). The association of the eNOS T-786C polymorphism with the severity of CAD (number of diseased vessel) was significant (P < 0.05). The gene expression levels of eNOS were significantly lower in the heterozygote (0.49 ± 0.1, P = 0.023) and mutant homozygote (0.36 ± 0.09, P = 0.011) genotypes than that of wild-type genotype (P < 0.05). In addition, NO levels were significantly lower in CAD patients compared with control subjects (42.62 ± 12.26 vs. 55.48 ± 16.57, P = 0.002) and showed intergenotypic variation in the CAD patients. Our study indicated that reduced NO levels and eNOS T-786C genetic polymorphism are significant risk factors for the development and severity of CAD in the Iranian population.


Possible Role of Plant Allelochemical in Clearance of Bacteria from the Gut of Spruce Budworm, Choristoneura fumiferana.
Field results, using Bacillus thuringiensis delta-endotoxin in controlling spruce budworms, Choristoneura fumiferana, are far less satisfactory than those from the laboratoriesThe role of septicemia has also been shown to be important in mortality. However its relationship with insect diet has not been studied. Insect gut juice from spruce budworm fed on balsam foliage inhibited bacterial growth. Such activity has not been observed in the gut juice from insects fed on artificial diet. Moreover, when bacteria were given to the insects orally, and the insects then fed on balsam foliage overnight, little or no bacterial colonies could be detected in their gut juices in the tryptic soy agar plates. Such bacterial growth inhibition activity could also be found in the water extract of balsam foliage, and was suggested to be due to tannins. This result explains the role of allelochemicals affecting septicemia in spruce budworms, and hence the efficacy, when using Bacillus thuringinesis delta-endotoxin as a biologic control agent.


High 18:2 trans-fatty acids in adipose tissue are associated with increased risk of nonfatal acute myocardial infarction in costa rican adults.
Trans-fatty acid intake is associated with coronary heart disease (CHD), but the atherogenic potential of individual trans-fatty acids (FA) from partially hydrogenated oils (18:1 and 18:2) or meat and dairy products (16:1 and 18:1) is unclear. Incident cases (n = 482) of a first nonfatal myocardial infarction (MI) were matched with population controls (n = 482) for age, gender and area of residence, all living in Costa Rica. Trans-FA in adipose tissue samples were assessed by gas chromatography. Odds ratios (OR) and 95% confidence intervals were calculated from conditional logistic regression models. Total adipose tissue trans-fat was positively associated with risk of MI. After adjusting for established risk factors and other confounders, the OR by quintiles of total trans-fat were 1.00, 1.34, 2.05, 2.22 and 2.94 (P-test for trend < 0.01). This association was attributed mainly to 18:2 trans-FA that were abundant in both adipose tissue and in partially hydrogenated soybean oil, margarines and baked products used by this population; OR = 1.00, 0.96, 2.09, 3.51 and 5.05 (P-test for trend < 0.001). Adipose tissue 16:1 trans-FA were also associated with MI; OR = 1.00, 1.57, 1.39, 1.34 and 2.58 (P-test for trend < 0.05). An association with 18:1 trans-FA was not detected. High 18:2 trans-FA in adipose tissue are associated with increased risk of MI. Because the use of hydrogenated oils is increasing worldwide, consumers should be aware of the harmful effects of products containing partially hydrogenated oils.


Acute promyelocytic leukemia-associated thrombosis.
Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. The bleeding complications are well known. In contrast, APL-associated thrombosis is relatively underappreciated. We aimed to explore the issue of APL-associated thrombosis events. In the past 20 years, 127 cases with APL were found in our hospital database. We collected their coagulation laboratory profiles, including leukemia burdens, white blood cell and platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen levels, and disseminated intravascular coagulation scores. Data were compared between patients with or without thrombosis. Clinical outcomes and potential risk factors were obtained for analysis. Ten cases with APL-associated thrombosis were found. The incidence of thrombosis was 7.9% in our cohort. Five patients had cerebral infarction, 5 had catheter-related thrombosis and 1 had acute myocardial infarction. No laboratory data were associated with clinical thrombosis. Three patients died during the induction phase but thrombosis was not the direct cause of death for any of them. We conclude that patients with APL are susceptible to thrombosis in addition to bleeding. Laboratory coagulation parameters did not predict thrombosis in our series. Ischemic stroke and catheter-related thrombosis were the most common events in our Taiwanese cohort. Such a thrombosis pattern is unique and worth further investigation.


Physical and genetic map of the genome of Staphylococcus carnosus TM300.
A genome map of Staphylococcus carnosus TM300, an important micro-organism in the food industry and long used as a starter culture, was constructed by pulsed-field gel electrophoresis of DNA fragments obtained after digestion with NotI, SfiI and ApaI. The size of the chromosome was estimated to be 2590 kb. The fragments were assembled into a physical map using a combination of complementary methods including multiple and partial digests of genomic DNA, hybridization with homologous gene probes, and cross-Southern hybridization. Fifteen genes or gene clusters were positioned on the physical map by Southern hybridization analysis. The map provides a basis for further analysis of the S. carnosus chromosome.


