Proof of the mysterious efficacy of ginseng: basic and clinical trials: suppression of adrenal medullary function in vitro by ginseng.
The root of Panax ginseng C.A. MEYER has been reported to have an anti-stress action. Therefore, the effects of ginseng components on functions of adrenal medulla, which is one of the most important organs responsive to stress, were investigated in vitro. First, the components of ginseng were mainly divided into two fractions, that is, the saponin-rich and non-saponin fractions. The saponin-rich fraction greatly reduced the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine (ACh), whereas the non-saponin fraction did not affect it at all. The protopanaxatriol-type saponins inhibited the ACh-evoked secretion much more strongly than the protopanaxadiol-type. On the other hand, the oleanane-type saponin, ginsenoside-Ro, had no such effect. Recent reports have demonstrated that the saponins in ginseng are metabolized and absorbed in digestive tracts following oral administration of ginseng. All of the saponin metabolites greatly reduced the ACh-evoked secretion. M4 was the most effective inhibitor among the metabolites. M4 blocked ACh-induced Na(+) influx and ion inward current into the chromaffin cells and into the Xenopus oocytes expressing human alpha3beta4 nicotinic ACh receptors, respectively, suggesting that the saponin metabolites modulate nicotinic ACh receptors followed by the reduction of catecholamine secretion. It is highly possible that these effects of ginsenosides and their metabolites are associated with the anti-stress action of ginseng.


Comparative mapping in the Poaceae family reveals translocations in the complex polyploid genome of sugarcane.
The understanding of sugarcane genetics has lagged behind that of other members of the Poaceae family such as wheat, rice, barley and sorghum mainly due to the complexity, size and polyploidization of the genome. We have used the genetic map of a sugarcane cultivar to generate a consensus genetic map to increase genome coverage for comparison to the sorghum genome. We have utilized the recently developed sugarcane DArT array to increase the marker density within the genetic map. The sequence of these DArT markers plus SNP and EST-SSR markers was then used to form a bridge to the sorghum genomic sequence by BLAST alignment to start to unravel the complex genomic architecture of sugarcane. Comparative mapping revealed that certain sugarcane chromosomes show greater levels of synteny to sorghum than others. On a macrosyntenic level a good collinearity was observed between sugarcane and sorghum for 4 of the 8 homology groups (HGs). These 4 HGs were syntenic to four sorghum chromosomes with from 98% to 100% of these chromosomes covered by these linked markers. Four major chromosome rearrangements were identified between the other four sugarcane HGs and sorghum, two of which were condensations of chromosomes reducing the basic chromosome number of sugarcane from x = 10 to x = 8. This macro level of synteny was transferred to other members within the Poaceae family such as maize to uncover the important evolutionary relationships that exist between sugarcane and these species. Comparative mapping of sugarcane to the sorghum genome has revealed new information on the genome structure of sugarcane which will help guide identification of important genes for use in sugarcane breeding. Furthermore of the four major chromosome rearrangements identified in this study, three were common to maize providing some evidence that chromosome reduction from a common paleo-ancestor of both maize and sugarcane was driven by the same translocation events seen in both species.


The target cell nucleus is not required for cell-mediated granzyme- or Fas-based cytotoxicity.
The requirement for target cell nuclei in the two apoptotic death pathways used by cytotoxic lymphocytes was tested using model effector systems in which the granzyme and Fas pathways of target damage are isolated. Mast cell tumors expressing granzymes A and B in addition to cytolysin/perforin lysed tumor target cells about 10-fold more efficiently than comparable effector cells without granzymes. Enucleated cytoplast targets derived from these cells were also lysed with a similar 10-fold effect of granzymes. In contrast to cytoplasts, effector granzyme expression did not influence lysis of red cell targets. The Fas pathway was assessed using the selected cytotoxic T lymphocyte hybridoma subline d11S, which lysed target cells expressing Fas but not those lacking Fas. Similarly, cytoplasts derived from Fas+ but not Fas- cells were also readily lysed by these effector cells. Thus, neither the nucleus itself nor the characteristic apoptotic nuclear damage associated with the two major cell death pathways used by cytotoxic lymphocytes are required for cell death per se.


Homo naledi, a new species of the genus Homo from the Dinaledi Chamber, South Africa.
Homo naledi is a previously-unknown species of extinct hominin discovered within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths. Cranial morphology of H. naledi is unique, but most similar to early Homo species including Homo erectus, Homo habilis or Homo rudolfensis. While primitive, the dentition is generally small and simple in occlusal morphology. H. naledi has humanlike manipulatory adaptations of the hand and wrist. It also exhibits a humanlike foot and lower limb. These humanlike aspects are contrasted in the postcrania with a more primitive or australopith-like trunk, shoulder, pelvis and proximal femur. Representing at least 15 individuals with most skeletal elements repeated multiple times, this is the largest assemblage of a single species of hominins yet discovered in Africa.


Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells.
Chronic inflammation involving both innate and adaptive immune cells is implicated in the pathogenesis of asthma. Intercellular communication is essential for driving and resolving inflammatory responses in asthma. Emerging studies suggest that extracellular vesicles (EVs) including exosomes facilitate this process. In this report, we have used a range of approaches to show that EVs contain markers of mitochondria derived from donor cells which are capable of sustaining a membrane potential. Further, we propose that these participate in intercellular communication within the airways of human subjects with asthma. Bronchoalveolar lavage fluid of both healthy volunteers and asthmatics contain EVs with encapsulated mitochondria; however, the % HLA-DR+ EVs containing mitochondria and the levels of mitochondrial DNA within EVs were significantly higher in asthmatics. Furthermore, mitochondria are present in exosomes derived from the pro-inflammatory HLA-DR+ subsets of airway myeloid-derived regulatory cells (MDRCs), which are known regulators of T cell responses in asthma. Exosomes tagged with MitoTracker Green, or derived from MDRCs transduced with CellLight Mitochondrial GFP were found in recipient peripheral T cells using a co-culture system, supporting direct exosome-mediated cell-cell transfer. Importantly, exosomally transferred mitochondria co-localize with the mitochondrial network and generate reactive oxygen species within recipient T cells. These findings support a potential novel mechanism of cell-cell communication involving exosomal transfer of mitochondria and the bioenergetic and/or redox regulation of target cells.


Response of chronic experimental cerebral vasospasm to methylprednisolone and dexamethasone.
The authors have previously demonstrated that high-dose methylprednisolone (30 mg/kg intravenously every 8 hours) prevents severe chronic vasospasm in dogs. In the present study, lesser doses of methylprednisolone (15 mg/kg intravenously every 8 hours) and dexamethasone (0.1 mg/kg intravenously every 8 hours), although better than no treatment at all, were significantly less effective than the higher dose of methylprednisolone. These data suggest that methylprednisolone can prevent chronic experimental vasospasm from occurring only when given in high doses (30 mg/kg).


Mitochondria as therapeutic targets in acute kidney injury.
Mitochondria are complex intracellular organelles with a variety of important functions. The kidney tubule is densely packed with mitochondria, and mitochondrial dysfunction is thought to be central to the pathogenesis of acute kidney injury (AKI). Mitochondria therefore represent potential targets for novel therapeutic interventions in AKI. Several mitochondrial targeted approaches have shown promise in recent preclinical studies of AKI, including measures to: reduce oxidative stress within mitochondria; prevent mitochondrial fission and activation of cell death pathways; enhance recycling of damaged mitochondria via autophagy and mitophagy; and accelerate mitochondrial biogenesis postinsult. Recent studies show that it is now eminently feasible to pharmacologically manipulate various key aspects of mitochondrial biology in the kidney, and this has much potential for the future treatment of AKI. However, significant hurdles will have to be overcome in the translational pathway for these strategies to successfully migrate to the clinic.


BLAST+: architecture and applications.
Sequence similarity searching is a very important bioinformatics task. While Basic Local Alignment Search Tool (BLAST) outperforms exact methods through its use of heuristics, the speed of the current BLAST software is suboptimal for very long queries or database sequences. There are also some shortcomings in the user-interface of the current command-line applications. We describe features and improvements of rewritten BLAST software and introduce new command-line applications. Long query sequences are broken into chunks for processing, in some cases leading to dramatically shorter run times. For long database sequences, it is possible to retrieve only the relevant parts of the sequence, reducing CPU time and memory usage for searches of short queries against databases of contigs or chromosomes. The program can now retrieve masking information for database sequences from the BLAST databases. A new modular software library can now access subject sequence data from arbitrary data sources. We introduce several new features, including strategy files that allow a user to save and reuse their favorite set of options. The strategy files can be uploaded to and downloaded from the NCBI BLAST web site. The new BLAST command-line applications, compared to the current BLAST tools, demonstrate substantial speed improvements for long queries as well as chromosome length database sequences. We have also improved the user interface of the command-line applications.


Transcriptome analysis of a barley breeding program examines gene expression diversity and reveals target genes for malting quality improvement.
Advanced cycle breeding utilizes crosses among elite lines and is a successful method to develop new inbreds. However, it results in a reduction in genetic diversity within the breeding population. The development of malting barley varieties requires the adherence to a narrow malting quality profile and thus the use of advanced cycle breeding strategies. Although attention has been focused on diversity in gene expression and its association with genetic diversity, there are no studies performed in a single breeding program examining the implications that consecutive cycles of breeding have on gene expression variation and identifying the variability still available for future improvement. Fifteen lines representing the historically important six-rowed malting barley breeding program of the University of Minnesota were genotyped with 1,524 SNPs, phenotypically examined for six malting quality traits, and analyzed for transcript accumulation during germination using the Barley1 GeneChip array. Significant correlation was detected between genetic and transcript-level variation. We observed a reduction in both genetic and gene expression diversity through the breeding process, although the expression of many genes have not been fixed. A high number of quality-related genes whose expression was fixed during the breeding process was identified, indicating that much of the diversity reduction was associated with the improvement of the complex phenotype "malting quality", the main goal of the University of Minnesota breeding program. We also identified 49 differentially expressed genes between the most recent lines of the program that were correlated with one or more of the six primary malting quality traits. These genes constitute potential targets for the improvement of malting quality within the breeding program. The present study shows the repercussion of advanced cycle breeding on gene expression diversity within an important barley breeding program. A reduction in gene expression diversity was detected, although there is diversity still present after forty years of breeding that can exploited for future crop improvement. In addition, the identification of candidate genes for enhancing malting quality may be used to optimize the selection of targets for further improvements in this economically important phenotype.


