13-valent pneumococcal conjugate vaccine: a review of its use in infants, children, and adolescents.
The 13-valent pneumococcal conjugate vaccine (Prevenar 13(®); Prevnar 13(®)) [PCV13] includes 13 serotype-specific polysaccharides of Streptococcus pneumoniae conjugated individually to non-toxic diphtheria CRM197 protein, thus providing wider coverage of pneumococcal serotypes than its 7-valent predecessor (PCV7). For pediatric populations, PCV13 was initially approved for use in infants and children up to 5 years of age, but recently received approval for expanded use (ages 6 weeks to 17 years) in the EU and the USA. This change in labeling was made primarily on the basis of results of Study 3011, which demonstrated the serotype-specific immunogenicity of a single dose of PCV13 in children ≥5 to <10 years of age who had previously received PCV7. Study 3011 also demonstrated functional immune responses after a single dose of PCV13 in a cohort ≥10 to <18 years of age who had not previously received PCV7. Importantly, prior to Study 3011, several randomized studies comparing PCV13 and PCV7 in infants and younger children demonstrated noninferiority of immune responses to the seven serotypes common to both vaccines after a two- or three-dose primary infant series and after the toddler booster dose; immunogenicity and functional immune responses were also demonstrated for the six additional serotypes. The safety and reactogenicity of PCV13 was generally similar to that of PCV7, and PCV13 did not interfere with the immune responses to coadministered routine pediatric vaccines. PCV13 is expected to substantially reduce the incidence of invasive pneumococcal diseases in a manner similar to that which occurred after PCV7 was introduced, and evidence of the protective effectiveness of PCV13 against pneumococcal diseases is emerging.


Triple valve endocarditis by mycobacterium tuberculosis: a case report.
Granulomas caused by Mycobacterium Tuberculosis have been observed at autopsy in the heart, pre-dominantly in the myocardium and endocardium, but rarely involving the coronary vessels and valvular structures. Mycobacterium tuberculosis valvular endocarditis is extremely rare, with most reports coming from autopsy series. We report the case of a 17 year old immunocompetent girl who presented with history of fever, malaise, foot gangrene and a left sided hemiparesis. On investigation she was found to have infective endocarditis involving the aortic, mitral and tricuspid valves. She had developed a right middle cerebral artery stroke. She underwent dual valve replacement and tricuspid repair. The vegetations showed granulomatous inflammation but blood cultures and other biological specimen cultures were negative for any organisms. She was started on antituberculous treatment and anticoagulation. This is the first reported case of triple valve endocarditis by Mycobacterium Tuberculosis in an immunocompetent host. Especially important is the fact that the right heart is involved which has been historically described in the setting of intravenous drug abuse.This implies that Tuberculosis should be considered in cases of culture negative endocarditis in endemic areas like Pakistan even in immunocompetent hosts.


Prevalence and distribution of Cryptosporidium and Giardia in wastewater and the surface, drinking and ground waters in the Lower Rhine, Germany.
Samples from different water sources (n = 396) were collected during 2009 and 2011. Wastewater (2-5 l) was purified by aluminium sulphate flocculation. Surface, ground and drinking waters (400-6400 l) were collected by filtration. Cryptosporidium oocysts and Giardia cysts were further concentrated by sucrose centrifugation. (Oo)cysts were identified by IFT (immunofluorescence test), DAPI (4',6-diamidino-2-phenylindole) staining and DICM (difference interference contrast microscopy). Out of 206 wastewater samples, 134 (65·0%) were found to be positive for Giardia cysts and 64 (31·1%) for Cryptosporidium oocysts. Parasite numbers ranged from 0 to 2436 cysts/l and 0 to 1745 oocysts/l. Eight (4·2%) surface and drinking water samples (n = 190) were found to be positive for Giardia cysts (0-56000/100 l), and 18 (9·5%) for Cryptosporidium oocysts (2400/100 l). The purpose of this study was to establish the prevalence and concentrations of Giardia lamblia and Cryptosporidium spp. by detecting (oo)cysts from water samples. This study provides substantial evidence that G. lamblia cysts and Cryptosporidium spp. oocysts are able to enter and circulate in the aquatic environment with negative implications for public health.


Processing Nasals with and without Consecutive Context Phonemes: Evidence from Explicit Categorization and the N100.
With neurophysiological (N100) and explicit behavioral measures (two-alternative forced-choice categorization), we investigated how the processing of nasal segments of German is affected by following context phonemes and their place of articulation. We investigated pre-lexical processing, with speech stimuli excised from naturally spoken utterances. Participants heard nasals (/n/, /m/, and place-assimilated /n'/), both with and without a subsequent context phoneme. Context phonemes were voiced or voiceless, and either shared or did not share their place of articulation with the nasals. The explicit forced-choice categorization of the isolated nasals showed /n'/ to be in-between the clear categorizations for /n/ and /m/. In early, implicit processing, /m/ had a significantly higher N100 amplitude than both /n/ and /n'/, with, most importantly, no difference between the latter two. When presented in context (e.g., /nb/, /mt/), explicit categorizations were affected by both the nasal and the context phoneme: a consecutive labial led to more M-categorizations, a following alveolar to more N-categorizations. The early processing of the nasal/+context stimuli in the N100 showed strong effects of context, modulated by the type of preceding nasal. Crucially, the context effects on assimilated nasals /n'/ were clearly different to effects on /m/, and indistinguishable from effects on /n/. The grouping of the isolated nasals in the N100 replicates previous findings, using magnetoencephalography and a different set of stimuli. Importantly, the same grouping was observed in the nasal/+context stimuli. Most models that deal with assimilation are either challenged by the mere existence of phonemic context effects, and/or use mechanisms that rely on lexical information. Our results support the existence, and early activation, of pre-lexical categories for phonemic segments. We suggest that due to experience with assimilation, specific speech-sound categories are flexible enough to accept (or even ignore) inappropriate place cues, in particular when the appropriate place information is still present in the signal.


Functionalization of bacterial cellulose wound dressings with the antimicrobial peptide ε-poly-L-Lysine.
Wound dressings based on bacterial cellulose (BC) can form a soft and conformable protective layer that can stimulate wound healing while preventing bacteria from entering the wound. Bacteria already present in the wound can, however, thrive in the moist environment created by the BC dressing which can aggravate the healing process. Possibilities to render the BC antimicrobial without affecting the beneficial structural and mechanical properties of the material would hence be highly attractive. Here we present methods for functionalization of BC with ε-poly-L-Lysine (ε-PLL), a non-toxic biopolymer with broad-spectrum antimicrobial activity. Low molecular weight ε-PLL was cross-linked in pristine BC membranes and to carboxymethyl cellulose functionalized BC using carbodiimide chemistry. The functionalization of BC with ε-PLL inhibited growth of S. epidermidis on the membranes but did not affect the cytocompatibility to cultured human fibroblasts as compared to native BC. The functionalization had no significant effects on the nanofibrous structure and mechanical properties of the BC. The possibility to functionalize BC with ε-PLL is a promising, green and versatile approach to improve the performance of BC in wound care and other biomedical applications.


Age-related decline in reendothelialization capacity of human endothelial progenitor cells is restored by shear stress.
Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1-induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men.


Molecular structure of human histocompatibility antigens: the HLA-C series.
The HLA-CW2 antigen of the B lymphoblastoid cell line BRI 8 is structurally homologous to the HLA-A and B antigens as judged by various criteria. Each antigen comprised a glycosylated polypeptide of 43 000 molecular weight that is noncovalently associated with beta2-microglobulin (beta2m). Some small differences in molecular parameters were, however, revealed. Thus, the deoxycholate-solubilized HLA-CW2 antigen sedimented at the same rate as the HLA-A antigens but at a slightly faster rate than the HLA-B antigens. This variation is apparently is apparently due to different amounts of bound deoxycholate. Also, whereas essentially all of the HLA-A and B antigens and about half of the HLA-CW2 antigen were adsorbed strongly by Lens culinaris lectin-Sepharose, the remaining HLA-CW2 antigen was bound much more weakly and did not require sugar for elution. This difference reflects some structural heterogeneity in the carbohydrate moiety of the HLA-CW2 antigen. The results of various studies suggest that the HLA-CW2 antigen is expressed to a lower extent than the HLA-A or B antigens and that essentially all of the beta2m of the BRI 8 plasma membrane is associated with the HLA-A, B and C alloantigenic polypeptides.


Identification and characterization of a novel porin family highlights a major difference in the outer membrane of chlamydial symbionts and pathogens.
The Chlamydiae constitute an evolutionary well separated group of intracellular bacteria comprising important pathogens of humans as well as symbionts of protozoa. The amoeba symbiont Protochlamydia amoebophila lacks a homologue of the most abundant outer membrane protein of the Chlamydiaceae, the major outer membrane protein MOMP, highlighting a major difference between environmental chlamydiae and their pathogenic counterparts. We recently identified a novel family of putative porins encoded in the genome of P. amoebophila by in silico analysis. Two of these Protochlamydiaouter membrane proteins, PomS (pc1489) and PomT (pc1077), are highly abundant in outer membrane preparations of this organism. Here we show that all four members of this putative porin family are toxic when expressed in the heterologous host Escherichia coli. Immunofluorescence analysis using antibodies against heterologously expressed PomT and PomS purified directly from elementary bodies, respectively, demonstrated the location of both proteins in the outer membrane of P. amoebophila. The location of the most abundant protein PomS was further confirmed by immuno-transmission electron microscopy. We could show that pomS is transcribed, and the corresponding protein is present in the outer membrane throughout the complete developmental cycle, suggesting an essential role for P. amoebophila. Lipid bilayer measurements demonstrated that PomS functions as a porin with anion-selectivity and a pore size similar to the Chlamydiaceae MOMP. Taken together, our results suggest that PomS, possibly in concert with PomT and other members of this porin family, is the functional equivalent of MOMP in P. amoebophila. This work contributes to our understanding of the adaptations of symbiotic and pathogenic chlamydiae to their different eukaryotic hosts.