Mining the soluble chloroplast proteome by affinity chromatography.
Chloroplasts are fundamental organelles enabling plant photoautotrophy. Besides their outstanding physiological role in fixation of atmospheric CO(2), they harbor many important metabolic processes such as biosynthesis of amino acids, vitamins or hormones. Technical advances in MS allowed the recent identification of most chloroplast proteins. However, for a deeper understanding of chloroplast function it is important to obtain a complete list of constituents, which is so far limited by the detection of low-abundant proteins. Therefore, we developed a two-step strategy for the enrichment of low-abundant soluble chloroplast proteins from Pisum sativum and their subsequent identification by MS. First, chloroplast protein extracts were depleted from the most abundant protein ribulose-1,5-bisphosphate carboxylase/oxygenase by SEC or heating. Further purification was carried out by affinity chromatography, using ligands specific for ATP- or metal-binding proteins. By these means, we were able to identify a total of 448 proteins including 43 putative novel chloroplast proteins. Additionally, the chloroplast localization of 13 selected proteins was confirmed using yellow fluorescent protein fusion analyses. The selected proteins included a phosphoglycerate mutase, a cysteine protease, a putative protein kinase and an EF-hand containing substrate carrier protein, which are expected to exhibit important metabolic or regulatory functions.


Impact of membrane solid-liquid separation on design of biological nutrient removal activated sludge systems.
Installing membranes for solid-liquid separation into biological nutrient removal (BNR) activated sludge (AS) systems makes a profound difference not only in the design of the BNR system itself, but also in the design approach for the whole wastewater treatment plant (WWTP). In multizone BNR systems with membranes in the aerobic reactor and fixed volumes for the anaerobic, anoxic, and aerobic zones (i.e., fixed volume fractions), the mass fractions can be controlled (within a range) with the interreactor recycle ratios. This zone mass fraction flexibility is a significant advantage in membrane BNR systems over conventional BNR systems with SSTs, because it allows for changing of the mass fractions to optimize biological N and P removal in conformity with influent wastewater characteristics and the effluent N and P concentrations required. For PWWF/ADWF ratios in the upper range (f(q) approximately 2.0), aerobic mass fractions in the lower range (f(maer) < 0.60), and high (usually raw) wastewater strengths, the indicated mode of operation of MBR BNR systems is as extended aeration WWTPs. Although the volume reduction compared with equivalent conventional BNR systems with secondary settling tanks is not as large (40% to 60%), the cost of the membranes can be offset against sludge thickening and stabilization costs. Moving from a flow-unbalanced raw wastewater system to a flow-balanced (f(q) = 1), low (usually settled) wastewater strength system can double the ADWF capacity of the biological reactor, but the design approach of the WWTP changes from extended aeration to include primary sludge stabilization. The cost of primary sludge treatment then has to be paid from the savings from the increased WWTP capacity.


Crystal structure of serotonin picrate, a donor-acceptor complex.
The crystal structure of the red picric acid salt of serotonin was determined by x-ray diffraction methods. The structure consists of parallel hydroxyindole and picrate planes which are intimately stacked with an interplanar separation of 3.3 to 3.4 angstroms. The stacking interaction appears to be of the donor-acceptor (charge-transfer) type, involving specific contacts between picrate nitro groups and atoms of the hydroxyindole moieties. Similar interactions might mediate biological processes involving serotonin.


Effect of tenecteplase versus alteplase on platelets during the first 3 hours of treatment for acute myocardial infarction: the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) platelet substudy.
Platelets play a pivotal role in the pathogenesis of acute myocardial infarction, as well as in the occurrence of coronary artery reocclusion and bleeding events. Therefore, the success of fibrinolytic therapy may be dependent on its direct effects on platelets. We sought to determine how tenecteplase (TNK) and alteplase (tPA) affect platelets in vitro in human volunteers and ex vivo by use of patient data from the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) trial. For the in vitro studies, whole blood from 9 healthy volunteers was incubated with 30 mg TNK and 60 mg tPA. Platelet function was measured by conventional aggregometry, bedside point-of-care devices, and sensitive flow cytometry techniques. For the ex vivo study, 41 patients were selected from the ASSENT-2 trial: 21 had received TNK and 20 had received tPA. Each patient underwent 7 serial blood draws every 30 minutes for 3 hours. Levels of platelet endothelial cell adhesion molecule-1 (PECAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, beta-thromboglobulin, platelet factor 4, thromboxane, and prostacyclin were measured by enzyme-linked immunosorbent assay. Significant inhibition of conventional and whole blood aggregation and reduced platelet function by point-of-care analyzers were observed for both agents, but mostly in the TNK-treated samples. After incubation with TNK, flow cytometry revealed decreased expression of glycoprotein IIb/IIIa, PECAM-1, vitronectin receptor, CD151, and formation of the platelet-monocyte aggregates. Serial samples from patients in the ASSENT-2 trial showed a significant decrease of soluble platelet-endothelial biomarkers in the TNK group. There was a trend toward decreased platelet function characteristics with tPA; however, these differences were much smaller than those observed with TNK. Both tPA and TNK were shown to affect platelet function in human volunteers and in patients with AMI early after thrombolysis. The antiplatelet properties of TNK were shown to be more profound than those of tPA. These findings are relevant to ongoing investigations of combination therapy with fibrinolytic and antiplatelet agents in patients with AMI.