Selected list of books and journals for the small medical library.
This revised list of 446 books and 137 journals is intended as a selection guide for small or medium-sized hospital libraries or for the small medical library serving a specified clientele. Books and journals are categorized by subject, with the books being followed by an author index and the journals by an alphabetical title listing. Items suggested for initial purchase by smaller libraries are indicated by an asterisk. To purchase the entire collection of books and to pay for annual subscriptions to all the journals would require an expenditure for about $14,500. The cost of only the asterisked items recommended for first purchase totals approximately $4,100.


How Should Medical Education Better Prepare Physicians for Opioid Prescribing?
Opioid overprescribing is a key contributor to the current crisis. Changing how ethics is taught in connection with opioid prescribing is one area for improvement. In US medical schools, current training in ethics and opioid prescribing is variable, incorporating a diverse range of concepts, teaching modes, assessment strategies, and faculty experience. This article recommends integrating clinical case-based teaching and longitudinal application, comprehensive assessment, and additional training in ethical deliberation about opioid prescribing to better prepare physicians to responsibly prescribe and manage opioid-based phases of patients' pain care.


Next-Generation Sequencing of Uveal Melanoma for Detection of Genetic Alterations Predicting Metastasis.
To clinically use the UCSF500, a pancancer, next-generation sequencing assay in uveal melanoma (UM) and to correlate results with gene expression profiling (GEP) and predictive factors for metastasis. Cohort study. Tumor samples of adult UM patients were analyzed with the UCSF500 and GEP. Main outcomes were copy number changes in chromosomes 1, 3, 6, and 8 and mutations in GNAQ, GNA11, SF3B1, EIF1AX, BAP1, SRSF2, U2AF1, and PLCB4. Chromosome 3 loss (a metastasis predictor) was tested for correlation with GEP class, tumor characteristics (largest basal diameter, thickness, ciliary body involvement, and extraocular extension), and histology (presence of epithelioid cells, closed loops, and mitotic count). The 62 patients had a mean age of 59 years (range, 24-89 years). Chromosome 3 loss was detected in 30 patients and was associated with larger basal tumor diameter (Wilcoxon rank sum test, P = 0.015), greater thickness (Wilcoxon rank sum test, P = 0.016) and tumor, node, metastasis stage (Fisher test, P = 0.006), epithelioid cytology (Fisher test, P < 0.001), BAP1 mutation (Fisher test, P < 0.001), and chromosome 8q gain (Fisher test, P < 0.001). Class 2 tumors were much more likely to have chromosome 3 loss than class 1 (odds ratio, 121; P < 0.001). Eleven patients developed metastatic UM, of which five died during the study. All metastatic cases had chromosome 3 loss, 8 gain, BAP1 mutation, and class 2 GEP. Five class 1 tumors had chromosome 3 loss. UCSF500 detects chromosomal copy number changes and missense mutations that correlate strongly with metastasis predictors, including GEP. Next-generation sequencing of UM should enhance survival prognostication.


Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.
Bradykinin-mediated angioedema (Bk-AE) can be life-threatening and requires specific targeted therapies. Knowledge of its epidemiology may help optimize its management. We systematically searched the medical literature to identify abstracts of interest indexed between 1948 and March, 2016. We used published national survey data on the proportion of the population treated with angiotensin-converting enzyme inhibitors (ACEI) to derive estimates of the population prevalence of ACEI-AE in the USA, Germany and France. For hereditary angioedema (C1-INH-HAE) and C1-inhibitor related acquired angioedema (C1-INH-AAE), publications had to contain original epidemiologic data collection within a defined geographical area. Hereditary angioedema with normal C1-INH was not included in the analysis due to lack of clearly defined criteria. We identified 4 relevant publications on the prevalence of ACEI-AE, 6 on the prevalence of C1-INH-HAE, and 1 on the prevalence of C1-INH-AAE. The 1st year cumulative incidence of ACEI-AE was estimated to vary between 0.12 (population-based analyses) and 0.30 (meta-analyses of clinical trials) per 100 patient-years. The population prevalence of ACEI-AE was modeled to vary between 7 and 26 in 100,000. The prevalence of C1-INH-HAE was estimated to vary between 1.1 and 1.6 per 100,000. The prevalence of C1-INH-AAE was estimated to be 0.15 per 100,000 in one epidemiological investigation of AAE in Denmark. Epidemiological evidence on Bk-AE is limited to North America and Europe. ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is more common than C1-INH-AAE (~ 10:1). More studies are needed to comprehensively assess the epidemiological burden of Bk-AE.


Samples of stars beyond the solar system: silicate grains in interplanetary dust.
We have identified six circumstellar silicate grains within interplanetary dust particles (IDPs). Their extrasolar origins are demonstrated by their extremely anomalous oxygen isotopic compositions. Three 17O-rich grains appear to originate from red giant or asymptotic giant branch stars. One 16O-rich grain may be from a metal-poor star. Two 16O-poor grains have unknown stellar sources. One of the grains is forsterite, and two are amorphous silicate "GEMS" (glass with embedded metal and sulfides), which is consistent with astronomical identifications of crystalline and amorphous silicates in the outflows of evolved stars. These observations suggest cometary origins of these IDPs and underscore the perplexing absence of silicates among circumstellar dust grains from meteorites.


Bacteriology and sensitivity patterns of pyogenic meningitis at Kenyatta National Hospital, Nairobi, Kenya.
A descriptive cross sectional study on bacteriology and sensitivity patterns of laboratory-proven pyogenic meningitis was carried out over a six month period. A total of 92 patients (52 adults, 40 children) were studied. In 75 (82%) of the cases, the cerebrospinal fluid cultures were bacteriologically positive. Common isolates included Streptococcus pneumoniae (45%), Neisseria meningitidis (14%) and Haemophilus influenzae (12%). Other isolates included Cryptococcus neoformans from four (4.3%) adults who were also HIV-l positive. Sensitivity to antibiotics was determined using the disk diffusion method. There was no resistance to chloramphenicol among the three most common bacterial isolates. However, 7% and 15% of Streptococcus pneumoniae and N. meningitidis isolates, respectively, were resistant to crystalline penicillin. Twenty seven percent of Haemophilus influenzae was resistant to ampicillin. Sensitivity of the three organisms to the third generation cephalosporin (ceftazidime, cefotaxime, ceftriaxone) a second generation cephalosporin (cefuroxime) and augmentin was almost 100%. We recommend that chloramphenicol and crystalline penicillin or ampicillin be initial blind therapy for adults and older children with pyogenic meningitis and ampicillin and chloramphenicol for pre-school children. The above cephalosporins and augmentin are alternative therapy but their use will be limited by cost.


TLR9 activation suppresses inflammation in response to Helicobacter pylori infection.
Helicobacter pylori (H. pylori) induces chronic gastritis in humans, and infection can persist for decades. One H. pylori strain-specific constituent that augments disease risk is the cag pathogenicity island. The cag island encodes a type IV secretion system (T4SS) that translocates DNA into host cells. Toll-like receptor 9 (TLR9) is an innate immune receptor that detects hypo-methylated CpG DNA motifs. In this study, we sought to define the role of the H. pylori cag T4SS on TLR9-mediated responses in vivo. H. pylori strain PMSS1 or its cagE- mutant, which fails to assemble a T4SS, were used to infect wild-type or Tlr9-/- C57BL/6 mice. PMSS1-infected Tlr9-/- mice developed significantly higher levels of inflammation, despite similar levels of colonization density, compared with PMSS1-infected wild-type mice. These changes were cag dependent, as both mouse genotypes infected with the cagE- mutant only developed minimal inflammation. Tlr9-/- genotypes did not alter the microbial phenotypes of in vivo-adapted H. pylori strains; therefore, we examined host immunological responses. There were no differences in levels of TH1 or TH2 cytokines in infected mice when stratified by host genotype. However, gastric mucosal levels of IL-17 were significantly increased in infected Tlr9-/- mice compared with infected wild-type mice, and H. pylori infection of IL-17A-/- mice concordantly led to significantly decreased levels of gastritis. Thus loss of Tlr9 selectively augments the intensity of IL-17-driven immune responses to H. pylori in a cag T4SS-dependent manner. These results suggest that H. pylori utilizes the cag T4SS to manipulate the intensity of the host immune response.


BMP-binding modules in chordin: a model for signalling regulation in the extracellular space.
A number of genetic and molecular studies have implicated Chordin in the regulation of dorsoventral patterning during gastrulation. Chordin, a BMP antagonist of 120 kDa, contains four small (about 70 amino acids each) cysteine-rich domains (CRs) of unknown function. In this study, we show that the Chordin CRs define a novel protein module for the binding and regulation of BMPs. The biological activity of Chordin resides in the CRs, especially in CR1 and CR3, which have dorsalizing activity in Xenopus embryo assays and bind BMP4 with dissociation constants in the nanomolar range. The activity of individual CRs, however, is 5- to 10-fold lower than that of full-length Chordin. These results shed light on the molecular mechanism by which Chordin/BMP complexes are regulated by the metalloprotease Xolloid, which cleaves in the vicinity of CR1 and CR3 and would release CR/BMP complexes with lower anti-BMP activity than intact Chordin. CR domains are found in other extracellular proteins such as procollagens. Full-length Xenopus procollagen IIA mRNA has dorsalizing activity in embryo microinjection assays and the CR domain is required for this activity. Similarly, a C. elegans cDNA containing five CR domains induces secondary axes in injected Xenopus embryos. These results suggest that CR modules may function in a number of extracellular proteins to regulate growth factor signalling.