C-peptide levels as a criterion in treatment of maturity-onset diabetes.
C-Peptide levels, both basal and glucose-stimulated, were contrasted in diet-controllable vs. nondiet-controllable maturity-onset diabetic patients. Fasting and glucose-stimulated plasma C-peptide values in diet-controlled diabetics were similar to those in normal subjects. Diabetic patients who were not solely diet controllable could be differentiated into two subgroups. One diet failure subgroup was truly insulin dependent, in that insulin treatment could not be stopped for even a brief period. In these patients, fasting C-peptide levels were very low, in the same range as in the majority of juvenile-onset diabetic patients. In the second diet failure subgroup, it was possible to manage patients without insulin therapy for varying periods of time, although most patients eventually needed insulin. Fasting C-peptide levels in this second subgroup were also in the same range as those in normal subjects. However, their C-peptide responses to glucose were significantly blunted. Measurement of C-peptide may furnish a useful criterion for the categorization of maturity-onset diabetic patients. Furthermore, C-peptide levels help considerably in the selection of treatment modalities for these patients. Low C-peptide levels identify those patients who require insulin treatment, whereas high C-peptide levels in insulin-treated patients suggest the possibility of discontinuing insulin.


A quasi-experimental evaluation of a breastfeeding support program for low income women in Michigan.
We examined the effectiveness of a peer counseling breastfeeding support program for low income women in Michigan who participate in WIC. Because there was more demand for services than could be met by the program, many women who requested services were not subsequently contacted by a peer counselor. We used a quasi-experimental methodology that utilized this excess demand for services to estimate the causal effect of the support program on several breastfeeding outcomes. We relied on data derived from administrative and survey-based sources. After providing affirmative evidence that our key assumption is consistent with the data, we estimated that the program caused the breastfeeding initiation to increase by about 27 percentage points and the mean duration of breastfeeding to increase by more than 3 weeks. The support program we evaluated was very effective at increasing breastfeeding among low income women who participate in WIC, a population that nationally breastfeeds at rates well below the national average and below what is recommended by public health professionals. Given the substantial evidence that breastfeeding is beneficial for both the child and mother, the peer counseling breastfeeding support program should be subjected to a cost/benefit analysis and evaluated at other locales.


Modulation of alpha-actinin levels affects cell motility and confers tumorigenicity on 3T3 cells.
alpha-Actinin is an abundant actin crosslinking protein, also localized at adherens type junctions. In adhesion plaques, alpha-actinin can link the actin filaments to integrin via vinculin and talin, or directly by binding to the cytoplasmic domain of beta 1-integrin. The expression of alpha-actinin is rapidly elevated in growth-activated quiescent cells, and is reduced in SV40-transformed 3T3 cells and various differentiating cell types (reviewed by Glück, U., Kwiatkowski, D. J. and Ben-Ze'ev, A. Proc. Nat. Acad. Sci. USA 90, 383-387, 1993). To study the effect of changes in alpha-actinin levels on cell behavior, alpha-actinin expression was elevated in 3T3 cells by transfection with a full-length human nonmuscle alpha-actinin cDNA. To suppress alpha-actinin levels, 3T3 cells were transfected with an antisense alpha-actinin cDNA construct. Cells overexpressing alpha-actinin by 40-60% displayed a significant reduction in cell motility, as demonstrated by their slower locomotion into an artificial wound, and by forming shorter phagokinetic tracks on colloidal gold-coated substrata. 3T3 cells in which the expression of alpha-actinin was reduced to 25-60% of control levels, after antisense alpha-actinin transfection, had an increased cell motility. Moreover, such alpha-actinin-deficient 3T3 cells formed tumors upon injection into nude mice. The results demonstrate that modulations in alpha-actinin expression can affect, in a major way, the motile and tumorigenic properties of cells, and support the view that decreased alpha-actinin expression could be a common regulatory pathway to malignant transformation of 3T3 cells.


Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. ClinicalTrials.gov NCT03814915.


Elongation factor 1 gamma mRNA expression in oesophageal carcinoma.
Elongation factor 1 gamma (EF1 gamma) is known to be a subunit of EF1, one of the G proteins that mediate the transport of aminoacyl tRNA to 80S ribosomes during translation. As little is known regarding the expression of EF1 gamma in human oesophageal carcinoma, this study looked at its expression using a northern blot analysis. Thirty six cases of oesophageal carcinoma and 15 oesophageal carcinoma cell lines were studied. The EF1 gamma mRNA overexpression at a level of twofold or more was seen in five (14%) of 36 carcinomatous tissues compared with the normal counterparts. All five overexpressed cases showed severe lymph node metastases compared with the non-overexpressed cases, and the difference was significant (p = 0.028). The stage of the disease of these five cases was far advanced compared with the nonoverexpressed cases (p = 0.012). All 15 oesophageal carcinoma cells expressed EF1 gamma mRNA relatively lower than the gastric or pancreatic carcinoma cell lines, in which EF1 gamma was originally isolated. As the expression of EF1 gamma mRNA could be detected even in the biopsy specimens, its overexpression in tumour tissue may provide preoperative useful information for predicting the aggressiveness of tumours.


Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study.
Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.


Genome Characterization of Bird-Related Rhabdoviruses Circulating in Africa.
Rhabdoviridae is the most diverse family of the negative, single-stranded RNA viruses, which includes 40 ecologically different genera that infect plants, insects, reptiles, fishes, and mammals, including humans, and birds. To date, only a few bird-related rhabdoviruses among the genera Sunrhavirus, Hapavirus, and Tupavirus have been described and analyzed at the molecular level. In this study, we characterized seven additional and previously unclassified rhabdoviruses, which were isolated from various bird species collected in Africa during the 1960s and 1970s. Based on the analysis of their genome sequences obtained by next generation sequencing, we observed a classical genomic structure, with the presence of the five canonical rhabdovirus genes, i.e., nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and polymerase (L). In addition, different additional open reading frames which code putative proteins of unknown function were identified, with the common presence of the C and the SH proteins, within the P gene and between the M and G genes, respectively. Genetic comparisons and phylogenetic analysis demonstrated that these seven bird-related rhabdoviruses could be considered as putative new species within the genus Sunrhavirus, where they clustered into a single group (named Clade III), a companion to two other groups that encompass mainly insect-related viruses. The results of this study shed light on the high diversity of the rhabdoviruses circulating in birds, mainly in Africa. Their close relationship with other insect-related sunrhaviruses raise questions about their potential role and impact as arboviruses that affect bird communities.


A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene.
Waardenburg syndrome (WS) is a hereditary auditory-pigmentary syndrome with hearing impairment and pigmentation anomaly of the skin and iris. In addition to these major symptoms, WS type 4 is associated with Hirschsprung disease. To date, three genes responsible for WS4 have been cloned: genes for a transcription factor SOX10, endothelin 3 (EDN3), and endothelin B receptor (EDNRB). We here describe a novel mutant mouse with a mutation of the Ednrb gene, and propose the mouse as an animal model of WS4. These mutants are with mixed genetic background of BALB/c and MSM (an inbred strain of Japanese wild mice) and have extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon: their colon distal to the megacolon lacked Auerbach's plexus cells. Interestingly, these mutants did not respond to sound, and the stria vascularis of their cochlea lacked intermediate cells, i.e., neural crest-derived melanocytes. Since these symptoms resembled those of human WS4 and were transmitted in autosomal recessive hereditary manner, the mutants were named WS4 mice. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis revealed that their Ednrb lacked 318 nucleotides encoding Ednrb transmembrane domains owing to deletion of exons 2 and 3. Interaction between endothelin 3 and its receptor is required for normal differentiation and development of melanocytes and Auerbach's plexus cells. We concluded that a missing interaction here led to a lack of these cells, which caused pigmentation anomaly, deafness, and megacolon in WS4 mice.


A case of acute subdural hematoma due to bleeding from metastatic chondrosarcoma of the skull.
Intra or peritumoral hemorrhage of brain and skull tumors sometimes presents as stroke. Skull metastasis of chondrosarcoma is relatively rare, and furthermore, a case of intratumoural hemorrhage of skull metastasis of chondrosarcoma has not been reported. A 73-year-old man underwent right lower leg amputation in the past because of chondrosarcoma and was operated for a skull metastasis. He presented with a sudden headache, and head computed tomography revealed a right acute subdural hematoma (SDH) adjacent to the recurrent skull metastatic tumor. The removal of the SDH and tumor resection were performed emergently. The intraoperative findings included metastatic invasion beyond the dura mater to as deep as the subdural space, and the histological diagnosis was metastatic chondrosarcoma. His postoperative course was uneventful. In the event of subdural invasion of a metastatic lesion, intratumoral hemorrhage may induce acute SDH, as in the present case. Similar to our case, most previous reports of intracranial chondrosarcoma hemorrhage have had an unclear etiology. Despite the rarity of this event, a patient with a history of malignancy presenting with nontraumatic acute SDH should be examined for the intratumoral hemorrhage of skull metastasis in the differential diagnosis.


Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.
Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.


Healthcare Stereotype Threat in Older Adults in the Health and Retirement Study.
Healthcare stereotype threat is the threat of being personally reduced to group stereotypes that commonly operate within the healthcare domain, including stereotypes regarding unhealthy lifestyles and inferior intelligence. The objective of this study was to assess the extent to which people fear being judged in healthcare contexts on several characteristics, including race/ethnicity and age, and to test predictions that experience of such threats would be connected with poorer health and negative perceptions of health care. Data were collected as part of the 2012 Health and Retirement Study (HRS). A module on healthcare stereotype threat, designed by the research team, was administered to a random subset (n=2,048 of the total 20,555) of HRS participants. The final sample for the present healthcare stereotype threat experiment consists of 1,479 individuals. Logistic regression was used to test whether healthcare stereotype threat was associated with self-rated health, reported hypertension, and depressive symptoms, as well as with healthcare-related outcomes, including physician distrust, dissatisfaction with health care, and preventative care use. Seventeen percent of respondents reported healthcare stereotype threat with respect to one or more aspects of their identities. As predicted, healthcare stereotype threat was associated with higher physician distrust and dissatisfaction with health care, poorer mental and physical health (i.e., self-rated health, hypertension, and depressive symptoms), and lower odds of receiving the influenza vaccine. The first of its kind, this study demonstrates that people can experience healthcare stereotype threat on the basis of various stigmatized aspects of social identity, and that these experiences can be linked with larger health and healthcare-related outcomes, thereby contributing to disparities among minority groups.


How to learn about teaching: An evolutionary framework for the study of teaching behavior in humans and other animals.
The human species is more reliant on cultural adaptation than any other species, but it is unclear how observational learning can give rise to the faithful transmission of cultural adaptations. One possibility is that teaching facilitates accurate social transmission by narrowing the range of inferences that learners make. However, there is wide disagreement about how to define teaching, and how to interpret the empirical evidence for teaching across cultures and species. In this article I argue that disputes about the nature and prevalence of teaching across human societies and nonhuman animals are based on a number of deep-rooted theoretical differences between fields, as well as on important differences in how teaching is defined. To reconcile these disparate bodies of research, I review the three major approaches to the study of teaching - mentalistic, culture-based, and functionalist - and outline the research questions about teaching that each addresses. I then argue for a new, integrated framework that differentiates between teaching types according to the specific adaptive problems that each type solves, and apply this framework to restructure current empirical evidence on teaching in humans and nonhuman animals. This integrative framework generates novel insights, with broad implications for the study of the evolution of teaching, including the roles of cognitive constraints and cooperative dilemmas in how and when teaching evolves. Finally, I propose an explanation for why some types of teaching are uniquely human, and discuss new directions for research motivated by this framework.


Plant acquisition of organic nitrogen in boreal forests.
Research on plant nitrogen (N) uptake and metabolism has more or less exclusively concerned inorganic N, particularly nitrate. Nevertheless, recent as well as older studies indicate that plants may have access to organic N sources. Laboratory studies have shown that ectomycorrhizal and ericoid mycorrhizal plants can degrade polymeric N and absorb the resulting products. Recent studies have also shown that some non-mycorrhizal plants are able to absorb amino acids. Moreover, amino acid transporters have been shown to be present in both plant roots and in mycorrhizal hyphae. Although both mycorrhizal and non-mycorrhizal plants appear to have a capacity for absorbing a range of organic N compounds, is this capacity realized in the field? Several lines of evidence show that plants are outcompeted by microorganisms for organic N sources. Such studies, however, have not addressed the issue of spatial and temporal separation between plants and microorganisms. Moreover, competition studies have not been able to separate uptake by symbiotic and non-symbiotic microorganisms. Qualitative assessment of organic N uptake by plants has been performed with dual-labelled glycine in several studies. These studies arrive at different conclusions: some indicate that plants do not absorb this organic N source when competing with other organisms in soil, while others conclude that significant fractions of amino acid N are absorbed as intact amino acid. These variable results may reflect species differences in the ability to absorb glycine as well as differences in experimental conditions and analytical techniques. Although theoretical calculations indicate that organic N might add significant amounts of N to plant N uptake, direct quantitative assessment of the fraction of plant N derived from uptake by organic N sources is a challenge for future research.


Comparative study of aflatoxins M1 and B1 production in solid-state and shaking liquid cultures.
Production of aflatoxins M1 (AFM) and B1 (AFB) by Aspergillus flavus NRRL 3251 in solid-state and shaking liquid cultures using rice as the carbon source was compared. In general, solid-state cultures produced more aflatoxins than shaking liquid cultures on an equal rice weight basis. Solid-state cultures with continuous shaking yielded higher levels of toxins than those with intermittent shaking. However, intermittent shaking is a feasible replacement for the continuous shaking method for AFM production. A typical solid rice culture supplemented with yeast extract produced 30 and 2600 mg per kg rice of AFM and AFB, respectively, in 8 days at 29 degrees C. The optimal culture conditions for toxin production in a shaking liquid culture were also studied. Parameters under consideration included the amount of carbon (rice) and nitrogen source, initial medium pH, and aeration rate. At optimum conditions, a representative shaking liquid culture produced 18 and 1680 mg per kg rice of AFM and AFB, respectively, in 5 days at 29 degrees C. This shaking liquid culture appears feasible for scaling up and routine production of AFM and AFB for toxicological investigations.


An (Eco)Toxicity Life Cycle Impact Assessment Framework for Per- And Polyfluoroalkyl Substances.
A framework for characterizing per- and polyfluoroalkyl substances (PFASs) in life cycle impact assessment (LCIA) is proposed. Thousands of PFASs are used worldwide, with special properties imparted by the fluorinated alkyl chain. Our framework makes it possible to characterize a large part of the family of PFASs by introducing transformation fractions that translate emissions of primary emitted PFASs into the highly persistent terminal degradation products: the perfluoroalkyl acids (PFAAs). Using a PFAA-adapted characterization model, human toxicity as well as marine and freshwater aquatic ecotoxicity characterization factors are calculated for three PFAAs, namely perfluorooctanoic acid (PFOA) perfluorohexanoic acid (PFHxA) and perfluorobutanesulfonic acid (PFBS). The model is evaluated to adequately capture long-term fate, where PFAAs are predicted to accumulate in open oceans. The characterization factors of the three PFAAs are ranked among the top 5% for marine ecotoxicity, when compared to 3104 chemicals in the existing USEtox results databases. Uncertainty analysis indicates potential for equally high ranks for human health impacts. Data availability constitutes an important limitation creating uncertainties. Even so, a life cycle assessment (LCA) case study illustrates practical application of our proposed framework, demonstrating that even low emissions of PFASs can have large effects on LCA results.


Unravelling the spatial dependency of the complex solid-state chemistry of Pb in a paint micro-sample from Rembrandt's Homer using XRD-CT.
The surface of many Old Master paintings has been affected by the appearance of whitish lead-rich deposits, which are often difficult to fully characterise, thereby hindering conservation. A paint micro-sample from Rembrandt's Homer was imaged using X-ray Diffraction Computed Tomography (XRD-CT) in order to understand the evolving solid-state Pb chemistry from the painting surface and beneath. The surface crust was identified as a complex mixture of lead sulfates. From the S : Pb ratios throughout the paint layer, we can conclude that S is from an external source in the form of SO2, and that the nature of Pb-SO4 product is dependent on the degree of diffusion/absorption of SO2 into the paint layers.


The hook test for distal biceps tendon avulsion.
Complete biceps tendon avulsions are frequently missed on clinical examination, suggesting the need for a reliable diagnostic test. Complete distal biceps avulsions can be reliably detected with the Hook test. Cohort study (diagnosis); Level of evidence, 2. The hook test was performed by a single surgeon in a cohort of 45 patients undergoing surgical exploration of the distal biceps tendon. While the patient actively supinates with the elbow flexed 90 degrees , an intact hook test permits the examiner to hook his or her index finger under the intact biceps tendon from the lateral side. With an abnormal hook test, indicating distal avulsion, there is no cord-like structure under which the examiner may hook a finger. Thirty-three patients had an avulsion and 12 had a partial tear. The hook test was abnormal in 33 of 33 (100%) patients with complete biceps avulsions, and intact in 12 of 12 with partial detachments. However, it was painful in 9 of those 12. In the noninjured contralateral arms, which served as the normal control group, 45 of 45 (100%) had a normal hook test. Magnetic resonance imaging (MRI) diagnosed a complete tear in 11 of 12 patients with partial tears and in 11 of 13 with complete lesions. The sensitivity and specificity were both higher with the hook test (both 100%) than with MRI (92% and 85%, respectively). The hook test is a highly sensitive and specific test for assessment of distal biceps tendon avulsions.