Protein translocation across the endoplasmic reticulum. II. Isolation and characterization of the signal recognition particle receptor.
The signal recognition particle (SRP)-mediated elongation arrest of the synthesis of nascent secretory proteins can be released by salt-extracted rough microsomal membranes (Walter, P., and G. Blobel, 1981, J. Cell Biol, 91:557-561). Both the arrest-releasing activity and the signal peptidase activity were solubilized from rough microsomal membranes using the nonionic detergent Nikkol in conjunction with 250 mM KOAc. Chromatography of this extract on SRP-Sepharose separated the arrest-releasing activity from the signal peptidase activity. Further purification of the arrest-releasing activity using sucrose gradient centrifugation allowed the identification of a 72,000-dalton polypeptide as the protein responsible for the activity. Based upon its affinity for SRP, we refer to the 72,000-dalton protein as the SRP receptor. A 60,000-dalton protein fragment (Meyer, D. I., and B. Dobberstein, 1980, J. Cell Biol., 87:503-508) that had been shown previously to reconstitute the translocation activity of protease-digested membranes, was shown here by peptide mapping and immunological criteria to be derived from the SRP receptor. Findings that are in part similar, and in part different from these reported here and in our preceding paper were made independently (Meyer, D. I., E. Krause, and B. Dobberstein, 1982, Nature (Lond.). 297:647-650) and the term "docking protein" was proposed for the SRP receptor. A lower membrane content of both SRP and the SRP receptor than that of membrane bound ribosomes suggests that the SRP-SRP receptor interaction may exist transiently during the formation of a ribosome-membrane junction and during translocation.


A periodic development of BPA and BSH based derivatives in boron neutron capture therapy (BNCT).
Boron neutron capture therapy (BNCT) is a particular type of radiotherapy that requires a selective and high concentration of boron accumulation in neoplastic cells. To distinguish the distribution of boron compounds between tumour and normal cells, multiple research groups have been involved and successively innovated a wide variety of boron-based compounds. Despite the development of numerous boron compounds, only boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH) have emerged as effective in clinical trials. Here, we highlight the detailed progress in the molecular design of BPA and BSH derivatives from the historical perspective to the latest advances in light of the widely accepted performance required for effective BNCT. In this report, we have provided an overview of a variety of derivatives of BPA and BSH, including amino acids, peptides, polymers, monoclonal antibodies and chelated complexes, and it is observed that such derivatives of BPA and BSH are judicious choices for BNCT. Finally, we have summarised the critical issues for BPA and BSH that must be addressed if BNCT is to become a more widely accepted clinical modality.


Higher levels of social support predict greater survival following acute myocardial infarction: the Corpus Christi Heart Project.
Although low levels of social support have been related to mortality from coronary heart disease, little is known about the role of social support among Mexican Americans. The authors therefore examined the relationship between social support and long-term survival in the Corpus Christi Heart Project. They developed a social support scale that used data collected during in-hospital interviews of 292 Mexican Americans and 304 non-Hispanic Whites who survived a myocardial infarction for more than 28 days. The scale incorporated three measures: marital status; if not married, whether living alone; and whether advised to seek help. During an average follow-up period of 43 months, 115 participants died. Survival following myocardial infarction was greater for those with high or medium social support than for those with low social support. With age, gender, ethnicity, education, employment, smoking, diabetes, hypertension, and hypercholesterolemia included in a proportional hazards regression model, the relative risk of mortality was 1.89 (95% CI, 1.20-2.97) for those with low social support. But when the two ethnic groups were analyzed separately, low social support was no longer a significant predictor of mortality for non-Hispanic Whites, whereas for Mexican Americans, the relative risk of mortality was 3.38 (95% CI, 1.73-6.62) for those with low social support.


Improve your hiring process with team interviews.
Hiring highly qualified employees in today's competitive job market is one of the most important responsibilities for managers. The time, effort, and money that are involved in recruiting, hiring, and training a new employee provide a powerful argument for improving the way we select new employees. Today, many organizations are using team interviews to improve their hiring processes. In this article, we discuss the ways team interviews can enhance selection accuracy and provide a range of benefits for both the candidate and the organization. Specific guidelines on how to use team interviews to make better hiring decisions also are discussed.