The effect of running shoes on lower extremity joint torques.
To determine the effect of modern-day running shoes on lower extremity joint torques during running. Two-condition experimental comparison. A 3-dimensional motion analysis laboratory. A total of 68 healthy young adult runners (37 women) who typically run in running shoes. All subjects ran barefoot and in the same type of stability running footwear at a controlled running speed. Three-dimensional motion capture data were collected in synchrony with ground reaction force data from an instrumented treadmill for each of the 2 conditions. Peak 3-dimensional external joint torques at the hip, knee, and ankle as calculated through a full inverse dynamic model. Increased joint torques at the hip, knee, and ankle were observed with running shoes compared with running barefoot. Disproportionately large increases were observed in the hip internal rotation torque and in the knee flexion and knee varus torques. An average 54% increase in the hip internal rotation torque, a 36% increase in knee flexion torque, and a 38% increase in knee varus torque were measured when running in running shoes compared with barefoot. The findings at the knee suggest relatively greater pressures at anatomical sites that are typically more prone to knee osteoarthritis, the medial and patellofemoral compartments. It is important to note the limitations of these findings and of current 3-dimensional gait analysis in general, that only resultant joint torques were assessed. It is unknown to what extent actual joint contact forces could be affected by compliance that a shoe might provide, a potentially valuable design characteristic that may offset the observed increases in joint torques.


Sorptive characteristics of organomontmorillonite toward organic compounds: a combined LFERs and molecular dynamics simulation study.
Linear free energy relationships (LFER) combined with molecular dynamics (MD) simulations were used to investigate the sorptive characteristics of organic compounds (OCs) on cetyltrimethylammonium (CTMA) intercalated montmorillonite (CTMA-Mont). The LFER for OCs sorption on CTMA-Mont, log K(oc) = (1.45 ± 0.20)E - (0.37 ± 0.15)S + (0.56 ± 0.15)A - (1.75 ± 0.25)B + (2.50 ± 0.45)V + (0.19 ± 0.35), was obtained by a multiple linear regression of the sorption coefficients of the OCs against their solvation descriptors. In comparison to water, CTMA-Mont is more polarizable, less polar and cohesive, and has stronger H-bond acceptor and weaker H-bond donor capacities. Using the above equation we calculated that vV and eE were the dominant solvation terms contributing to the sorption for all the OCs. MD simulations provided atomic-level insight into the interlayer structure of CTMA-Mont. Phenol molecules were shown to be sorbed into the nanosized aggregates formed by CTMA alkyl chains. The hydrophobic environment within the aggregates is responsible for the sorbent's more polarizable, less polar and cohesive characteristics. CTMA-Mont has strong H-bond acceptor and weak H-bond donor capacities as oxygen atoms on the siloxane surface act as H-bond acceptors for both water and OC molecules. With the combination of the results of the two methods, we can provide new insights for understanding the sorptive characteristics of organomontmorillonite.


Barrel maturation, oak alternatives and micro-oxygenation: influence on red wine aging and quality.
The impact of micro-oxygenation (MOX) in conjunction with a variety of oak alternatives on phenolic composition and red wine aging was investigated and compared with traditional barrel aging. Although several studies concluded that MOX give similar results to barrel aging, few have compared them directly and none directly compared MOX with and without wood alternatives and barrel aging. Results confirmed that MOX had a positive effect on colour density, even after 5 months of bottle aging. This is supported by an increase in polymeric phenol and pigment content not only with aging but in the MOX compared to barrel matured wine treatments. Descriptive analysis showed that MOX in combination with wood alternatives such as oak chips and staves could mimic short term (six months) barrel aging in new American and French oak barrels in regards to sensory characteristics.


Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans.
The origins of the First Americans remain contentious. Although Native Americans seem to be genetically most closely related to east Asians, there is no consensus with regard to which specific Old World populations they are closest to. Here we sequence the draft genome of an approximately 24,000-year-old individual (MA-1), from Mal'ta in south-central Siberia, to an average depth of 1×. To our knowledge this is the oldest anatomically modern human genome reported to date. The MA-1 mitochondrial genome belongs to haplogroup U, which has also been found at high frequency among Upper Palaeolithic and Mesolithic European hunter-gatherers, and the Y chromosome of MA-1 is basal to modern-day western Eurasians and near the root of most Native American lineages. Similarly, we find autosomal evidence that MA-1 is basal to modern-day western Eurasians and genetically closely related to modern-day Native Americans, with no close affinity to east Asians. This suggests that populations related to contemporary western Eurasians had a more north-easterly distribution 24,000 years ago than commonly thought. Furthermore, we estimate that 14 to 38% of Native American ancestry may originate through gene flow from this ancient population. This is likely to have occurred after the divergence of Native American ancestors from east Asian ancestors, but before the diversification of Native American populations in the New World. Gene flow from the MA-1 lineage into Native American ancestors could explain why several crania from the First Americans have been reported as bearing morphological characteristics that do not resemble those of east Asians. Sequencing of another south-central Siberian, Afontova Gora-2 dating to approximately 17,000 years ago, revealed similar autosomal genetic signatures as MA-1, suggesting that the region was continuously occupied by humans throughout the Last Glacial Maximum. Our findings reveal that western Eurasian genetic signatures in modern-day Native Americans derive not only from post-Columbian admixture, as commonly thought, but also from a mixed ancestry of the First Americans.


Effect of strikes by health workers on mortality between 2010 and 2016 in Kilifi, Kenya: a population-based cohort analysis.
Health workers' strikes are a global occurrence. Kenya has had several strikes by health workers in recent years but their effect on mortality is unknown. We assessed the effect on mortality of six strikes by health workers that occurred from 2010 to 2016 in Kilifi, Kenya. Using daily mortality data obtained from the Kilifi Health and Demographic Surveillance System, we fitted a negative binomial regression model to estimate the change in mortality during strike periods and in the 2 weeks immediately after strikes. We did subgroup analyses by age, cause of death, and strike week. Between Jan 1, 2010, and Nov 30, 2016, we recorded 1 829 929 person-years of observation, 6396 deaths, and 128 strike days (median duration of strikes, 18·5 days [range 9-42]). In the primary analysis, no change in all-cause mortality was noted during strike periods (adjusted rate ratio [RR] 0·93, 95% CI 0·81-1·08; p=0·34). Weak evidence was recorded of variation in mortality rates by age group, with an apparent decrease among infants aged 1-11 months (adjusted RR 0·58, 95% CI 0·33-1·03; p=0·064) and an increase among children aged 12-59 months (1·75, 1·11-2·76; p=0·016). No change was noted in mortality rates in post-strike periods and for any category of cause of death. The brief strikes by health workers during the period 2010-16 were not associated with obvious changes in overall mortality in Kilifi. The combined effects of private (and some public) health care during strike periods, a high proportion of out-of-hospital deaths, and a low number of events might have led us to underestimate the effect. Wellcome Trust and MRC Tropical Epidemiology Group.


Protective effect of porphyra-334 on UVA-induced photoaging in human skin fibroblasts.
The significant increase in life expectancy is closely related to the growing interest in the impact of aging on the function and appearance of the skin. Skin aging is influenced by several factors, and solar ultraviolet (UV) irradiation is considered one of the most important causes of skin photoaging. The aim of this study was to examine the anti-photoaging role of porphyra-334 from Porphyra (P.) yezoensis, a mycosporine-like amino acid (MAA), using high-performance liquid chromatography (HPLC), and electrospray ionization‑mass spectrometry (ESI-MS). In the present study, extracted UV‑absorbing compounds from P. yezoensis included palythine, asterina-330 and porphyra-334. Porphyra-334 was the most abundant MAA in P. yezoensis, and it was therefore used for conducting antiphotoaging experiments. The effect of porphyra-334 on the prevention of photoaging was investigated by measuring reactive oxygen species (ROS) production and matrix metalloproteinase (MMP) levels, as well as extracellular matrix (ECM) components and protein expression in UVA‑irradiated human skin fibroblasts. Porphyra-334 suppressed ROS production and the expression of MMPs following UVA irradiation, while increasing levels of ECM components, such as procollagen, type I collagen, elastin. These results suggest that porphyra-334 has various applications in cosmetics and toiletries because of its anti‑photoaging activities and may serve as a novel anti-aging agent.


[Subjective certainty to increase the acceptance of automated and connected driving].
An important factor for the acceptance and thus the spread of automated and connected driving (ACD) is the degree of subjective uncertainty that users experience when interacting with automated vehicles. Subjective uncertainties always occur when people are not able to predict the further course of a situation or future events due to lack of experience or information. If such uncertainties occur during the use of automated vehicles, the development of trust and thus acceptance of this technology is impaired by the negative emotions accompanying subjective uncertainties. Within the AutoAkzept project (which full title translates to: Automation without uncertainty to increase the acceptance of automated and connected driving), solutions for user-focused automation have been developed that put vehicle occupants at the center of system development. User-focused systems take into account two basic human needs in human-machine interaction, the need to understand and the need to be understood. For this purpose, user-focused systems use different sensors to detect subjective uncertainties and their influencing factors in real time, integrate this information with context data and make adjustments that reduce subjective uncertainties. The systemic adaptations of user-focused systems follow a holistic approach that includes the levels of vehicle guidance, interior adaptation and information presentation as well as target guidance are included. By reducing or avoiding subjective uncertainties, the project developments contribute to a positive, comfortable user experience and help to increase the acceptance of ACD. This paper presents research results of AutoAkzept on the topics of user state and activity modelling as well as needs-based adaptation strategies, which represent key components for the implementation of user-focused automation.