Functional expression of the extracellular calcium sensing receptor (CaSR) in equine umbilical cord matrix size-sieved stem cells.
The present study investigates the effects of high external calcium concentration ([Ca(2+)](o)) and the calcimimetic NPS R-467, a known calcium-sensing receptor (CaSR) agonist, on growth/proliferation of two equine size-sieved umbilical cord matrix mesenchymal stem cell (eUCM-MSC) lines. The involvement of CaSR on observed cell response was analyzed at both the mRNA and protein level. A large (>8 µm in diameter) and a small (<8 µm) cell line were cultured in medium containing: 1) low [Ca(2+)](o) (0.37 mM); 2) high [Ca(2+)](o) (2.87 mM); 3) NPS R-467 (3 µM) in presence of high [Ca(2+)](o) and 4) the CaSR antagonist NPS 2390 (10 µM for 30 min.) followed by incubation in presence of NPS R-467 in medium with high [Ca(2+)](o). Growth/proliferation rates were compared between groups. In large cells, the addition of NPS R-467 significantly increased cell growth whereas increasing [Ca(2+)](o) was not effective in this cell line. In small cells, both higher [Ca(2+)](o) and NPS R-467 increased cell growth. In both cell lines, preincubation with the CaSR antagonist NPS 2390 significantly inhibited the agonistic effect of NPS R-467. In both cell lines, increased [Ca(2+)](o) and/or NPS R-467 reduced doubling time values.Treatment with NPS R-467 down-regulated CaSR mRNA expression in both cell lines. In large cells, NPS R-467 reduced CaSR labeling in the cytosol and increased it at cortical level. In conclusion, calcium and the calcimimetic NPS R-467 reduce CaSR mRNA expression and stimulate cell growth/proliferation in eUCM-MSC. Their use as components of media for eUCM-MSC culture could be beneficial to obtain enough cells for down-stream purposes.


A computational model for rhythmic and discrete movements in uni- and bimanual coordination.
Current research on discrete and rhythmic movements differs in both experimental procedures and theory, despite the ubiquitous overlap between discrete and rhythmic components in everyday behaviors. Models of rhythmic movements usually use oscillatory systems mimicking central pattern generators (CPGs). In contrast, models of discrete movements often employ optimization principles, thereby reflecting the higher-level cortical resources involved in the generation of such movements. This letter proposes a unified model for the generation of both rhythmic and discrete movements. We show that a physiologically motivated model of a CPG can not only generate simple rhythmic movements with only a small set of parameters, but can also produce discrete movements if the CPG is fed with an exponentially decaying phasic input. We further show that a particular coupling between two of these units can reproduce main findings on in-phase and antiphase stability. Finally, we propose an integrated model of combined rhythmic and discrete movements for the two hands. These movement classes are sequentially addressed in this letter with increasing model complexity. The model variations are discussed in relation to the degree of recruitment of the higher-level cortical resources, necessary for such movements.


Photothermal-enhanced catalysis in core-shell plasmonic hierarchical Cu7S4 microsphere@zeolitic imidazole framework-8.
Conventional semiconductor photocatalysis based on band-edge absorption remains inefficient due to the limited harvesting of solar irradiation and the complicated surface/interface chemistry. Herein, novel photothermal-enhanced catalysis was achieved in a core-shell hierarchical Cu7S4 nano-heater@ZIF-8 heterostructures via near-infrared localized surface plasmon resonance. Our results demonstrated that both the high surface temperature of the photothermal Cu7S4 core and the close-adjacency of catalytic ZIF-8 shell contributed to the extremely enhanced catalytic activity. Under laser irradiation (1450 nm, 500 mW), the cyclocondensation reaction rate increased 4.5-5.4 fold compared to that of the process at room temperature, in which the 1.6-1.8 fold enhancement was due to the localized heating effect. The simulated sunlight experiments showed a photothermal activation efficiency (PTAE) of 0.07%, further indicating the validity of photothermal catalysis based on the plasmonic semiconductor nanomaterials. More generally, this approach provides a platform to improve reaction activity with efficient utilization of solar energy, which can be readily extended to other green-chemistry processes.


Nitrogen form and mycorrhizal inoculation amount and timing affect flavonol biosynthesis in onion (Allium cepa L.).
Mycorrhizal symbiosis is known to be the most prevalent form of fungal symbiosis with plants. Although some studies focus on the importance of mycorrhizal symbiosis for enhanced flavonoids in the host plants, a comprehensive understanding of the relationship still is lacking. Therefore, we studied the effects of mycorrhizal inoculation of onions (Allium cepa L.) regarding flavonol concentration and the genes involved in flavonol biosynthesis when different forms of nitrogen were supplied. We hypothesized that mycorrhizal inoculation can act as a biotic stress and might lead to an increase in flavonols and expression of related genes. The three main quercetin compounds [quercetin-3,4'-di-O-β-D-glucoside (QDG), quercetin-4'-O-β-D-glucoside (QMG), and isorhamnetin-4'-O-β-D-glucoside (IMG)] of onion bulbs were identified and analyzed after inoculating with increasing amounts of mycorrhizal inocula at two time points and supplying either predominantly NO3- or NH4+ nitrogen. We also quantified plant dry mass, nutrient element uptake, chalcone synthase (CHS), flavonol synthase (FLS), and phenyl alanine lyase (PAL) gene expression as key enzymes for flavonol biosynthesis. Inoculation with arbuscular mycorrhizal fungi (highest amount) and colonization at late development stages (bulb growth) increased QDG and QMG concentrations if plants were additionally supplied with predominantly NH4+. No differences were observed in the IMG content. RNA accumulation of CHS, FLS, and PAL was affected by the stage of the mycorrhizal symbiosis and the nitrogen form. Accumulation of flavonols was not correlated, however, with either the percentage of myorrhization or the abundance of transcripts of flavonoid biosynthesis genes. We found that in plants at late developmental stages, RNA accumulation as a reflection of a current physiological situation does not necessarily correspond with the content of metabolites that accumulate over a long period. Our findings suggest that nitrogen form can be an important factor determining mycorrhizal development and that both nitrogen form and mycorrhizas interact to influence flavonol biosynthesis.


Shape-controlled continuous synthesis of metal nanostructures.
A segmented flow-based microreactor is used for the continuous production of faceted nanocrystals. Flow segmentation is proposed as a versatile tool to manipulate the reduction kinetics and control the growth of faceted nanostructures; tuning the size and shape. Switching the gas from oxygen to carbon monoxide permits the adjustment in nanostructure growth from 1D (nanorods) to 2D (nanosheets). CO is a key factor in the formation of Pd nanosheets and Pt nanocubes; operating as a second phase, a reductant, and a capping agent. This combination confines the growth to specific structures. In addition, the segmented flow microfluidic reactor inherently has the ability to operate in a reproducible manner at elevated temperatures and pressures whilst confining potentially toxic reactants, such as CO, in nanoliter slugs. This continuous system successfully synthesised Pd nanorods with an aspect ratio of 6; thin palladium nanosheets with a thickness of 1.5 nm; and Pt nanocubes with a 5.6 nm edge length, all in a synthesis time as low as 150 s.


Omentum is highly effective in the management of complex cardiothoracic surgical problems.
Vascularized, pedicled tissue flaps are often used for cardiothoracic surgical problems complicated by factors that adversely affect healing, such as previous irradiation, established infection, or steroid use. We reviewed our experience with use of the omentum in these situations to provide a yardstick against which results with other vascularized flaps (specifically muscle flaps) could be compared. A retrospective review was undertaken of 85 consecutive patients in whom omentum was used in the chest. In 47 patients (group I), use of omentum was prophylactic to aid in the healing of closures or anastomoses considered to be at high risk for failure. In 32 patients (group II), omentum was used in the treatment of problems complicated by established infection. In 6 patients (group III), omentum was used for coverage of prosthetic chest wall replacements after extensive chest wall resection. Overall, omental transposition was successful in its prophylactic or therapeutic purpose in 88% of these difficult cases (75/85). Success with omentum was achieved for 89% of patients (42/47) in group I, 91% of patients (29/32) in group II, and 67% of patients (4/6) in group III. Three patients (3.5%) had complications of omental mobilization. Four patients (4.7%) died after the operation as a result of failure of the omentum to manage the problem for which it was used. Results with omental transposition compare favorably with published series of similarly challenging cases managed with muscle transposition. Complications of omental mobilization are rare. We believe that its unique properties render the omentum an excellent choice of vascularized pedicle in the management of the most complex cardiothoracic surgical problems.


Catumaxomab with and without prednisolone premedication for the treatment of malignant ascites due to epithelial cancer: results of the randomised phase IIIb CASIMAS study.
This two-arm, randomised, multicentre, open-label, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a co-primary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites.