Investigations on the sporicidal and fungicidal activity of disinfectants.
The sporicidal and fungicidal activity of disinfectants was studied in a suspension test. Glutaraldehyde 4%, sodium-dichloroisocyanurate-dihydrate (2400 ppm active chlorine) and peracetic acid 0.25% demonstrated after 30 min of exposure at 20 degrees C in the presence of 4% horse serum a clear activity against spores of Bacillus cereus. Under the same conditions formaldehyde 4% and glutaraldehyde 2% were also found to be sporicidal, but only after a longer time of exposure. Spores of Bacillus anthracis and B. cereus appeared to be comparably resistant against the investigated disinfectants, whereas conidiospores of Aspergillus fumigatus and Aspergillus niger were less resistant. Of the micro-organisms tested Candida albicans proved to be slightest resistant, while spores of Bacillus subtilis were found the most resistant.


Characterization of the Optical and Thermal Properties of Cardiac Tissue as a Function of Temperature.
In this work, we devised the first characterization of the optical and thermal properties of ex vivo cardiac tissue as a function of different selected temperatures, ranging from room temperature to hyperthermic and ablative temperatures. The broadband (i.e., from 650 nm to 1100 nm) estimation of the optical properties, i.e., absorption coefficient (μa) and reduced scattering coefficient $({\mu ^{\prime}}_s)$, was performed by means of time-domain diffuse optics. Besides, the measurement of the thermal properties was based on the transient hot-wire technique, employing a dual-needle probe to estimate the tissue thermal conductivity (k), thermal diffusivity (α), and volumetric heat capacity (Cv). Increasing the tissue temperature led to variations in the spectral characteristics of μa (e.g., the redshift of the 780 nm peak, the rise of a new peak at 840 nm, and the formation of a valley at 900 nm). Moreover, an increase in the values of ${\mu ^{\prime}}_s$ was assessed as tissue temperature raised (e.g., for 800 nm, at 25 °C ${\mu ^{\prime}}_s = 9.8{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$, while at 77 °C ${\mu ^{\prime}}_s = 29.1{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$). Concerning the thermal properties characterization, k was almost constant in the selected temperature interval. Conversely, α and Cv were subjected to an increase and a decrease with temperature, respectively; thus, they registered values of 0.190 mm2/s and 3.03 MJ/(m3•K) at the maximum investigated temperature (79 °C), accordingly.Clinical Relevance- The experimentally obtained optical and thermal properties of cardiac tissue are useful to improve the accuracy of simulation-based tools for thermal therapy planning. Furthermore, the measured properties can serve as a reference for the realization of tissue-mimicking phantoms for medical training and testing of medical instruments.


Neurotrophins: structural relatedness and receptor interactions.
Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are structurally related proteins that allow the survival of specific populations of embryonic vertebrate neurons. The primary structure of these neurotrophins, deduced from their nucleotide sequences, indicates that all three are synthesized in the form of precursor proteins presumably allowing for appropriate folding, including the formation of disulphide bridges, cleavage and secretion. While no information is yet available on the 3-dimensional structures of the neurotrophins, results from binding studies using the three neurotrophins as ligands indicate that their receptors do recognize similarities, as well as differences, between them. High-affinity receptors, that presumably mediate the biological response, as well as low-affinity receptors are present on neurons responsive to the neurotrophins. Whereas a large excess of heterologous ligand is needed to reduce binding of a particular neurotrophin to its high-affinity receptor, the same concentration of homologous or heterologous ligand similarly reduce the binding of any of the three neurotrophins to the low-affinity receptor. For all three, the low-affinity receptor appears to be the already characterized NGF low-affinity receptor that seems to be an integral part of the high-affinity receptor complexes. These results suggest that the regulation of neuronal survival by target cells can, in part, be explained by the release from these cells of limiting quantities of the structurally related neurotrophins, each being recognized by a specific high-affinity receptor complex located on the nerve terminals of the responsive neurons.


HECTAR: a method to predict subcellular targeting in heterokonts.
The heterokonts are a particularly interesting group of eukaryotic organisms; they include many key species of planktonic and coastal algae and several important pathogens. To understand the biology of these organisms, it is necessary to be able to predict the subcellular localisation of their proteins but this is not straightforward, particularly in photosynthetic heterokonts which possess a complex chloroplast, acquired as the result of a secondary endosymbiosis. This is because the bipartite target peptides that deliver proteins to these chloroplasts can be easily confused with the signal peptides of secreted proteins, causing currently available algorithms to make erroneous predictions. HECTAR, a subcellular targeting prediction method which takes into account the specific properties of heterokont proteins, has been developed to address this problem. HECTAR is a statistical prediction method designed to assign proteins to five different categories of subcellular targeting: Signal peptides, type II signal anchors, chloroplast transit peptides, mitochondrion transit peptides and proteins which do not possess any N-terminal target peptide. The recognition rate of HECTAR is 96.3%, with Matthews correlation coefficients ranging from 0.67 to 0.95. The method is based on a hierarchical architecture which implements the divide and conquer approach to identify the different possible target peptides one at a time. At each node of the hierarchy, the most relevant outputs of various existing subcellular prediction methods are combined by a Support Vector Machine. The HECTAR method is able to predict the subcellular localisation of heterokont proteins with high accuracy. It also efficiently predicts the subcellular localisation of proteins from cryptophytes, a group that is phylogenetically close to the heterokonts. A variant of HECTAR, called HECTARSEC, can be used to identify signal peptide and type II signal anchor sequences in proteins from any eukaryotic organism. Both HECTAR and HECTARSEC are available as a web application at the following address: http://www.sb-roscoff.fr/hectar/.