Primary Hip Arthroscopy for Femoroacetabular Impingement Syndrome in Adolescents Improves Outcomes and Clinical Benefit Achievement Rates at Short-Term Follow-Up: A Multicenter Analysis.
To report minimum 2-year follow-up patient-reported outcome scores (PROs) and rates of achieving the minimal clinically important difference (MCID), the patient-acceptable symptomatic state (PASS), and the maximal outcome improvement (MOI) on adolescents following primary hip arthroscopy for femoroacetabular impingement syndrome (FAIS). Second, to determine risk factors for revision surgery. Prospectively collected data from two high-volume hip arthroscopy centers were retrospectively reviewed on adolescents (≤19 years old) who underwent primary hip arthroscopy between November 2008 and February 2019. Adolescents with a minimum 2-year follow-up for the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sports Specific Subscale (HOS-SSS), International Hip Outcome Tool-12 (iHOT-12), and visual analog scale (VAS) for pain were included regardless of their growth plate status. Exclusion criteria were Tönnis grade >1, lateral center edge-angle <18°, and previous ipsilateral hip surgery or conditions. Preoperative and postoperative radiographic data, MCID, PASS, MOI, secondary surgeries, and complications were reported. A multivariable survival analysis for risk factors for secondary surgery was conducted. A total of 287 hips (249 patients) were included (74.9% females). The mean values for age, body mass index, and follow-up were 16.3 ± 1.3 years, 22.3 ± 3.5, and 26.6 ± 9.4 months, respectively. Further, 88.9% underwent labral repair, 81.5% femoroplasty, and 85.4% capsular closure. Improvement for all PROs was reported (P < .001) with high patient satisfaction (8.8 ± 1.5). Achievement for the MCID was 71.7%, 83.0%, 68.1%, and 79.5% for the mHHS, NAHS, HOS-SSS, and iHOT-12, respectively. Achievement for the PASS was 68.3% for the mHHS and 73.2% for the NAHS. The MOI for mHHS, NAHS, and VAS was 58.3%, 77.0%, and 59.6%, respectively. Rates of revision hip arthroscopy, cam recurrence, and heterotopic ossification were 5.8%, 1.7%, and 5.5%, respectively. Acetabular retroversion was found to be a risk factor for revision surgery (P = .03). The results of this multi-center study demonstrated that adolescents who underwent primary hip arthroscopy for FAIS reported significant improvement in all PROs, with satisfactory achievement rates for the MCID, PASS, MOI, and high patient satisfaction at a minimum 2-year follow-up. IV, retrospective multicenter study.


Prediction of mortality and major cardiovascular complications in type 2 diabetes: External validation of UK Prospective Diabetes Study outcomes model version 2 in two European observational cohorts.
To externally validate the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2) by comparing the predicted and observed outcomes in two European population-based cohorts of people with type 2 diabetes. We used data from the Casale Monferrato Survey (CMS; n = 1931) and a subgroup of the Hoorn Diabetes Care System (DCS) cohort (n = 5188). The following outcomes were analysed: all-cause mortality, myocardial infarction (MI), ischaemic heart disease (IHD), stroke, and congestive heart failure (CHF). Model performance was assessed by comparing predictions with observed cumulative incidences in each cohort during follow-up. All-cause mortality was overestimated by the UKPDS-OM2 in both the cohorts, with a bias of 0.05 in the CMS and 0.12 in the DCS at 10 years of follow-up. For MI, predictions were consistently higher than observed incidence over the entire follow-up in both cohorts (10 years bias 0.07 for CMS and 0.10 for DCS). The model performed well for stroke and IHD outcomes in both cohorts. CHF incidence was predicted well for the DCS (5 years bias -0.001), but underestimated for the CMS cohort. The UKPDS-OM2 consistently overpredicted the risk of mortality and MI in both cohorts during follow-up. Period effects may partially explain the differences. Results indicate that transferability is not satisfactory for all outcomes, and new or adjusted risk equations may be needed before applying the model to the Italian or Dutch settings.


Diosmetin inhibits osteoclast formation and differentiation and prevents LPS-induced osteolysis in mice.
Osteolytic bone diseases are closely linked to the over-activation of osteoclasts and enhancement of bone resorption. It has become a major health issue in orthopedic practice worldwide. Inhibition of osteoclasts is proposed to be the main treatment for osteolytic disorders. Diosmetin (DIO) is a natural flavonoid with properties of antioxidant, anti-infection, and antishock. The effect of DIO on osteoclast differentiation is poorly understood. In this study project, we found that DIO could inhibit osteoclastic formation induced by receptor activator of nuclear factor kappa-B ligand (RANKL) in a dose-dependent manner. The expression of the osteoclast differentiation marker genes, cathepsin K, nuclear factor of activated T-cells 1 (NFATc1), Acp5, Ctr, Atp6v0d2, and Mmp9 were also decreased by the treatment of DIO. In addition, DIO attenuated the formation of actin ring and the ability of bone resorption. Further, the western blotting showed that DIO inhibits the phosphorylation of the mitogen-activated protein kinases signaling pathway induced by RANKL, accompanied by the downregulation of NFATc1 and c-Fos expression. We also found that DIO could reduce the accumulation of reactive oxygen species (ROS) induced by RANKL. In vivo, the study revealed that DIO can significantly reduce LPS-induced osteolysis in mice. Collectively, our study shows that DIO can inhibit osteoclast formation and activation, and could serve as a potential therapeutic drug for osteolytic bone diseases.


Functional impairment, stress, and psychosocial intervention in bipolar disorder.
The longitudinal course of bipolar disorder (BD) is highly impairing. This article reviews recent research on functional impairment in the course of BD, the roles of social and intrafamilial stress in relapse and recovery, and the role of adjunctive psychosocial interventions in reducing risk and enhancing functioning. Comparative findings in adult and childhood BD are highlighted. Life events and family-expressed emotion have emerged as significant predictors of the course of BD. Studies of social information processing suggest that impairments in the recognition of facial emotions may characterize both adult- and early-onset bipolar patients. Newly developed psychosocial interventions, particularly those that focus on family and social relationships, are associated with more rapid recovery from episodes and better psychosocial functioning. Family-based psychoeducational approaches are promising as early interventions for children with BD or children at risk of developing the disorder. For adults, interpersonal therapy, mindfulness-based strategies, and cognitive remediation may offer promise in enhancing functioning.


Relationship of blood pressure measures with coronary artery calcification.
Increased blood pressure level is a major risk factor for coronary artery disease. Previous studies of relationships of blood pressure level and hypertension status with coronary artery calcification (CAC), a measure of subclinical atherosclerosis, were restricted to participants who were physician- or self-referred, high risk, selected on hypertension status, or young adults. 803 asymptomatic individuals at least age 40 years were studied from a community. Blood pressure level was measured and blood pressure diagnostic category (i.e. hypertension vs. normotension) was determined by considering reported history of physician-diagnosed hypertension, use of antihypertensive medication, and measured blood pressure levels. CAC was measured non-invasively with electron beam computed tomography. Tobit regression models allowed simultaneous modeling of presence and quantity of CAC. In men, age, having ever smoked, having hypertension, LDL-C level, and body mass index were significantly and positively associated with presence and quantity of CAC. In women, age, systolic blood pressure level, use of lipid lowering medications, and waist-to-hip ratio were significantly and positively associated with presence and quantity of CAC. Relationships of measures of blood pressure with CAC were modified by age, but no other risk factors, in both sexes. Our results indicated that measures of blood pressure make a relatively large contribution to predictions of CAC at younger ages. CAC quantification, especially among younger individuals, may allow for early assessment of the presence and extent of target organ disease.


Phage p1-derived artificial chromosomes facilitate heterologous expression of the FK506 gene cluster.
We describe a procedure for the conjugative transfer of phage P1-derived Artificial Chromosome (PAC) library clones containing large natural product gene clusters (≥70 kilobases) to Streptomyces coelicolor strains that have been engineered for improved heterologous production of natural products. This approach is demonstrated using the gene cluster for FK506 (tacrolimus), a clinically important immunosuppressant of high commercial value. The entire 83.5 kb FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488 present in one 130 kb PAC clone was introduced into four different S. coelicolor derivatives and all produced FK506 and smaller amounts of the related compound FK520. FK506 yields were increased by approximately five-fold (from 1.2 mg L(-1) to 5.5 mg L(-1)) in S. coelicolor M1146 containing the FK506 PAC upon over-expression of the FK506 LuxR regulatory gene fkbN. The PAC-based gene cluster conjugation methodology described here provides a tractable means to evaluate and manipulate FK506 biosynthesis and is readily applicable to other large gene clusters encoding natural products of interest to medicine, agriculture and biotechnology.


Gender-based market constraints to informal fish retailing: Evidence from analysis of variance and linear regression.
Over the last decade, Egypt's aquaculture sector has expanded rapidly, which has contributed substantially to per capita fish supply, and the growth of domestic fish markets and employment across the aquaculture value chain. Despite the growing importance of aquaculture sector in Egyptian labour force, only a few studies have explored the livelihoods of Egypt's women and men fish retailers. Even fewer studies have examined gender-based market constraints experienced by these informal fish retailers. This study uses sex-disaggregated data collected in 2013 in three governorates of Lower Egypt to examine the economic and social constraints to scale of enterprises between women (n = 162) and men informal fish retailers (n = 183). Specifically, we employ linear regression method to determine the correlates of enterprise performance. We found that both women and men retailers in the informal fish market earn low profits and face livelihood insecurities. However, women's enterprise performance is significantly lower than that of men even after controlling for individual socio-economic and retailing characteristics. Specifically, the burden of unpaid household work and lack of support therein impedes women's ability to generate higher revenues. These findings strengthen the argument for investing in understanding how gender norms and attitudes affect livelihood options and outcomes. This leads to recommendations on gender-responsive interventions that engage with both men and women and enhance the bargaining power and collective voice of fish retailers.


Oxidative Stress Resistance in Metastatic Prostate Cancer: Renewal by Self-Eating.
Resistant cancer phenotype is a key obstacle in the successful therapy of prostate cancer. The primary aim of our study was to explore resistance mechanisms in the advanced type of prostate cancer cells (PC-3) and to clarify the role of autophagy in these processes. We performed time-lapse experiment (48 hours) with ROS generating plumbagin by using multimodal holographic microscope. Furthermore, we also performed the flow-cytometric analysis and the qRT-PCR gene expression analysis at 12 selected time points. TEM and confocal microscopy were used to verify the results. We found out that autophagy (namely mitophagy) is an important resistance mechanism. The major ROS producing mitochondria were coated by an autophagic membrane derived from endoplasmic reticulum and degraded. According to our results, increasing ROS resistance may be also accompanied by increased average cell size and polyploidization, which seems to be key resistance mechanism when connected with an escape from senescence. Many different types of cell-cell interactions were recorded including entosis, vesicular transfer, eating of dead or dying cells, and engulfment and cannibalism of living cells. Entosis was disclosed as a possible mechanism of polyploidization and enabled the long-term survival of cancer cells. Significantly reduced cell motility was found after the plumbagin treatment. We also found an extensive induction of pluripotency genes expression (NANOG, SOX2, and POU5F1) at the time-point of 20 hours. We suppose, that overexpression of pluripotency genes in the portion of prostate tumour cell population exposed to ROS leads to higher developmental plasticity and capability to faster respond to changes in the extracellular environment that could ultimately lead to an alteration of cell fate.


Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis.
Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis; however, the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (ECs) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1-deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic ECs. We observed that knockdown of PAI-1 in ECs enhances cell-associated plasmin activity and increases spontaneous apoptosis in vitro. We further demonstrate that plasmin cleaves FasL at Arg144-Lys145, releasing a soluble proapoptotic FasL fragment from the surface of ECs. The data provide a mechanism explaining the proangiogenic activity of PAI-1.


Metallic Transition Metal Dichalcogenides of Group VIB: Preparation, Stabilization, and Energy Applications.
Layered transition metal dichalcogenides (TMDs) of group VIB have been widely used in the realms of energy storage and conversions. Along with the existence of semiconducting states, their metallic phases have recently attracted numerous attentions owing to their fascinating physical and chemical properties. Many efforts have been devoted to obtain metallic TMDs with high purity and yield. Nevertheless, such metallic phase is thermodynamically metastable and tends to convert into semiconducting phase, which necessitates the exploration over effective strategies to ensure the stability. In this review, typical fabrication routes are introduced and those critical factors during preparation are elaborately discussed. Moreover, the stabilized strategies are summarized with concrete examples highlighting the key mechanisms toward efficient stabilization. Finally, emerging energy applications are overviewed. This review presents comprehensive research status of metallic group VIB TMDs, aiming to facilitate further scientific investigations and promote future practical applications in the fields of energy storage and conversion.


Human urinary bladder regeneration through tissue engineering - an analysis of 131 clinical cases.
Replacement of urinary bladder tissue with functional equivalents remains one of the most challenging problems of reconstructive urology over the last several decades. The gold standard treatment for urinary diversion after radical cystectomy is the ileal conduit or neobladder; however, this technique is associated with numerous complications including electrolyte imbalances, mucus production, and the potential for malignant transformation. Tissue engineering techniques provide the impetus to construct functional bladder substitutes de novo. Within this review, we have thoroughly perused the literature utilizing PubMed in order to identify clinical studies involving bladder reconstruction utilizing tissue engineering methodologies. The idea of urinary bladder regeneration through tissue engineering dates back to the 1950s. Many natural and synthetic biomaterials such as plastic mold, gelatin sponge, Japanese paper, preserved dog bladder, lyophilized human dura, bovine pericardium, small intestinal submucosa, bladder acellular matrix, or composite of collagen and polyglycolic acid were used for urinary bladder regeneration with a wide range of outcomes. Recent progress in the tissue engineering field suggest that in vitro engineered bladder wall substitutes may have expanded clinical applicability in near future but preclinical investigations on large animal models with defective bladders are necessary to optimize the methods of bladder reconstruction by tissue engineering in humans.


Office-based treatment of glottal dysplasia and papillomatosis with the 585-nm pulsed dye laser and local anesthesia.
Treatment of glottal papillomatosis and dysplasia was mirror-guided and performed in surgeons' offices in the 19th century. It migrated to the operating room in the 20th century to accommodate direct laryngoscopic surgery, which required assistants to administer anesthesia and procedural support. Presently, the primary treatment goals, which are disease regression and voice restoration or maintenance, are tempered by the morbidity of general anesthesia and potential treatment-induced vocal deterioration. In fact, general anesthesia has been appropriately considered to be an acceptable source of morbidity for the promise of a precise procedure, which usually ensures airway safety and an optimal vocal outcome. However, patients with recurrent glottal papillomatosis and keratosis with dysplasia are typically monitored with various degrees of watchful waiting until there is a subjective judgment (on the part of the patient and surgeon) that the disease is more of a liability than is the procedure to treat it. Innovations in the 585-nm pulsed dye laser delivery system have allowed for its use in the clinic with local anesthesia through the working channel of a flexible fiberoptic laryngoscope. A prospective assessment was done on 51 patients in 82 cases of recurrent glottal papillomatosis (30) and dysplasia (52). All individuals had previously undergone microlaryngoscopic management with histopathologic evaluation. Five procedures could not be completed because of impaired exposure (2) or discomfort (3). Of those patients who could be treated, there was at least a 50% disease involution in 68 of 77 cases (88%) and 25% to 50% disease regression in the remaining 9 (12%). Patient self-assessment of the voice revealed that 34 of 77 were improved, 39 were unchanged, 4 were slightly worse, and none were substantially worse. These data confirm that diseased mucosa can be normalized without resection or substantial loss of vocal function. The putative mechanisms, which vary according to the fluence (energy) delivered by the laser, are photoangiolysis of sublesional microcirculation. denaturing of epithelial basement membrane linking proteins, and cellular destruction. Furthermore, this relatively safe, effective technique allowed for treatment of many patients (in a clinic setting) in whom classic surgery-related morbidity would have often delayed intervention.


A group approach to mental health fieldwork.
Fieldwork opportunities in mental health settings are limited and difficult to find. There is increased pressure for occupational therapy supervisors to accept more students although they have less time to devote to them. This article describes a group approach to training occupational therapy students that was used at one fieldwork site. The occupational therapy staff members were each responsible for specific teaching assignments that allowed them to work with a number of students simultaneously. Program development and evaluation meetings created an alternative forum for exploring ideas and practice issues and for providing guidance and supervision. This approach reduced the amount of time each therapist spent with students, provided students with several role models, and encouraged independent thinking in students.


Effect of phoenix dactyliferia (date palm) pit powder on nicotine induced spermatotoxicty in adult albino mice.
To study the effect of Phoenix Dactyliferia pit powder on nicotine-induced spermatotoxicty in adult albino mice. The study was conducted at the University of Health Sciences, Lahore, from February to November 2012, and comprised adult male albino mice aged 6-8 weeks. The animals were divided into five equal groups. Group A consisted of controls who were treated with 1.5ml/kg of normal saline for 15 days, while nicotine 0.5mg/kg was administered intraperitoneally daily to experimental groups B, C and D for the first 15 days. Group B was sacrificed on the 15th day to confirm toxicity, whereas nicotine treatment was stopped in groups C and D. Group C was given normal saline (1.5ml/kg) whereas group D was given date palm pit powder 500mg/kg for the next 30 days. However, Group E was given nicotine 0.5mg/kg for 45 days and date palm pit powder was added orally from the 16th day and it continued daily till the end of the experiment. SPSS 18 was used for statistical analysis. The mean weight of each of the 40 animals in the study was 30±5gm, and all the five groups hacL8(20%) mice each. Group B exhibited features of toxicity evident by statistically significant decrease in Johnsen score (p<0.001) and diameter of seminiferous tubule (p<0.001). Group C showed partial reversal of toxic effects but these positive effects were less compared to group D which showed complete reversal of toxicity evident by statistically significant increase in Johnsen score (p<0.001) and diameter of seminiferous tubule (p<0.001). However, reversal of toxic effect was not evident in group E. Partial recovery from nicotine-induced spermatotoxicity occurred after withdrawal of nicotine treatment whereas near normal restoration of structure was seen with administration of date palm pit powder after the stoppage of nicotine.


Vomiting in pregnancy is associated with a higher risk of low birth weight: a cohort study.
Low birth weight has important short- and long-term health implications. Previously it has been shown that pregnancies affected by hyperemesis gravidarum in the mother are at higher risk of having low birth weight offspring. In this study we tested whether such risks are also evident with less severe nausea and vomiting in pregnancy. One thousand two hundred thirty-eight women in the prospective Cambridge Baby Growth Study filled in pregnancy questionnaires which included questions relating to adverse effects of pregnancy and drugs taken during that time. Ordinal logistic regression models, adjusted for parity, ethnicity, marital and smoking status were used to relate the risk of giving birth to low birth weight (< 2.5 kg) babies to nausea and/or vomiting in pregnancy that were not treated with anti-emetics and did not report suffering from hyperemesis gravidarum. Only three women in the cohort reported having had hyperemesis gravidarum although a further 17 women reported taking anti-emetics during pregnancy. Of those 1218 women who did not take anti-emetics 286 (23.5%) did not experience nausea or vomiting, 467 (38.3%) experienced nausea but not vomiting and 465 experienced vomiting (38.2%). Vomiting during pregnancy was associated with higher risk of having a low birth weight baby (odds ratio 3.5 (1.2, 10.8), p = 0.03). The risk associated with vomiting was found in the first (p = 0.01) and second (p = 0.01) trimesters but not the third (p = 1.0). The higher risk was not evident in those women who only experienced nausea (odds ratio 1.0 (0.3, 4.0), p = 1.0). Vomiting in early pregnancy, even when not perceived to be sufficiently severe to merit treatment, is associated with a higher risk of delivering a low birth weight baby. Early pregnancy vomiting might therefore be usable as a marker of higher risk of low birth weight in pregnancy. This may be of benefit in situations where routine ultrasound is not available to distinguish prematurity from fetal growth restriction, so low birth weight is used as an alternative.


An acid-activated nucleobase transporter from Leishmania major.
Parasitic protozoa are unable to synthesize purines de novo and must import preformed purine nucleobases or nucleosides from their hosts. Leishmania major expresses two purine nucleobase transporters, LmaNT3 and LmaNT4. Previous studies revealed that at neutral pH, LmaNT3 is a broad specificity, high affinity nucleobase transporter, whereas LmaNT4 mediates the uptake of only adenine. Because LmaNT4 is required for optimal viability of the amastigote stage of the parasite that lives within acidified phagolysomal vesicles of mammalian macrophages, the function of this permease was examined under acidic pH conditions. At acidic pH, LmaNT4 acquires the ability to transport adenine, hypoxanthine, guanine, and xanthine with Km values in the micromolar range, indicating that this transporter is activated at low pH. Thus, LmaNT4 is an acid-activated purine nucleobase transporter that functions optimally under the physiological conditions the parasite is exposed to in the macrophage phagolysosome. In contrast, LmaNT3 functions optimally at neutral pH. Two-electrode voltage clamp experiments performed on LmaNT3 and LmaNT4 expressed in Xenopus oocytes revealed substrate-induced inward directed currents at acidic pH, and application of substrates induced acidification of the oocyte cytosol. These observations imply that LmaNT3 and LmaNT4 are nucleobase/proton symporters.


Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle.
While statins significantly reduce cholesterol levels and thereby reduce the risk of cardiovascular disease, the development of myopathy with statin use is a significant clinical side effect. Recent guidelines recommend increasing inclusion criteria for statin treatment in diabetic individuals; however, the impact of statins on skeletal muscle health in those with diabetes (who already suffer from impairments in muscle health) is ill defined. Here, we investigate the effects of fluvastatin treatment on muscle health in wild type (WT) and streptozotocin (STZ)-induced diabetic mice. WT and STZ-diabetic mice received diet enriched with 600 mg/kg fluvastatin or control chow for 24 days. Muscle morphology, intra and extracellular lipid levels, and lipid transporter content were investigated. Our findings indicate that short-term fluvastatin administration induced a myopathy that was not exacerbated by the presence of STZ-induced diabetes. Fluvastatin significantly increased ectopic lipid deposition within the muscle of STZ-diabetic animals, findings that were not seen with diabetes or statin treatment alone. Consistent with this observation, only fluvastatin-treated diabetic mice downregulated protein expression of lipid transporters FAT/CD36 and FABPpm in their skeletal muscle. No differences in FAT/CD36 or FABPpm mRNA content were observed. Altered lipid compartmentalization resultant of a downregulation in lipid transporter content in STZ-induced diabetic skeletal muscle was apparent in the current investigation. Given the association between ectopic lipid deposition in skeletal muscle and the development of insulin-resistance, our findings highlight the necessity for more thorough investigations into the impact of statins in humans with diabetes.


Induction of chalcone synthase expression by rhizobia and nod factors in root hairs and roots.
Chalcone synthase (CHS) of Vigna unguiculata is encoded by a gene family that is abundantly transcribed in leaves and nodules. Inoculation with Rhizobium sp. NGR234, which nodulates V. unguiculata, or with NGR delta nodABC, a mutant deficient in Nod factor production, induced rapid accumulation of CHS mRNAs in roots and root hairs. As both Nod+ and Nod- bacteria provoke responses, induction of CHS gene expression may involve symbiotic or defense responses. Four days after inoculation with the wild-type Rhizobium sp., the transcript levels increased in roots but decreased in root hairs. Use of a region unique to the 5' end of a specific CHS gene (VuCHS1) showed that increases of transcript levels in root hairs 24 h after inoculation with both rhizobia were specific to this gene. Transcripts of this gene in roots were only detectable 4 days after treatment with NGR234. It is possible therefore that accumulation of VuCHS1 follows the infection pathway of rhizobia entering legume roots. Purified Nod factors induced accumulation of transcripts, showing that they might be part of the signal transduction pathway leading to CHS expression.


Malaria knowledge and agricultural practices that promote mosquito breeding in two rural farming communities in Oyo State, Nigeria.
Agricultural practices such as the use of irrigation during rice cultivation, the use of ponds for fish farming and the storage of water in tanks for livestock provide suitable breeding grounds for anthropophylic mosquitoes. The most common anthropophylic mosquito in Nigeria which causes much of the morbidity and mortality associated with malaria is the anopheles mosquito. Farmers are therefore at high risk of malaria - a disease which seriously impacts on agricultural productivity. Unfortunately information relating to agricultural practices and farmers' behavioural antecedent factors that could assist malaria programmers plan and implement interventions to reduce risk of infections among farmers is scanty. Farmers' knowledge about malaria and agricultural practices which favour the breeding of mosquitoes in Fashola and Soku, two rural farming communities in Oyo State were therefore assessed in two rural farming communities in Oyo State. This descriptive cross-sectional study involved the collection of data through the use of eight Focus Group Discussions (FGDs) and the interview of 403 randomly selected farmers using semi-structured questionnaires. These sets of information were supplemented with observations of agricultural practices made in 40 randomly selected farms. The FGD data were recorded on audio-tapes, transcribed and subjected to content analysis while the quantitative data were analyzed using descriptive and inferential statistics. Most respondents in the two communities had low level of knowledge of malaria causation as only 12.4% stated that mosquito bite could transmit the disease. Less than half (46.7%) correctly mentioned the signs and symptoms of malaria as high body temperature, body pains, headache, body weakness and cold/fever. The reported main methods for preventing mosquito bites in the farming communities included removal of heaps of cassava tuber peelings (62.3%), bush burning/clearing (54.6%) and clearing of ditches (33.7%). The dumping of cassava tuber peelings which allows the collection of pools of water in the farms storage of peeled cassava tubers soaked in water in uncovered plastic containers, digging of trenches, irrigation of farms and the presence of fish ponds were the observed major agricultural practices that favoured mosquito breeding on the farms. A significant association was observed between respondents' knowledge about malaria and agricultural practices which promote mosquito breeding. Respondents' wealth quintile level was also seen to be associated with respondents' knowledge about malaria and agricultural practices which promote mosquito breeding. Farmers' knowledge of malaria causation and signs and symptoms was low, while agricultural practices which favour mosquito breeding in the farming communities were common. There is an urgent need to engage farmers in meaningful dialogue on malaria reduction initiatives including the modification of agricultural practices which favour mosquito breeding. Multiple intervention strategies are needed to tackle the factors related to malaria prevalence and mosquito abundance in the communities.


Characterization of the complete genomes of Camelus dromedarius papillomavirus types 1 and 2.
Camel papillomatosis has been described previously, but the genome of the suspected papillomavirus (PV) has not been identified. An outbreak of papillomatosis occurred in a dromedary farm of 55 animals in Sudan during August 2009. The disease was only present in young animals aged about 3-7 months, of which 44 % (11/25) were affected with lesions, mainly on the lips and lower jaw. This study reports for the first time the complete genomes of Camelus dromedarius papillomavirus types 1 (CdPV1) and 2 (CdPV2), isolated from a cauliflower-like nodule and a round oval raised nodule, respectively. Pairwise comparisons of their L1 nucleotide sequences revealed 69.2 % identity, and phylogenetic analyses suggested that these two PV types are grouped within the genus Deltapapillomavirus. Both viruses were isolated from fibropapillomas, although no putative E5 proteins homologous to that of bovine papillomavirus type 1 were identified. The genetic information will be useful for evolutionary studies of the family Papillomaviridae, as well as for the development of diagnostic methods for surveillance of the disease in dromedaries.


Neurofilaments in blood is a new promising preclinical biomarker for the screening of natural scrapie in sheep.
Scrapie is a fatal neurodegenerative disease of sheep and goats belonging to the group of Transmissible Spongiform Encephalopathy or prion diseases. The EU has adopted mandatory measures for scrapie surveillance to safeguard public and animal health because it is highly contagious and might decimate all genetic susceptible animals in affected flocks. Definite diagnosis of scrapie relies on the detection of the pathological prion protein in brain tissues and there are still no blood biomarkers available for making diagnosis in living animals that can be used for the screening of sheep in scrapie-affected flocks. Neurofilament light (NfL) protein, a valid biomarker for neuronal and axonal damages, can now be easily measured in blood by the ultra-sensitive single molecule array (Simoa) technology. Recent work reported that serum NfL is increased in neurodegenerative diseases, including human prion diseases, but no data are available for scrapie or other animal prion diseases. Here, we found that the median serum NfL concentration in scrapie animals (56.2, IQR 42.2-84.8, n = 9) was more than 15 times higher (p = 0.00084) than that found in control samples (3.4, IQR 3.0-26.3, n = 11). Moreover, serum NfL concentration in scrapie sheep with clinical signs (n = 2; 75.3, 15.7 pg/ml) did not significantly (p = 0.541; t-test) differ from scrapie animals without clinical signs (n = 7; 61.0, 10.7 pg/ml). The receiver operating characteristic (ROC) curve analysis estimated the cut-off value of 31 pg/ml serum NfL for distinguishing scrapie-infected sheep from controls. The application of this cut-off value gives an accuracy of the test of 95% (percent error of 5.23%). These data indicate that the Simoa test for serum NfL might be a useful screening method for detecting preclinical scrapie in living sheep. Finally, the preliminary data reported here need confirmation in large and more structured studies.


[Use of transgenic animals in the European Union]
Transgenic animals present unique possibilities for medical, agricultural and fundamental research, and as a means of producing valuable pharmaceutical and nutrient products. Their use has increased dramatically in recent years and is set to increase further in the near future. It has been claimed that transgenic animals might allow reduction and refinement in animal use, via more-precise gene targeting in breeding programmes. However, these objectives are threatened by transgenic procedures which may promote greater animal use, more-varied applications, and the greater likelihood of animal suffering. Current legislation on animal experimentation, for example, Directive 86/609/EU, was passed and implemented before the full implications of transgenesis were recognised. For this reason, ECVAM organised a workshop which was held in Southwell, Nottinghamshire, UK, on 7-11 April 1997. The aim of this workshop was to reach a consensus on a set of guidelines designed to assist regulatory authorities in their decision-making process. The conclusions of the workshop are subdivided into general considerations, proposals to use transgenic animals, production and use of transgenic animals, specific considerations relating to animals used as basic research/disease models, animals used in testing for toxicity and carcinogenicity, and transgenic farm animals. 14 recommendations have been derived from these conclusions and should make an important contribution to ensuring that the interests and welfare of animals are given due respect. They demonstrate a willingness by scientists to respond to public concerns and they should facilitate a consistent, harmonised and equitable regulatory approach within the EU.