Impact of five annual rounds of mass drug administration with diethylcarbamazine and albendazole on Wuchereria bancrofti infection in American Samoa.
American Samoa began a territory-wide mass drug administration (MDA) program with diethylcarbamazine and albendazole in 2000 after baseline surveys indicated that 16.5% of 2,989 residents were infected with Wuchereria bancrofti based on tests for circulating filarial antigen. Follow-up surveys were conducted in 2001, 2003, and 2006, using convenience samples of residents of sentinel villages. Antigenemia prevalence in 2001 (11.5%) and 2003 (13.5%) showed no change. After the 2003 sentinel assessment, improvements were made in the social mobilization and drug distribution strategies. In 2006, after a total of 5 years of MDA and 3 years of improved MDA participation, the antigenemia prevalence dropped from 11.5% (2001) to 0.95% (2006) (P < 0.0001). In 2006, antigenemia prevalence was greater in males (1.5%) than females (0.4%) (P = 0.04). The decline in antigenemia prevalence shows the effectiveness of MDA and changes made in social mobilization and drug distribution.


Model-based decoding, information estimation, and change-point detection techniques for multineuron spike trains.
One of the central problems in systems neuroscience is to understand how neural spike trains convey sensory information. Decoding methods, which provide an explicit means for reading out the information contained in neural spike responses, offer a powerful set of tools for studying the neural coding problem. Here we develop several decoding methods based on point-process neural encoding models, or forward models that predict spike responses to stimuli. These models have concave log-likelihood functions, which allow efficient maximum-likelihood model fitting and stimulus decoding. We present several applications of the encoding model framework to the problem of decoding stimulus information from population spike responses: (1) a tractable algorithm for computing the maximum a posteriori (MAP) estimate of the stimulus, the most probable stimulus to have generated an observed single- or multiple-neuron spike train response, given some prior distribution over the stimulus; (2) a gaussian approximation to the posterior stimulus distribution that can be used to quantify the fidelity with which various stimulus features are encoded; (3) an efficient method for estimating the mutual information between the stimulus and the spike trains emitted by a neural population; and (4) a framework for the detection of change-point times (the time at which the stimulus undergoes a change in mean or variance) by marginalizing over the posterior stimulus distribution. We provide several examples illustrating the performance of these estimators with simulated and real neural data.


A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.
DNA and RNA nucleases play a critical role in a growing number of cellular processes ranging from DNA repair to immune surveillance. Nevertheless, many nucleases have unknown or poorly characterized activities. Elucidating nuclease substrate specificities and co-factors can support a more definitive understanding of cellular mechanisms in physiology and disease. Using fluorescence-based methods, we present a quick, safe, cost-effective, and real-time versatile nuclease assay, which uniquely studies nuclease enzyme kinetics. In conjunction with a substrate library we can now analyse nuclease catalytic rates, directionality, and substrate preferences. The assay is sensitive enough to detect kinetics of repair enzymes when confronted with DNA mismatches or DNA methylation sites. We have also extended our analysis to study the kinetics of human single-strand DNA nuclease TREX2, DNA polymerases, RNA, and RNA:DNA nucleases. These nucleases are involved in DNA repair, immune regulation, and have been associated with various diseases, including cancer and immune disorders.


Gastric emptying of liquid in children suffering from acute rotaviral gastroenteritis.
Nausea and vomiting commonly occur in children suffering from rotaviral diarrhoea. Gastric emptying was studied in 10 children (age six to 12 months) suffering from acute diarrhoea caused by rotavirus using a dye dilution double sampling technique. The test meal was 5% dextrose in water and this test was repeated 12 weeks after recovery. The median (range) of the percentages of the liquid meal remaining in the stomach at 5, 10, 20, 40, and 60 minutes after instillation of the meal were 82 (79-90), 70 (61-86), 51 (38-76), 26 (14-53), and 13 (2-35) respectively in the acute stage, whereas after the recovery period the values were 76 (70-79), 58 (49-63), 33 (24-40), 11 (2-26), and 3 (0-7). The differences were statistically significant. The half time of gastric emptying (t1/2) was 19.5 (14-30) minutes in acute stage, and 13.1 (10-15) minutes during follow up (p less than 0.01). Rotaviral gastroenteritis is accompanied by abnormal gastric motor function, as manifested by delayed emptying of a liquid meal.


Cataract surgeons outperform medical students in Eyesi virtual reality cataract surgery: evidence for construct validity.
To investigate construct validity for modules hydromaneuvers and phaco on the Eyesi surgical simulator. Seven cataract surgeons and 17 medical students performed capsulorhexis, hydromaneuvers, phaco, navigation, forceps, cracking and chopping modules in a standardized manner. Three trials were performed on each module (two on phaco) in the above order. Performance parameters as calculated by the simulator for each trial were saved. Video recordings of the second trial of the modules capsulorhexis, hydromaneuvers and phaco were evaluated with the modified Objective Structured Assessment of Surgical Skill (OSATS) and Objective Structured Assessment of Cataract Surgical Skill (OSACSS) tools. Cataract surgeons outperformed medical students with regard to overall score on capsulorhexis (p < 0.001, p = 0.035, p = 0.010 for the tree iterations, respectively), navigation (p = 0.024, p = 0.307, p = 0.007), forceps (p = 0.017, p = 0.03, p = 0.028). Less obvious differences in overall score were found for modules cracking and chopping (p = 0.266, p = 0.022, p = 0.324) and phaco (p = 0.011, p = 0.081 for the two iterations, respectively). No differences in overall score were found on hydromaneuvers (p = 0.588, p = 0.503, p = 0.773), but surgeons received better scores from the evaluations of the modified OSATS (p = 0.001) and OSACSS (capsulorhexis, p = 0.003; hydromaneuvers, p = 0.017; phaco, p = 0.001). Construct validity was found on several modules previously not investigated (phaco, hydromaneuvers, cracking and chopping, navigation), and our results confirm previously demonstrated construct validity for capsulorhexis and forceps modules. Interestingly, validation of the hydromaneuvers module required OSACSS video evaluation tool. A further development of the scoring system in the simulator for the hydromaneuvers module would be advantageous and make training and evaluation of progress more accessible and immediate.


Peptide nucleic acids inhibit growth of Brucella suis in pure culture and in infected murine macrophages.
Peptide nucleic acids (PNAs) are single-stranded, synthetic nucleic acid analogues containing a pseudopeptide backbone in place of the phosphodiester sugar-phosphate. When PNAs are covalently linked to cell-penetrating peptides (CPPs) they readily penetrate the bacterial cell envelope, inhibit expression of targeted genes and cause growth inhibition both of Gram-positive and Gram-negative bacteria. However, the effectiveness of PNAs against Brucella, a facultative intracellular bacterial pathogen, was unknown. The susceptibility of a virulent Brucella suis strain to a variety of PNAs was assessed in pure culture as well as in murine macrophages. The studies showed that some of the PNAs targeted to Brucella genes involved in DNA (polA, dnaG, gyrA), RNA (rpoB), cell envelope (asd), fatty acid (kdtA, acpP) and protein (tsf) synthesis inhibit the growth of B. suis in culture and in macrophages after 24 h of treatment. PNA treatment inhibited Brucella growth by interfering with gene expression in a sequence-specific and dose-dependent manner at micromolar concentrations. The most effective PNA in broth culture was that targeting polA at ca. 12 μM. In contrast, in B. suis-infected macrophages, the most effective PNAs were those targeting asd and dnaG at 30 μM; both of these PNAs had little inhibitory effect on Brucella in broth culture. The polA PNA that inhibits wild-type B. suis also inhibits the growth of wild-type Brucella melitensis 16M and Brucella abortus 2308 in culture. This study reveals the potential usefulness of antisense PNA constructs as novel therapeutic agents against intracellular Brucella.


Improved delivery of the Neuroform 3 stent: technical note.
Intracranial stents have expanded endovascular therapy to wide neck aneurysms whose dimensions and configurations are not amendable to coil embolization alone. Stents however have not eliminated all problems due to technical factors with their delivery systems. The Neuroform stent system is one of the most widely used for this purpose and has undergone several technical modifications to improve deliverability. Despite improvements in the delivery system there are still reports of failure of stent deployment with the Neuroform 3. Here a simple back table modification is described in which the stent is pushed several centimeters back into the delivery catheter from its manufactured location. This makes the catheter tip more flexible and in our experience improves navigation through vessel curvature and increases deployment rate. Our institution's cerebrovascular database was reviewed retrospectively in compliance with institutional review board approval to identify all Neuroform 3 stents used for assistance with aneurysm embolization since the current stent design became clinically available. Records were reviewed to identify cases of failure of stent placement using the above described technical modification. 139 Neuroform 3 stents were placed at our institution for assistance with aneurysm embolization with the technique described above. Only three instances of failure of stent placement related to trackability of the delivery system were identified for a technical failure rate of 2.2%. A simple back table modification to the Neuroform 3 delivery system is described which in our single center experience may improve trackability and ultimately successful stent deployment.


Plant life needs cell death, but does plant cell death need Cys proteases?
Caspases are key regulators of apoptosis in animals. This correlation has driven plant researchers for decades to look for caspases regulating programmed cell death (PCD) in plants. These studies revealed caspase-like activities, caspase-related proteases, and cysteine (Cys) proteases regulating PCD in plants, but identified no caspases and no conserved, apoptosis-like death pathway. Here, we critically review the evidence for Cys proteases implicated in PCD in plants. We discuss the role of papain-like Cys proteases, vacuolar processing enzymes, and metacaspases in PCD during the development of tracheary elements, seed coat, suspensor, and tapetum, and during the hypersensitive response. There are several convincing cases where these Cys proteases are required for PCD, but this requirement is often not conserved across different plant species. There are also cases where Cys proteases contribute to the speed, but not the timing of PCD, while other Cys proteases are nonessential for PCD, but have other roles, e.g., in the clearance of cell remains after PCD. These data illustrate the need for caution when generalizing the role of Cys proteases in regulating PCD in plants, and call for studies that further investigate plant Cys proteases and other PCD regulators.