Roasted soybeans and an estrogenic growth promoter affect the thyroid status of beef steers.
We investigated the interactive effects of a roasted soybean (RSB)-supplemented diet and an estrogen ear implant [Synovex-S (SYN), 20 mg estradiol benzoate + 200 mg progesterone] in young beef steers on measures of thyroid status before and after challenge injections of thyrotropin-releasing hormone (TRH) + growth hormone-releasing hormone (GHRH). Twenty steers (body weight 255 +/- 5 kg) were assigned to the following treatments: 1) no SYN and a soybean meal-supplemented diet, 2) no SYN and a RSB-supplemented diet, 3) plus SYN and soybean meal, and 4) plus SYN and RSB. Steers were individually fed 1.13 MJ metabolizable energy/kg metabolic body wt daily of an 18% protein diet. After a 5-wk growth period, all steers were challenged (intravenous injection) over a 3-wk period with three dose levels of a combination of TRH + GHRH (0.1 + 0.01, 1.0 + 0.1 and 2.5 + 0.25 microg/kg body wt). There were no dose by SYN or RSB interactions. Across dose levels, values for baseline plasma thyroid-stimulating hormone (TSH) were 0.37, 0.35, 0.61 and 0.33 microg/L for treatments 1, 2, 3 and 4, respectively (SYN, P < 0.07; RSB, P < 0.01; SYN x RSB, P < 0.03; SEM 0.06). Net areas under the response curve for TSH were 66.4, 51.3, 91.4 and 64.4 (microg/L) x min, respectively (RSB, P < 0.08; SEM 12.0). Similar treatment effects and/or numerical differences after challenge were noted for thyroxine (T4) but not triiodothyronine (T3). Baseline (2.22 vs. 2.00 microg/L, P < 0.02) and peak (3.07 vs. 2.03 microg/L, P < 0.03) T3 concentrations were less for steers fed RSB than for steers fed soybean meal. This study indicates that in young growing beef steers, SYN increases TSH release from the adenohypophysis and that the primary effect of RSB is reduced plasma T3, possibly through an effect on peripheral T4 deiodination.


Preoperative fluorine 18 fluorodeoxyglucose tumoral uptake ratio between upper and lower abdomen in primary advanced-stage ovarian cancer.
The objective of this study was to assess whether the ratio of upper abdomen (UA) to lower abdomen (LA) (relative to the umbilicus) standardized fluorine 18 fluorodeoxyglucose uptake, as measured by preoperative positron emission tomography and computed tomography, is predictive of recurrence, survival, and suboptimal cytoreduction (residual tumor >1.0 cm) in advanced-stage ovarian cancer (AOC). Positron emission tomography/computed tomography before surgical staging was performed in 159 AOC patients. The ratio between the highest maximum standardized uptake value (SUV(max)) in the UA and the LA was expressed as UA/LA SUV(max). Clinicopathological characteristics and follow-up information were collected retrospectively. Cox proportional hazards analysis was used to identify prognostic factors for recurrence and survival. Logistic regression analysis was used to identify predictors of suboptimal cytoreduction. The median age and follow-up period were 55 years (range, 27-80 years) and 32 months (range, 1-92 months), respectively; 133 and 26 patients had stage III and IV disease, respectively. There were 120 and 54 cases of recurrence and disease-specific death, respectively. Multivariate analysis showed that recurrence was associated significantly with high UA/LA SUV(max) (P < 0.05; hazard ratio [HR], 4.902; 95% confidence interval [CI], 2.521-9.531) and suboptimal cytoreduction (P < 0.05; HR, 2.431; 95% CI, 1.561-3.788), and that disease-specific death was significantly associated with high UA/LA SUV(max) (P < 0.05; HR, 2.777; 95% CI, 1.270-6.075), suboptimal cytoreduction (P < 0.05; HR, 1.951; 95% CI, 1.080-3.524), and histology (P < 0.05; HR, 4.134; 95% CI, 1.676-10.196). Upper abdomen/lower abdomen SUV(max) was the only independent predictor of suboptimal cytoreduction (P < 0.05; odds ratio, 4.644; 95% CI, 1.676-12.862). High preoperative UA/LA SUV(max) was significantly associated with poor prognosis and may be predictive of suboptimal cytoreduction in AOC. This parameter may be considered in the treatment of AOC patients.