Linking the sender to the receiver: vocal adjustments by bats to maintain signal detection in noise.
Short-term adjustments of signal characteristics allow animals to maintain reliable communication in noise. Noise-dependent vocal plasticity often involves simultaneous changes in multiple parameters. Here, we quantified for the first time the relative contributions of signal amplitude, duration, and redundancy for improving signal detectability in noise. To this end, we used a combination of behavioural experiments on pale spear-nosed bats (Phyllostomus discolor) and signal detection models. In response to increasing noise levels, all bats raised the amplitude of their echolocation calls by 1.8-7.9 dB (the Lombard effect). Bats also increased signal duration by 13%-85%, corresponding to an increase in detectability of 1.0-5.3 dB. Finally, in some noise conditions, bats increased signal redundancy by producing more call groups. Assuming optimal cognitive integration, this could result in a further detectability improvement by up to 4 dB. Our data show that while the main improvement in signal detectability was due to the Lombard effect, increasing signal duration and redundancy can also contribute markedly to improving signal detectability. Overall, our findings demonstrate that the observed adjustments of signal parameters in noise are matched to how these parameters are processed in the receiver's sensory system, thereby facilitating signal transmission in fluctuating environments.


Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites.
A founder mutation in the Thanatos-associated (THAP) domain containing, apoptosis associated protein 1 (THAP1) gene causing primary dystonia was originally described in the Amish-Mennonites. However, there may be both genotypic and phenotypic heterogeneity of dystonia in this population that may also inform studies in other ethnic groups. Genotyping for THAP1 and for guanine nucleotide binding protein (G protein), α-activating activity polypeptide, olfactory type (GNAL) mutations and genotype-phenotype comparisons were performed for 76 individuals of Amish-Mennonites heritage with primary dystonia. Twenty-seven individuals had mutations in THAP1-most with the founder indel mutation-but two had different THAP1 mutations, 8 had mutations in GNAL, and 1 had a de novo GAG deletion in torsin 1A (TOR1A) (dystonia 1 [DYT1]). In the primary analysis comparing THAP1 carriers versus all non-THAP1, non-GNAL, non-TOR1A individuals, age at onset was lower in THAP1 carriers (mean age ± standard deviation, 15.5 ± 9.2 years [range, 5-38 years] vs. 39.2 ± 17.7 years [range, 1-70 years]; P < 0.001), and THAP1 carriers were more likely to have onset of dystonia in an arm (44.4% vs. 15.0%; P = 0.02) and to have arm involvement (88.9% vs. 22.5%; P < 0.01), leg involvement (51.9% vs. 10.0%; P = 0.01), and jaw/tongue involvement (33.3% vs. 7.5%; P = 0.02) involvement at their final examination. Carriers were less likely to have dystonia restricted to a single site (11.11% in carriers vs. 65.9% in noncarriers; P < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of THAP1 carriers vs. 52.5% of noncarriers; P = 0.04). Primary dystonia in the Amish-Mennonites is genetically diverse and includes not only the THAP1 indel founder mutation but also different mutations in THAP1 and GNAL as well as the TOR1A GAG deletion. Phenotype, particularly age at onset combined with final distribution, may be highly specific for the genetic etiology.


Protective effect of respiratory devices in farmers with occupational asthma.
To the authors' knowledge there have been no previous reports on the protection afforded by powered filtering respirators in farmers with occupational asthma attributed to the inhalation of organic dust. In order to investigate this question, 26 farmers with occupational asthma were challenged with an exposure to work-related dusts for up to 60 min. This resulted in highly significant increases in airway resistance (Raw), thoracic gas volume (TGV) and specific airway resistance (sRaw) compared to baseline values. After a mean period of 21 weeks the farmers were subjected to a second challenge, this time wearing a protective respiratory device (RD) with a P2 filter. Significant increases in Raw, TGV and sRaw were again observed, but on average these were 50-80% smaller than the increases seen when RDs were not worn. These differences were found to be statistically significant. This shows that the use of a respiratory device in farmers suffering from occupational asthma reduces the development of bronchial obstruction but does not prevent it. The use of this kind of respiratory device cannot substitute for the proper management of asthma since the devices do not offer complete protection.


Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway.
A MEK1/2 inhibitor, binimetinib is promising as a therapeutic agent for malignant melanoma with N-RAS mutation. We examined in vitro effects of binimetinib on 10 human myeloid/lymphoid leukemia cell lines, and found that three of five cell lines with N-RAS mutation and one of five without N-RAS mutation were responsive to treatment with binimetinib. Binimetinib inhibited cell growth mainly by inducing G1 arrest and this action mechanism was assisted by gene set enrichment analysis. To identify signaling pathways associated with binimetinib response, we examined the status of MAP kinase/ERK and PI3Kinase/Akt pathways. The basal levels of phosphorylated ERK and Akt varied between the cell lines, and the amounts of phosphorylated ERK and Akt appeared to be reciprocal of each other. Interestingly, most of the binimetinib-resistant cell lines revealed strong Akt phosphorylation compared with binimetinib-sensitive ones. The effect of binimetinib may not be predicted by the presence/absence of N-RAS mutation, but rather by Akt phosphorylation status. Moreover, combination of binimetinib with a PI3K/Akt inhibitor showed additive growth-suppressive effects. These results suggest that binimetinib shows potential anti-leukemic effects and the basal level of phosphorylated Akt might serve as a biomarker predictive of therapeutic effect.


Prognostic factors for recovery in chronic nonspecific low back pain: a systematic review.
Few data are available on predictors for a favorable outcome in patients with chronic nonspecific low back pain (CNLBP). The aim of this study was to assess prognostic factors for pain intensity, disability, return to work, quality of life, and global perceived effect in patients with CNLBP at short-term (≤ 6 months) and long-term (>6 months) follow-up. Relevant studies evaluating the prognosis of CNLBP were searched in PubMed, CINAHL, and EMBASE (through March 2010). Study Selection Articles with all types of study designs were included. Inclusion criteria were: participants were patients with CNLBP (≥ 12 weeks' duration), participants were older than 18 years of age, and the study was related to prognostic factors for recovery. Fourteen studies met the inclusion criteria. Two reviewers extracted the data and details of each study. A qualitative analysis using "level of evidence" was performed for all included studies. Data were summarized in tables and critically appraised. The results of the studies reviewed were limited by their methodological weaknesses. At short-term follow-up, no association was found for the factors of age and sex with the outcomes of pain intensity and disability. At long-term follow-up, smoking had the same result. At long-term follow-up, pain intensity and fear of movement had no association with disability. At short-term follow-up, conflicting evidence was found for the association between the outcomes pain intensity and disability and the factor of fear of movement. At long-term follow-up, conflicting evidence was found for the factors of age, sex, and physical job demands. At long-term follow-up, conflicting evidence also was found for the association between return to work and age, sex, and activities of daily living. At baseline, there was limited evidence of a positive influence of lower pain intensity and physical job demands on return to work. No high-quality studies were found for the outcomes of quality of life and global perceived effect.


Three-dimensional carbon network confined antimony nanoparticle anodes for high-capacity K-ion batteries.
Antimony (Sb) represents a promising anode for K-ion batteries (KIBs) due to its high theoretical capacity and suitable working voltage. However, the large volume change that occurs in the potassiation/depotassiation process can lead to severe capacity fading. Herein, we report a high-capacity anode material by in situ confining Sb nanoparticles in a three-dimensional carbon framework (3D SbNPs@C) via a template-assisted freeze-drying treatment and subsequent carbothermic reduction. The as-prepared 3D SbNPs@C hybrid material delivers high reversible capacity and good cycling stability when used as the anode for KIBs. Furthermore, cyclic voltammetry and in situ X-ray diffraction analysis were performed to reveal the intrinsic mechanism of a K-Sb alloying reaction. Therefore, this work is of great importance to understand the electrochemical process of the Sb-based alloying reaction and will pave the way for the exploration of high performance KIB anode materials.


Symptoms of anxiety and depression and risk of acute myocardial infarction: the HUNT 2 study.
The nature of the association of depression and anxiety with risk for acute myocardial infarction (AMI) remains unclear. We aimed to study the prospective association of single and recurrent self-reported symptoms of anxiety and depression with a risk of AMI in a large Norwegian population based cohort. In the second wave of the Nord-Trøndelag Health Study (HUNT2, 1995-97) baseline data on anxiety and depression symptoms, sociodemographic variables, health status including cardiovascular risk factors and common chronic disorders were registered for 57,953 adult men and women free of cardiovascular disease. The cohort was followed up during a mean (SD) 11.4 (2.9) years for a first AMI from baseline through 2008. A total of 2111 incident AMIs occurred, either identified at hospitals or by the National Cause of Death Registry. The multi-adjusted hazard ratios were 1.31 (95% CI 1.03-1.66) for symptoms of depression and 1.25 (CI 0.99-1.57) for anxiety. Two episodes of mixed symptoms of anxiety and depression (MSAD), reported 10 years apart, increased the risk for AMI by 52% (11-108%). After exclusion of the first 5 years of follow-up, the association of depression symptoms with AMI risk was attenuated. Relative risk for AMI with anxiety symptoms and MSAD weakened when participants with chronic disorders were excluded. Self-reported symptoms of depression and anxiety, especially if recurrent, were moderately associated with the risk of incident AMI. We had some indications that these associations might partly reflect reverse causation or confounding from common chronic diseases.


Assessing Inspiratory Muscle Strength for Early Detection of Respiratory Failure in Motor Neuron Disease: Should We Use MIP, SNIP, or Both?
Motor neuron disease (MND) invariably impacts on inspiratory muscle strength leading to respiratory failure. Regular assessment of sniff nasal inspiratory pressure (SNIP) and/or maximal mouth inspiratory pressure (MIP) contributes to early detection of a requirement for ventilatory support. The aim of this study was to compare the feasibility, agreement, and performance of both tests in MND. Patients with MND followed by a multidisciplinary consultation were prospectively included. Pulmonary follow-up included forced expiratory volumes, vital capacity (VC) seated and supine, MIP, SNIP, pulse oximetry, and daytime arterial blood gases. A total of 61 patients were included. SNIP and MIP could not be performed in 14 (21%) subjects; 74% of the subjects showed a decrease in MIP or SNIP at inclusion versus 31% for VC. Correlation between MIP and SNIP (Pearson's rho: 0.68, p < 0.001) was moderate, with a non-significant bias in favor of SNIP (3.6 cm H2O) and wide limits of agreement (-34 to 41 cm H2O). Results were similar in "bulbar" versus "non-bulbar" patients. At different proposed cut-off values for identifying patients at risk of respiratory failure, the agreement between MIP and SNIP (64-79%) and kappa values (0.29-0.53) was moderate. MIP and SNIP were equally feasible. There was no significant bias in favor of either test, but a considerable disparity in results between tests, suggesting that use of both tests is warranted to screen for early detection of patients at risk of respiratory failure and avoid over diagnoses. SNIP, MIP, and VC all follow a relatively linear downhill course with a steeper slope for "bulbar" versus "non-bulbar" patients.