MicroRNA-582-5p Reduces Propofol-induced Apoptosis in Developing Neurons by Targeting ROCK1.
Propofol is an intravenous drug commonly used in anesthesia procedures and intensive care in children. However, it also has neurotoxic effects on children. MicroRNA plays an important role in neurological diseases and neurotoxicity. In this study, primary rat hippocampal neurons were used to investigate the role of miR- 582-5p in propofol-induced neurotoxicity. Cell viability was monitored by 3-(4,5-dimethylthiazolyl)- 2,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while the expression of proteins was monitored by real-time quantitation polymerase chain reaction (RT-qPCR) and western blot. TargetScan and double luciferase report assay were used to predict the targeting relationship between miR-582-5p and Rho-associated serine-threonine protein kinase 1 (ROCK1). In the present study, the viability of neurons and the expression of miR-582-5p were decreased in a time-dependent manner after propofol treatment. Besides, miR-582-5p overexpression significantly reduced the toxicity of propofol on neuron cells but had no significant effect on normal nerve cells. In addition, miR-582-5p overexpression significantly reversed the expression of apoptosis-related proteins (cleaved caspase 3 and cleaved caspase 9) induced by propofol but had no significant effect in normal nerve cells. TargetScan and Dual-luciferase report assay revealed that ROCK1 was a targeted regulatory gene for miR-582-5p, and propofol treatment up-regulated ROCK1 expression by inhibiting miR-582-5p expression. Notably, miR-582-5p overexpression significantly increased cell viability, while ROCK1 overexpression reversed the effect of miR-582- 5p. Taken together, these findings suggest that miR-582-5p alleviated propofol-induced apoptosis of newborn rat neurons by inhibiting ROCK1.


Gender differences in the subjective effects of MDMA.
3.4-Methylenedioxymethamphetamine (MDMA) mainly releases serotonin (5-HT) and is contained in the recreational drug Ecstasy. 5-HT is known to play an important role in mood and anxiety disorders, for which there is a female preponderance. To date, there are no systematic data on gender differences in the subjective effects of MDMA. The present work analyzed the pooled data from three controlled studies on the psychological and physiological effects of MDMA in healthy volunteers with no or minimal MDMA experience. A particular focus of the analyses were possible gender differences. A total of 74 subjects (54 male, 20 female) participated in all three studies. MDMA in oral doses ranging from 70-150 mg (1.35-1.8 mg/kg) was administered under double-blind placebo-controlled conditions. Subjective peak changes were assessed by standardized psychometric rating scales. Physiological measures were blood pressure, heart rate, and peripheral body temperature. Adverse drug effects were assessed during the experimental session and after 24 h. Psychoactive effects of MDMA were more intense in women than in men. Women especially had higher scores for MDMA-induced perceptual changes, thought disturbances, and fear of loss of body control. The dose of MDMA positively correlated with the intensity of perceptual changes in women. Acute adverse effects and sequelae were also more frequent in female than in male subjects. In contrast, men showed higher increases in blood pressure than woman. The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the 5-HT-releasing effects of MDMA. Our results also indicate that increasing doses of MDMA produce more hallucinogen-like perceptual alterations, particularly in women.


Can self-testing increase HIV testing among men who have sex with men: A systematic review and meta-analysis.
Globally, four out of ten individuals living with HIV have not been tested for HIV. Testing is especially important for men who have sex with men (MSM), among whom an increasing HIV epidemic has been identified in many regions of the world. As a supplement to site-based HIV testing services, HIV self-testing (HIVST) provides a promising approach to promote HIV testing. However, evidence is scattered and not well-summarized on the effect of HIVST to improve HIV testing behaviors, especially for MSM. Seven databases (PubMed, Web of Science, Cochrane Library, PsycINFO, CINAHL Plus, WanFang, and China National Knowledge Internet) and conference abstracts from six HIV/sexually transmitted infections conferences were searched from January 2000-April 2017. Of 1,694 records retrieved, 23 studies were identified, 9 conducted in resource-limited countries and 14 in high-income countries. The pooled results showed that HIVST increased HIV test frequency for MSM by one additional test in a 6-month period (mean difference = 0.88 [95% CI 0.52-1.24]). The pooled proportion of first-time testers among those who took HIVST was 18.7% (95% CI: 9.9-32.4) globally, with a rate 3.32 times higher in resource-limited country settings (32.9% [95% CI: 21.3-47.6]) than in high-income countries (9.9% [95% CI: 7.4-13.8]). The pooled proportions included non-recent testers, 32.9% (95% CI: 28.1-38.3); ever or currently married MSM, 16.7% (95% CI: 14.5-19.4); and HIV positive men, 3.8% (95% CI: 2.0-5.7) globally; 6.5% [95% CI: 0.38-12.3] in resource-limited country settings; and 2.9% [95% CI: 2.0-5.0] in high-income countries). The rates reported for linkage to care ranged from 31.3% to 100%. HIVST could increase HIV testing frequency and potentially have capacity equivalent to that of site-based HIV testing services to reach first-time, delayed, married, and HIV-infected testers among MSM and link them to medical care. However, more rigorous study designs are needed to explore the specific self-testing approach (oral-fluid based or finger-prick based) on improving HIV testing for MSM in different social and economic settings.


Exploration of new water stable proton-conducting materials in an amino acid-templated metal phosphate system.
Two new metal phosphates, namely, Zn(HPO4)(dl-C3H7NO2) (SCU-4) and In(HPO4)(H2PO4)(dl-C3H7NO2) (SCU-12), were prepared in the presence of the amino acid l-alanine. SCU-4 has a ladderlike structure with edge-sharing 4-rings. SCU-12 represents the first example of a three-dimensional metal phosphate templated by an amino acid. It remains stable in boiling water and shows a high proton conductivity at room temperature under 98% relative humidity.


Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.


12-month color stability of enamel, dentine, and enamel-dentine samples after bleaching.
The study aimed to quantify the color regression of enamel (E), dentine (D), and combined enamel-dentine (ED) of differently bleached ED specimens over a period of 12 months in vitro. Two ED samples were obtained from the labial surfaces of bovine teeth and prepared to a standardized thickness with the enamel and dentine layer each 1 mm. The ED samples were distributed on four groups (each n = 80), in which the different bleaching products were applied on enamel (1, Whitestrips; 2, Illuminé 15%; 3, Opalescence Xtra Boost) or dentine surfaces (4, mixture of sodium perborate/distilled water). Eighty ED samples were not bleached (control). Color (L*a*b*) of ED was assessed at baseline, subsequently after bleaching and at 3, 6, and 12 months of storage after bleaching (each 20 samples/group). E and D samples were prepared by removing the dentine or enamel layer of ED samples to allow for separate color analysis. Bleaching resulted in a significant color change (Delta E) of ED specimens. Within the observation period, Delta L but not Delta b declined to baseline. L* values of E and D samples also declined and were not significantly different from control samples after 12 months, while b* values did not decrease to baseline. Generally, no differences between the bleaching agents could be observed. Color change of enamel, dentine, and combined ED of in vitro bleached tooth samples is not stable over time with regard to lightness. However, yellowness did not return to baseline within 1 year.


Cellular repair of CNS disorders: an immunological perspective.
Cellular repair is a promising strategy for treating central nervous system (CNS) disorders. Several strategies have been contemplated including replacement of neurons or glia that have been lost due to injury or disease, use of cellular grafts to modify or augment the functions of remaining neurons and/or use of cellular grafts to protect neural tissue by local delivery of growth or trophic factors. Depending on the specific disease target, there may be one or many cell types that could be considered for therapy. In each case, an additional variable must be considered--the role of the immune system in both the injury process itself and in the response to incoming cells. Cellular transplants can be roughly categorized into autografts, allografts and xenografts. Despite the immunological privilege of the CNS, allografts and xenografts can elicit activation of the innate and adaptive immune system. In this article, we evaluate the various effects that immune cells and signals may have on the survival, proliferation, differentiation and migration/integration of transplanted cells in therapeutic approaches to CNS injury and disease.


Rapid protein immobilization for thin film continuous flow biocatalysis.
A versatile enzyme immobilization strategy for thin film continuous flow processing is reported. Here, non-covalent and glutaraldehyde bioconjugation are used to immobilize enzymes on the surfaces of borosilicate reactors. This approach requires only ng of protein per reactor tube, with the stock protein solution readily recycled to sequentially coat >10 reactors. Confining reagents to thin films during immobilization reduced the amount of protein, piranha-cleaning solution, and other reagents by ∼96%. Through this technique, there was no loss of catalytic activity over 10 h processing. The results reported here combines the benefits of thin film flow processing with the mild conditions of biocatalysis.