In-Season Variations in Head Impact Exposure among Youth Football Players.
Head impact exposure (HIE) is often summarized by the total exposure measured during the season and does not indicate how the exposure was accumulated, or how it varied during the season. Therefore, the objective of this study was to compare HIE during pre-season, the first and second halves of the regular season, and playoffs in a sample of youth football players (n = 119, aged 9-13 years). Athletes were divided into one of four exposure groups based on quartiles computed from the distribution of risk-weighted cumulative exposure (RWECP). Mean impacts per session and mean 95th percentile linear and rotational acceleration in practices and games were compared across the four exposure groups and time frames using mixed effects models. Within games, the mean 95th percentile accelerations for the entire sample ranged from 47.2g and 2331.3 rad/sec2 during pre-season to 52.1g and 2533.4 rad/sec2 during the second half of regular season. Mean impacts per practice increased from pre-season to the second half of regular season and declined into playoffs among all exposure groups; however, the variation between time frames was not greater than two impacts per practice. Time of season had a significant relationship with mean 95th percentile linear and rotational acceleration in games (both, p = 0.01) but not with practice accelerations or impacts per session. The in-practice mean levels of 95th percentile linear and rotational acceleration remained fairly constant across the four time frames, but in games these changed over time depending on exposure group (interactions, p ≤ 0.05). The results of this study improve our understanding of in-season variations in HIE in youth football and may inform important opportunities for future interventions.


FGF Expression in HPV16-positive and -negative SCC After Treatment With Small-molecule Tyrosine Kinase Inhibitors and Everolimus.
Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 μmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms.


Human monkeypox.
Human monkeypox, occurring in the tropical rainforest of west and central Africa, is regarded as the most important orthopoxvirus infection for epidemiological surveillance during the post-smallpox era. This disease, first recognized in Zaïre in 1970 resembles smallpox clinically but differs epidemiologically. Clinical features, their evolution and sequelae of monkeypox could be compared with discrete ordinary or modified type of smallpox. A case-fatality rate of 14% has been observed but some cases can be exceedingly mild or atypical and may easily remain undetected and unreported. Pronounced lymphadenopathy has been the only clinical feature found commonly in monkeypox but not in smallpox. Fifty-seven cases of human monkeypox have occurred since 1970, in the tropical rainforests in six west and central African countries, the majority of them (45) being reported from Zaïre. The disease appears to be more frequent in dry season. Children below ten years of age comprise 84% of the cases. Smallpox vaccination protects against monkeypox. Clusters of cases have been observed in certain areas within countries and within affected households. Human-to-human spread has possibly occurred seven times. No cases of possible tertiary spread were observed. The secondary attack rate among susceptible close household contacts was 10%, among all susceptible contacts 5%. This is much lower than that occurring with smallpox, which is between 25-40%. The limited avidity of monkeypox virus for human beings indicates that monkeypox is probably a zoonosis, although the animal reservoir(s) have not yet been identified. The low transmissibility, resulting in low frequency of disease in man indicates that monkeypox is not a public health problem. Human monkeypox has been a relatively newly recognized disease. Studies are in progress to identify the natural cycle of monkeypox virus and to define better its clinical and epidemiological characteristics. Special surveillance is maintained in endemic areas with the aim to provide assurance that in spite of waning immunity of the human population following cessation of the smallpox vaccination, the disease does not constitute a potential danger to man.


Delphinidin Ameliorates Hepatic Triglyceride Accumulation in Human HepG2 Cells, but Not in Diet-Induced Obese Mice.
Anthocyanin consumption is linked to benefits in obesity-related metabolic alterations and non-alcoholic fatty liver disease (NAFLD), though the functional role of delphinidin (Dp) is yet to be established. Therefore, this study examined the effects of Dp on metabolic alterations associated with NAFLD, and molecular mechanisms in HepG2 cells and diet-induced obese mice. Cells incubated with palmitate to induce lipid accumulation, concomitantly treated with Dp, reduced triglyceride accumulation by ~53%, and downregulated gene expression of CPT1A, SREBF1, and FASN without modifying AMP-activated protein kinase (AMPK) levels. C57BL/6Nhsd mice were fed a standard diet (control) or a high-fat/high-carbohydrate diet (HFHC) for 16 weeks. Mice in the HFHC group were subdivided and treated with Dp (HFHC-Dp, 15 mg/kg body weight/day) or a vehicle for four weeks. Dp did not affect body weight, energy intake, hyperglycemia, insulin resistance, or histological abnormalities elicited by the HFHC diet. Furthermore, the messenger RNA (mRNA) expressions of Acaca, and Fasn in hepatic or epididymal adipose tissue, and the hepatic sirtuin 1 (SIRT1)/liver kinase B1 (LKB1)/AMPK and proliferator-activated receptor alpha (PPARα) signaling axis did not significantly change due to the HFHC diet or Dp. In summary, Dp effectively reduced triglyceride accumulation in vitro through the modulation of lipid metabolic gene expression. However, a dose of Dp administrated in mice simulating the total daily anthocyanin intake in humans had no effect on either metabolic alterations or histological abnormalities associated with HFHC diets.