Fiber-optic sensor for liquid level measurement.
A novel (to the best of our knowledge) liquid level sensor based on multimode interference (MMI) effects is proposed and demonstrated. By using a multimode fiber (MMF) without cladding, known as no-core fiber, liquids around the MMF modify the self-imaging properties of the MMI device and the liquid level can be detected. We show that the sensor exhibits a highly linear response with the sensing range and multiplexed operations easily controlled by just modifying the length of the no-core fiber. At the same time, we can measure the refractive index of the liquid based on the maximum peak wavelength shift. We can also use the sensor for continuous and discrete liquid level sensing applications, thus providing a liquid level sensor that is inexpensive with a very simple fabrication process.


Sexually transmitted disease and the evolution of mating systems.
Sexually transmitted diseases (STDs) have been shown to increase the costs of multiple mating and therefore favor relatively monogamous mating strategies. We examine another way in which STDs can influence mating systems in species in which female choice is important. Because more popular males are more likely to become infected, STDs can counteract any selective pressure that generates strong mating skews. We build two models to investigate female mate choice when the sexual behavior of females determines the prevalence of infection in the population. The first model has no explicit social structure. The second model considers the spatial distribution of matings under social monogamy, when females mated to unattractive males seek extrapair fertilizations from attractive males. In both cases, the STD has the potential to drastically reduce the mating skew. However, this reduction does not always happen. If the per contact transmission probability is low, the disease dies out and is of no consequence. In contrast, if the transmission probability is very high, males are likely to be infected regardless of their attractiveness, and mating with the most attractive males imposes again no extra cost for the female. We also show that optimal female responses to the risk of STDs can buffer the prevalence of infection to remain constant, or even decrease, with increasing per contact transmission probabilities. In all cases considered, the feedback between mate choice strategies and STD prevalence creates frequency-dependent fitness benefits for the two alternative female phenotypes considered (choosy vs. randomly mating females or faithful vs. unfaithful females). This maintains mixed evolutionarily stable strategies or polymorphisms in female behavior. In this way, a sexually transmitted disease can stabilize the populationwide proportion of females that mate with the most attractive males or that seek extrapair copulations.


Effect of therapy on left ventricular function in hypertension.
1. Twelve untreated hypertensive patients whose blood pressure was 171.8 +/- 5.5 mmHg systolic and 119.7 +/- 3.4 mmHg diastolic (mean +/- SEM) were treated aggressively with diuretics plus other antihypertensive agents. Echocardiograms were performed before, and 2 weeks, 3 months and 6 months after therapy. Blood pressures were lowered to an average of 142/98 mmHg over the 6 month period. 2. Mean velocity of circumferential fibre shortening rose from 1.1 +/- 0.09 to 1.3 +/- 0.06 diameters/s at 2 weeks and remained elevated at the end of 3 months (1.3 +/- 0.03 diameters/s) (P < 0.025), but returned to the control level in 6 months. Similarly, ejection fraction increased significantly during the same period from a control value of 65.1 +/- 4.4 to 73.4 +/- 1.8% (P < 0.025) and persisted in this range at 3 months. At 6 months the ejection fraction had returned to pretreatment levels. There were significant reductions in left ventricular end-systolic and end-diastolic dimensions. Left ventricular mass index decreased from 182.3 +/- 18.3 to 163.8 +/- 12.4 g/m2 after 6 months of therapy. 3. These results indicate that in the early stages of blood pressure reduction there is a temporary increase in ejection phase indices, probably related to afterload reduction. The reduction in the left ventricular mass index suggests that increased cardiac muscle mass due to elevated blood pressure may be partially reversible after long-term reduction in blood pressure.


Identification of probiotic microorganisms in South African products using PCR-based DGGE analysis.
Probiotic microorganisms in commercial yoghurts and other food products are currently identified by traditional methods such as growth on selective media, morphological and biochemical characteristics. In this study, PCR-based DGGE analysis was used for the rapid and accurate identification of probiotic microorganisms from South African yoghurts and lyophilized preparations in capsule and tablet form. To identify the microorganisms present in these products, the DGGE profiles obtained were compared to two reference markers (A and B) composed of five lactobacilli and seven Bifidobacterium species, respectively. The results obtained were confirmed by species-specific PCR, as well as sequence analyses of unknown bands not present in the reference markers. It was found that only 54.5% of the probiotic yoghurts contained the microorganisms stated on the label compared to only a third (33.3%) of the lyophilized probiotic products. Some Bifidobacterium species were incorrectly identified and various microorganisms were detected that were not listed on the label. Sequence analyses confirmed the presence of Streptococcus spp. other than the yoghurt starter, Streptococcus thermophilus, in some of these products and in some instances label information was vague and non-scientific. PCR-based DGGE analyses proved to be a valuable culture-independent approach for the rapid and specific identification of the microbial species present in South African probiotic products.


Ongoing improvements in postoperative survival of glioblastoma in the temozolomide era: a population-based data linkage study.
Translating outcomes achieved by clinical trials into routine care is crucial to improving outcomes of glioblastoma (GBM). This study examines the extent to which an advance in treatment for GBM has translated into meaningful, population-level survival benefits in New South Wales (NSW), Australia. This retrospective cohort study used linked population-based cancer registry, admitted patient, and mortality datasets. The cohort (n = 2604) included NSW residents aged ≥18 years with a histologically confirmed GBM and a surgical resection between July 2001 and December 2012. The study outcome was all-cause survival, examined using multivariable proportional hazard models. The main study factor was period of surgery, categorized into 4 periods corresponding to different eras in temozolomide (TMZ) use. Survival was examined over time by age (≤70 and >70 years) and for a subcohort selected to approximate the seminal European Organisation for Research and Treatment of Cancer (Stupp) protocol trial cohort. TMZ use was estimated using aggregate prescription claims data. Median survival in 2001-2003, 2004-2006, 2007-2009, and 2010-2012 was 7.4, 9.0, 9.8, and 10.6 months, and risk-adjusted 2-year survival was 8.2%, 13.8%, 15.5%, and 18.3%, respectively. Survival improved for those aged ≤70 years and those aged >70 years. In the proxy trial subcohort, median and 2-year survival were 14.3 months and 27.3%, respectively. The volume of TMZ prescribed annually increased rapidly from 2005. Introduction of TMZ into standard care in 2005 coincided with improvements in survival and a rapid increase in TMZ prescribing. Optimization of care has continued to improve survival of people with GBM in subsequent years.


Early fatherhood: a mapping of the evidence base relating to pregnancy prevention and parenting support.
Teenage pregnancy prevention programmes targeted at young women have received considerable attention from researchers and programme developers. However, to date, relatively limited information is available on preventing teenage fatherhood or improving outcomes for young fathers. A notable gap is concerned with understanding the forms of sexual health programmes that are most effective from the perspective of young men. We conducted a systematic mapping to identify studies involving young men aimed at preventing teenage pregnancy, improving outcomes for teenage fathers or exploring the perspectives of young men around pregnancy and fatherhood. We searched a wide range of electronic databases from January 1996 to August 2008. Three quantitative and 15 qualitative studies were identified, of which nine were UK based. Key themes related to the inappropriateness of current sexual health promotion to respond to the needs of young men. While young men often possessed very similar ideals to young women, existing programmes were problematic when they negatively stereotyped young men and ineffectively addressed models of masculinity or the difficulties young men may have forming meaningful relationships. Further investigations are required on programme development for young men, particularly on sexual health promotion interventions for 'looked-after' young men and those from unstable childhoods.


Pragmatic tolerance: implications for the acquisition of informativeness and implicature.
Recent investigations of the acquisition of scalar implicature report that young children do not reliably reject a sentence with a weak scalar term, e.g. 'some of the books are red', when it is used as a description of a situation where a stronger statement is true, e.g. where all the books are red. This is taken as evidence that children do not interpret the sentence with the implicature that the stronger statement does not hold. We propose that (a) these tasks cannot differentiate between actual implicature derivation and mere sensitivity to violations of informativeness; and that (b) children's apparent failure is not due to lack of competence (whether with informativeness or implicature) but due to their tolerance of pragmatic violations. We report three studies with 5-to-6-year-old English-speaking children and adults employing utterances involving scalar and non-scalar expressions. These show that both age-groups are competent with informativeness, but also tolerant of pragmatic infelicity. These findings have implications for the well-established literature on whether children are aware of ambiguity in referential communication tasks.


Effect of allergen challenge on airway responsiveness to histamine and sodium metabisulphite in mild asthma.
Airway responsiveness to histamine and methacholine, direct smooth muscle spasmogens, is increased following inhalation of allergen. Although the aetiology of this phenomenon is unclear, increased cellular or neural activity may be involved since allergen also induces increases in airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) and the neural stimulus bradykinin. To explore this further, the airway responsiveness to sodium metabisulphite (MBS), an indirect neural stimulus with similar characteristics to bradykinin, was compared in 18 mild steroid-naive asthmatic subjects with the airway responsiveness to histamine before and after allergen challenge with extracts of house dust mite, grass pollen, or cat. All subjects inhaled doubling increments of histamine and MBS until the concentration provoking a 20% fall in forced expiratory volume in one second (PC20) was reached before and three hours after allergen challenge. Twelve of the subjects had additional challenges at 24 hours after the allergen. Following allergen challenge all subjects showed an early response and 14 also had a late asthmatic response. For histamine there was a significant increase in airway responsiveness at both three and 24 hours compared with values before the allergen (0.89 (0.25) and 1.53 (0.52) doubling dose changes, respectively). In contrast, airway responsiveness to MBS was unaltered by allergen challenge (0.29 (0.27) and -0.33 (0.28) doubling dose changes compared with pre-allergen values at three and 24 hours, respectively). These data suggest that activation of airway sensory nerves is unlikely to contribute to the increase in airway responsiveness following inhalation of allergen. The previously observed allergen induced increase in airway responsiveness to bradykinin and AMP may involve non-neural pathways.


Breast cancer recurrence in relation to antidepressant use.
Women with breast cancer frequently use antidepressants; however, questions about the effect of these medications on breast cancer recurrence remain. We identified 4,216 women ≥18 years with an incident stage I or II breast cancer diagnosed between 1990 and 2008 in a mixed-model healthcare delivery system linked to a cancer registry. Recurrences were ascertained from chart review. Medication exposures were extracted from electronic pharmacy records. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to assess the association between antidepressant use and breast cancer recurrence and mortality. We also conducted analyses restricted to tamoxifen users. Antidepressants overall, tricyclic antidepressants, and selective serotonin reuptake inhibitors were not associated with risk of breast cancer recurrence or mortality. Women taking paroxetine only (adjusted HR: 1.66; 95 % CI 1.02, 2.71) and trazodone only (adjusted HR: 1.76; 95 % CI 1.06, 2.92), but not fluoxetine only (adjusted HR: 0.92; 95 % CI 0.55, 1.53), had higher recurrence risks than antidepressant nonusers. There was some suggestion of an increased recurrence risk with concurrent paroxetine and tamoxifen use compared with users of tamoxifen only (adjusted HR: 1.49; 95 % CI 0.79, 2.83). In general, antidepressants did not appear increase risk of breast cancer recurrence, though there were some suggested increases in risk that warrant further investigation in other datasets. Our results combined systematically and quantitatively with results from other studies may be useful for patients and providers making decisions about antidepressant use after breast cancer diagnosis.


Idiopathic Myointimal Hyperplasia of Mesenteric Veins: An Uncommon Cause of Ischemic Colitis With Distinct Mucosal Features.
Idiopathic myointimal hyperplasia of mesenteric veins causes chronic ischemic mucosal injury with segmental strictures that mimic inflammatory bowel disease and nonocclusive ischemic colitis. It is characterized by myointimal proliferative changes that narrow the lumina of veins combined with ischemic injury and ulcers. Most cases reported to date have been diagnosed following surgical resection. The aim of this study was to determine whether mucosal changes of idiopathic myointimal hyperplasia of mesenteric veins are sufficiently sensitive and specific to allow its recognition in biopsy material. The study group consisted of 10 patients with idiopathic myointimal hyperplasia of mesenteric veins who underwent surgical resection of the affected colon, 7 of whom had available prior endoscopic biopsies. The control group included 10 patients each with radiation, nonocclusive ischemia, Crohn disease, diverticulitis, and mucosal amyloidosis, and 5 cases of small vessel (leukocytoclastic) vasculitis. Study patients were mostly older men with distal colorectal disease. All resection specimens showed mucosal ischemia with numerous thick-walled (arteriolized) capillaries and glassy subendothelial fibrin deposits; numerous hyalinized, eosinophilic thrombi were detected in 90% of colectomy specimens. Biopsies showed arteriolized capillaries (100%), subendothelial fibrin deposits (86%), fibrin thrombi (43%), and perivascular hyalinization (43%). Fibrin thrombi were observed in only one case each of ischemic colitis and small vessel vasculitis, and none of the other abovementioned features were seen in any of the controls. We conclude that arteriolized capillaries, subendothelial fibrin deposits, and perivascular hyalinization are frequent and specific features that can facilitate recognition of idiopathic myointimal hyperplasia of mesenteric veins in biopsy samples.


Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor.
Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells. In addition to endothelial cells, cancer cells express the three receptors, suggesting that the antiangiogenic inhibitors affect tumor cells. In fact, we previously demonstrated that regorafenib directly acted on human colorectal cancer cells and accelerated their apoptosis resistance and migration capability. Thus, we here elucidated how regorafenib induced the malignant phenotypes in colorectal cancer cells. To identify the responsible receptor among the regorafenib-targeting proangiogenic receptors, we examined the effects of a potent selective inhibitor for VEGF-R, FGF-R or PDGF-R on apoptosis resistance and migration capability. We clarified that blockade of VEGF-R, but not FGF-R and PDGF-R, induced the malignant phenotypes. We confirmed that blocking of VEGF ligands derived from colorectal cancer cells also induced the phenotypes. These results suggest that regorafenib progressed the malignancy via prevention of autocrine and paracrine VEGF signaling in colorectal cancer cells. J. Med. Invest. 64: 262-265, August, 2017.


Interleukin-6 enhances manganese accumulation in SH-SY5Y cells: implications of the up-regulation of ZIP14 and the down-regulation of ZnT10.
Exposure to an excess amount of manganese causes neurological symptoms similar to Parkinson's disease. Zinc transporters such as Zrt, Irt-related protein 8 (ZIP8), and ZIP14 have been shown to have affinities for Mn(2+) as well as Zn(2+), but their roles in Mn(2+) uptake in neuronal cells remain unclear. Recent studies have shown that another zinc transporter ZnT10 may be involved in manganese excretion. Here we examined the roles of ZIP8, ZIP14, and ZnT10 in the transport of manganese in human SH-SY5Y neuroblastoma cells. The introduction of siRNA of ZIP14 decreased the uptake of Mn(2+), suggesting a significant role of ZIP14 in Mn(2+) uptake in SH-SY5Y cells. The pretreatment of SH-SY5Y cells with interleukin-6 (IL-6) markedly increased the accumulation of manganese to approx. 3-fold that of the control, which could be partly explained by the increased uptake of Mn(2+) due to the up-regulation of ZIP14 by IL-6. The treatment of SH-SH5Y cells with IL-6 clearly decreased both the mRNA and protein levels of ZnT10 with a concomitant decrease in the manganese excretion efficiency. These results suggest that both the up-regulation of ZIP14 and the down-regulation of ZnT10 by IL-6 might have enhanced the accumulation of manganese in SH-SY5Y cells. Our results provide new insight into the roles of zinc transporters in the aberrant manganese accumulation in neuronal cells, particularly in the presence of inflammatory cytokines such as IL-6.


Predicting Professional Examination Outcomes: A Case of the Registered Health Information Administration Certification Examination.
To determine whether differences existed among candidates for the Registered Health Information Administrator (RHIA) certification examination that may have characterized the likelihood of acquiring professional certification upon graduation. Records of total of 197 former students were acquired from accredited health information administration education programs located across the United States. Final course grades in coding and introduction to health information administration and professional curriculum grade point average were strongly associated with the RHIA examination score. Subsequently, a 95% approximate prediction interval was computed. Certain academic and demographic variables can be used to predict which students may be at risk for unsuccessfully completing the certification examination. A regression model which can accurately predict the student's examination score was developed.


Mature results of a phase II trial of concomitant cisplatin/pelvic radiotherapy for locally advanced squamous cell carcinoma of the cervix.
Patients with locally advanced squamous cell carcinoma of the cervix have a poor prognosis when treated by standard radiotherapy (RT) alone. Factors such as large tumor volume or nodal disease result in pelvic and distant treatment failures. Cisplatin (CDDP), a known radiosensitizer with documented activity in squamous cell carcinomas, was used in a phase II prospective study to evaluate the efficacy of combined chemo/radiotherapy in locally advanced squamous cell carcinomas of the cervix. CDDP was administered (20 mg/m2) daily X 5 at 21-day intervals with concomitant external beam and intracavity RT. Standard RT was delivered at 1.8-2.0 Gy/day, 5 fractions per week for 5 weeks. Intracavitary cesium insertions were planned to treat point A to approximately 80 Gy. Fifty-nine patients were enrolled from March 1986 to July 1990. Four patients were voluntarily withdrawn, leaving 55 patients evaluable for response. Of these, 16 were Stage IB/IIA, 11 were Stage IIB, 24 were Stage III, and 4 were Stage IV. The median age of patients enrolled was 47 years (range 27-79). Median follow-up time was 65 months (range 60-113). Histopathologic confirmation of node status was available in 33 patients, of whom 45.5% (15/33) had nodal metastases. Overall response was 96% (CR = 87%, PR = 9.0%) and 3.6% had progressive disease during treatment. Forty-six patients were evaluable at 5 years for overall and disease-free survival. Calculations were based on Kaplan-Meier product limit estimates. The 5-year survival was 73% for Stage IB/IIA, 60% for Stage IIB, 67% for Stage III, and 25% for Stage IV. The disease-free survival at 5 years was 73% for Stage for IB/IIA, 50% for Stage IIB, 67% for Stage III, and 25% for Stage IV. Hematologic toxicity was severe but tolerable. No treatment-related deaths occurred. Concomitant CDDP/RT is a safe and tolerable method of treating patients with locally advanced squamous cell carcinoma of the cervix. Our data suggest a benefit in both disease-free and 5-year survival, particularly notable among patients with Stage III disease.