Comparison of 2 clindamycin 1%-benzoyl peroxide 5% topical gels used once daily in the management of acne vulgaris.
Combination therapy for the topical treatment of acne vulgaris using benzoyl peroxide (BPO) and an antibiotic is more efficacious and better tolerated than treatment with either component alone. Moreover, the addition of BPO to antibiotic therapy is recommended as a means of preventing the development of Propionibacterium acnes antibiotic resistance. However, BPO is an irritant, and the dryness and irritation experienced by some patients using topical therapy containing BPO can negatively impact compliance. Historically, once-daily treatment application has enhanced compliance versus twice daily. The current 12-week study aimed to compare the efficacy of a clindamycin 1%-BPO 5% topical gel with the hydrating excipients dimethicone and glycerin (C/BPO HE) and a clindamycin 1%-BPO 5% topical gel that does not contain hydrating excipients (C/BPO) applied once daily for the treatment of 20 participants with facial acne vulgaris and to determine if there were differences in product preference and participant acceptability between the treatments. Both C/BPO HE and C/BPO were effective in the treatment of acne, with substantive reductions (-60.8% and -61.3%, respectively) in total inflammatory lesions at week 4 in both treatment groups. Participants receiving C/BPO HE demonstrated a more consistent treatment response than with C/BPO, with incremental reductions in total inflammatory lesions at each time point, whereas the response to C/BPO waned at week 8. As a result, greater percentage reductions in inflammatory and noninflammatory lesions were observed with C/BPO HE treatment than C/BPO treatment at week 8 (papules: -71.9% vs -49.4%, P=.053; pustules: -64.8% vs -28.0%, P=.134; open comedones: -44.5% vs 2.6%, P=.480; closed comedones: -35.5% vs -26.3%, P=.501). With the exception of papules, greater reductions in all lesion subtypes also were observed at week 12. None of the between-group differences reached statistical significance. Both treatment groups displayed similar disease signs and symptoms throughout the study period. However, scaling, erythema, dryness, and pruritus occurred more frequently in participants using C/BPO. Treatment satisfaction was greatest with C/BPO HE; participants reported that this formulation was easy to apply and 100% (9/9) of participants reported that they would continue using C/BPO HE compared with 80% (8/10) of participants using C/BPO. Both treatments were well-tolerated. In this pilot study, both formulations were effective in the treatment of inflammatory and noninflammatory acne lesions, but C/BPO HE produced a more consistent reduction in total inflammatory lesions over 12 weeks. The addition of hydrating excipients in the C/BPO HE formulation appears to improve patient tolerance and acceptance, which will likely help patients to comply with therapy.


Hippocampal afterdischarges in rats. I. Effects of antiepileptics.
Hippocampal afterdischarges (ADs) are considered to be a model of complex partial seizures. To study the pharmacology of these ADs, stimulation electrodes were implanted into the dorsal hippocampus of 33 male Wistar rats. Stimulation (15-s series of monophasic rectangular pulses with a duration of 1 ms and frequency of 8 Hz) was applied four times with interstimulation intervals of 15 min. Drugs (carbamazepine 50 and 100 mg/kg; clonazepam 0.2 and 0.5 mg/kg; ethosuximide 125 and 250 mg/kg; phenobarbital 40 and 80 mg/kg) as well as solvent and isotonic saline were injected intraperitoneally 2 min after the cessation of the first AD. Duration of AD, of the latent period between AD and recurrent AD and duration of recurrent AD and the number of wet dog shakes were measured. ADs were markedly shortened by both doses of clonazepam and phenobarbital and by the higher dose of carbamazepine. The action of ethosuximide was negligible. Wet dog shakes were influenced in the same way as AD duration. Recurrent ADs were more sensitive to antiepileptics than ADs and wet dog shakes.


Use of mulberry-soybean intercropping in salt-alkali soil impacts the diversity of the soil bacterial community.
Diverse intercropping system has been used to control disease and improve productivity in the field. In this research, the bacterial communities in salt-alkali soils of monoculture and intercropping mulberry and soybean were studied using 454-pyrosequencing of the 16S rDNA gene. The dominant taxonomic groups were Proteobacteria, Acidobacteria, Actinobacteria, Chloroflexi, Bacteroidetes, Planctomycetes and Gemmatimonadetes and these were present across all samples. However, the diversity and composition of bacterial communities varied between monoculture and intercropping samples. The estimated bacterial diversity (H') was higher with intercropping soybean than in monoculture soybean, whereas H' showed an opposite pattern in monoculture and intercropping mulberry. Populations of Actinobacteria, Acidobacteria, and Proteobacteria were variable, depending on growth of plants as monoculture or intercropped. Most of Actinobacteria and Chloroflexi were found in intercropping samples, while Acidobacteria and Proteobacteria were present at a higher percentage in monoculture samples. The plant diversity of aboveground and microbial diversity of belowground was linked and soil pH seemed to influence the bacterial community. Finally, the specific plant species was the major factor that determined the bacterial community in the salt-alkali soils.


Cost estimate of bovine tuberculosis to Ethiopia.
While bovine tuberculosis (BTB) has been eliminated in some industrialized countries, it prevails worldwide, particularly in Africa. In Ethiopia, BTB is prevalent as numerous studies have shown its occurrence in livestock and in abattoirs but it has not been demonstrated in wildlife and only very few cases have been found in humans. The objective of this study is to estimate the cost of BTB to Ethiopia with the aim of informing Ethiopian policy on options for BTB control. BTB in livestock affects both animal productivity and herd demographic composition. The Livestock Development Planning System (LDPS2, FAO) was modified to allow for stochastic simulation of parameters. We performed an incremental cost of disease analysis, comparing livestock production with and without BTB. For the rural scenario we considered an endemically stable 4 % comparative intradermal test (CIDT) prevalence and for the urban scenario an endemically stable 32 % CIDT prevalence among cattle. The net present value of rural Ethiopian livestock products in 2005 is estimated at 65.7 billion (thousand million) Ethiopian Birr (95 % Confidence Interval (CI) 53.8-77.7 billion Birr), which is the equivalent of 7.5 billion US$ (95 %CI 6.1-8.9 billion US$) at a rate of 8.7 Birr per US$ in 2005. The cost of BTB ranges from 646 million Birr (75.2 million US$) in 2005 to 3.1 Billion Birr in 2011 (358 million US$) but is within the range of uncertainty of our estimate and can thus not be distinguished from zero. The cost of disease in the urban livestock production ranges from 5 to 42 million Birr (500,000-4.9 million US$) between 2005 and 2011 but is also within the range of uncertainty of our estimate. Our study shows no measurable loss in asset value or cost of disease due to BTB in rural and urban production systems in Ethiopia. This does not mean that there is not a real cost of disease, but the variability of the productivity parameters and prices are high and would require more precise estimates. This study does not preclude in any way the urgent need to control BTB in the urban dairy herd of Addis Ababa for other than financial reasons.


Evaluation of interobserver agreement in scoring immunohistochemical results of HER-2/neu (c-erbB-2) expression detected by HercepTest, Nichirei polyclonal antibody, CB11 and TAB250 in breast carcinoma.
To examine interobserver reproducibility in the judgments of HER-2/neu (c-erbB-2) oncoprotein expression, HER-2/neu expression was scored immunohistochemically. A total of 106 breast carcinomas were independently scored by five or six pathologists, using four commercially available anti-bodies (HercepTest, Nichirei polyclonal antibody, CB11 and TAB250). Two systems were used for the evaluation. In the Dako system, the intensity of membrane staining was primarily evaluated whereas in the Tohoku system, the area of the membrane-staining-positive cells was primarily evaluated. All four antibodies gave excellent concordance rates among the pathologists' judgments of the scores. Using the HercepTest and Nichirei polyclonal antibody, dividing the cases into two groups designated score 3+ and score 0/1+/2+ achieved a higher percentage of concordant cases than division into groups designated score 2+/3+ and score 0/1+. Using the HercepTest, the Dako system tended to achieve higher concordance than the Tohoku system. Conversely, CB11 and TAB250 showed similar concordance rates under both the Dako and the Tohoku systems, regardless of how the cases were divided. High interobserver agreement levels were achieved only when HER-2/neu overexpression was defined as a score of 3+, using any of the antibodies; these were similar between the Dako system and the Tohoku system. Positivity by TAB250 was lower than that by CB11. Using the HercepTest and Nichirei polyclonal antibody, cases with a score of 3+ almost always achieved complete interobserver agreement and showed HER-2/neu gene amplification. Conversely, cases with a score of 2+ achieved a low percentage of interobserver agreement and showed no gene amplification. Because judgment of a case as score 2+ was not very reproducible, and a score of 3+ was of biological significance and had high interobserver reproducibility, we suggest that only a score of 3+ be considered as overexpression. When cases of score 2+ are entered into a protocol, evaluation should be given by multiple observers and/or by using other tests such as fluorescence in situ hybridization.


Can we mix behavioral therapy with hypnotics when treating insomniacs?
This study asks whether insomniacs undergoing behavioral training need to do so while totally free of hypnotics. Twenty-six insomniacs participated in the study, which included extensive monitoring of sleep both in the laboratory and at home. All subjects received six sessions of training in sleep hygiene and relaxation. About half the subjects were also given a hypnotic for occasional use; the others were asked to abstain from all hypnotics. Follow-up was performed immediately after treatment and again 10 months later. When compared with a waiting list, 6 hours of behavioral therapy improved insomniacs' sleep latency and sleep efficiency immediately after treatment, whether or not hypnotics were given concomitantly. Immediately following the 6 hours of therapy, those who had combined pharmacotherapy and behavior therapy improved about the same as those who had received behavior therapy alone. However, on the 10-month follow-up, those who had learned sleep hygiene and relaxation without the help of occasional hypnotics had more sleep and a better sleep efficiency than those who had been allowed an occasional hypnotic. We conclude that when teaching sleep hygiene and behavioral therapy to insomniacs, it might be advantageous to disallow the concomitant use of hypnotics as needed.