Synthetic antimicrobial oligomers induce a composition-dependent topological transition in membranes.
Antimicrobial peptides (AMPs) are cationic amphiphiles that comprise a key component of innate immunity. Synthetic analogues of AMPs, such as the family of phenylene ethynylene antimicrobial oligomers (AMOs), recently demonstrated broad-spectrum antimicrobial activity, but the underlying molecular mechanism is unknown. Homologues in this family can be inactive, specifically active against bacteria, or nonspecifically active against bacteria and eukaryotic cells. Using synchrotron small-angle X-ray scattering (SAXS), we show that observed antibacterial activity correlates with an AMO-induced topological transition of small unilamellar vesicles into an inverted hexagonal phase, in which hexagonal arrays of 3.4-nm water channels defined by lipid tubes are formed. Polarized and fluorescence microscopy show that AMO-treated giant unilamellar vesicles remain intact, instead of reconstructing into a bulk 3D phase, but are selectively permeable to encapsulated macromolecules that are smaller than 3.4 nm. Moreover, AMOs with different activity profiles require different minimum threshold concentrations of phosphoethanolamine (PE) lipids to reconstruct the membrane. Using ternary membrane vesicles composed of DOPG:DOPE:DOPC with a charge density fixed at typical bacterial values, we find that the inactive AMO cannot generate the inverted hexagonal phase even when DOPE completely replaces DOPC. The specifically active AMO requires a threshold ratio of DOPE:DOPC = 4:1, and the nonspecifically active AMO requires a drastically lower threshold ratio of DOPE:DOPC = 1.5:1. Since most gram-negative bacterial membranes have more PE lipids than do eukaryotic membranes, our results imply that there is a relationship between negative-curvature lipids such as PE and antimicrobial hydrophobicity that contributes to selective antimicrobial activity.


NTP Toxicology and Carcinogenesis Studies of Rotenone (CAS No. 83-79-4) in F344/N Rats and B6C3F1 Mice (Feed Studies).
Toxicology and carcinogenesis studies of rotenone (more than 98% pure), a pesticide, were conducted in B6C3F1 mice and F344/N rats for 14 days, 13 weeks, and 2 years. Results of the Fourteen-Day Studies: In the 14-day studies (dietary rotenone concentrations of 0-600 ppm in the first 14-day studies and 0-4,800 ppm in the second 14-day studies), rough hair coats and dose-related decreases in mean body weight gain were observed in rats. Rats fed diets containing rotenone at concentrations of 1,200 ppm or higher lost weight. No compound-related toxic effects were observed in mice. Results of the Thirteen-Week Studies: In the 13-week studies (concentrations of 0-1,200 ppm rotenone in feed for rats and 0-50,000 ppm for mice), compound-related effects included lower body weight gain in rats at 150 ppm or more; and bone marrow atrophy and inflammation and hyperplasia of the forestomach in male rats at 300 ppm or more and in female rats at 150 ppm or more. These findings were used to establish the dietary concentrations of rotenone for the 2-year studies. Experimental Design for the Two-Year Studies: Two-year studies of rotenone were conducted by administering diets containing 0, 38, or 75 ppm rotenone to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered diets containing 0, 600, or 1,200 ppm rotenone on the same schedule. The estimated average amount of rotenone consumed per day was 1.7 mg/kg or 3.5 mg/kg for low dose or high dose rats and 115 mg/kg or 250 mg/kg for low dose and high dose mice. Survival and Mean Body Weight in the Two-Year Studies: Survival of control and dosed rats was similar (male: control, 22/50; low dose. 31/50; high dose, 30/50; female: control, 27/50; low dose, 32/50; high dose, 31/50). Mean body weights of dosed and control male rats were comparable. Mean body weights of high dose female rats were 5%-9% lower than those of the controls between weeks 58 and 88. Survival of high dose male mice was significantly greater than that of the controls (male: 29/50; 36/50; 47/50; female: 37/50; 42/50; 45/50). Final mean body weights of dosed mice were lower than those of the controls by 8%-13% for males and 17%-24% for females. Neoplastic Effects in the Two-Year Studies: Parathyroid gland adenomas were observed in 1/41 control, 0/44 low dose, and 4/44 high dose male rats. The historicalincidence of this uncommon tumor in untreated control male rats in NTP studies is 4/1,314 (0.3%). Because these tumors are rare and because the highest incidence ever seen in a control group is 1/50, the increase in these tumors may have been related to rotenone administration. The incidence of subcutaneous tissue fibromas, fibrosarcomas, sarcomas, myxosarcomas, or neurofibrosarcomas (combined) in low dose female rats was greater (P<0.05) than that in the controls (0/50; 5/50; 3/50). These tumors were combined because of their possible common histiogenic origin from fibroblasts or undifferentiated mesenchymal cells. The incidence of those tumors in the low dose females was greater than the historical rats at this laboratory (9/337, 3% +/- 1%) and throughout the Program (50/2,021, 2% +/- 2%). Because of the lack of a significant dose-related trend and because statistical significance was attained only by combining tumors of differing morphology, the subcutaneous tissue tumors in female rats were not considered to be chemically related. The incidences of these tumors in dosed male rats were not significantly different from that in the controls. Hepatocellular adenomas or carcinomas (combined) occurred in male mice with a negative (P<0.02) trend, and the incidence in the high dose group was lower than that in the controls (12/47; 12/49; 1/50). Because this low rate of combined liver tumors is unusual, this decrease may have been related to rotenone administration. Subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) in male mice occurred with a significant (P<0.05) negative trend (8/49; 4/50; 2/50). The incidence in the high dose group was signignificant (P<0.05) negative trend (8/49; 4/50; 2/50). The incidence in the high dose group was significantly lower than that in the controls by the life table test (P=0.01). Genotoxicity: Rotenone was not mutagenic when tested according to a preincubational protocol with Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with or without metabolic activation by rat or hamster liver S9. Rotenone induced forward mutations in the mouse L5178Y/TK± lymphoma assay without activation; it was not tested in the presence of S9. Results of tests with rotenone in Chinese hamster ovary cells were negative for induction of sister chromatid exchanges (SCEs) in the absence of exogenous metabolic activation (at concentrations at which the chemical was very toxic), equivocal for SCEs in the presence of rat liver S9 (due to a nonrepeatable positive response when tests were conducted up to toxic concentrations), and negative for chromosomal aberrationsin both the presence and absence of metabolic activation. Data Audit: An audit of the experimental data was conducted for the 2-year studies of rotenone. No data discrepancies were found that influenced the final interpretations. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of rotenone for male F344/N rats, as indicated by an increased incidence of parathyroid gland adenomas (uncommon tumors). There was no evidence of carcinogenic activity in female F344/N rats fed diets containing 38 or 75 ppm rotenone. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 600 or 1,200 ppm rotenone for 2 years. The decreased incidence of liver neoplasms in male mice may have been related to the administration of rotenone. Synonym: 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-1-methylethenyl)-[1]benzopyrano[3,4-b]furo2,3-h][1]benzopyran-6(6H)-one Trade Names of Formulations: Derrin; Derris; Tubatoxin; Nicouline; Prentox; Noxfish; Rotocide; Barbasco; Cube Root; Haiari; Dactinol


The Chinese Children and Families Cohort Study: The Nutrition, Physical Activity, and Ultraviolet Radiation Data Collection.
This article reports the study design, methodological issues and early results of a pilot study testing methods for collecting nutrition, physical activity, and ultraviolet (UV) radiation exposure data in a groundbreaking study in China. Epidemiological studies suggest that exposures across the entire life course, including in utero, early childhood, and adolescence, may be important in the etiology of adult cancers and other chronic diseases. The Chinese Children and Families Cohort Study intends to follow-up subjects from the 1993 to 1995 Community Intervention Program of folic acid supplementation for the prevention of neural tube defects. This cohort is unique in that only folic acid exposure during pregnancy varies between groups as other supplements were not available, and there were nutrient deficiencies in the populations. Prior to launching a large-scale follow-up effort, a pilot study was conducted to assess the feasibility of recontacting original study participants to collect extensive diet, physical activity, and UV radiation exposure data in this population. The pilot study included 92 mothers and 184 adolescent children aged 14 to 17 years from 1 urban and 1 rural Community Intervention Program site. Subjects completed a Food Frequency Questionnaire, a 3-day food record, a physical activity questionnaire, a 3-day sun exposure diary together with 3 days of personal UV dosimetry, and 7 days of pedometry measurements and provided blood, saliva, and toenail samples. Grip strength and body composition measurements were taken, and ambient solar UV radiation was monitored in both study sites. While most of the assessments were successful, future studies would likely require different dietary intake instruments. The purpose of this report is to describe the study design and methodological issues emerging from this pilot work relevant for the follow-up of this large birth cohort.


Mitochondrial, Y-chromosomal and autosomal variation in Mbenzele Pygmies from the Central African Republic.
In this paper, we carry out a combined analysis of autosomal (ten microsatellites and an Alu insertion), mitochondrial (HVR-1 sequence, 360 nucleotides) and Y-chromosomal (seven microsatellites) variation in the Mbenzele Pygmies from the Central African Republic. This study focuses on two important questions concerning the admixture and origin of African Pygmies. Ethnographic observations suggest a sex-biased gene flow between the Bantus and Pygmies, an issue which could be clarified through genetic analyses may shed light. A study of intrapopulational variation of mtDNA and Y-chromosome produces results in accordance with the hypothesized matrimonial behaviour. In fact, while shared mitochondrial haplotypes belonging to the L1c5 (or L1c1a1 clade) sub-haplogroup provides evidence of a Pygmy-to-Bantu female biased gene flow, a male biased gene flow from Bantu to Pygmies is supported by the distribution of the Y-chromosomes bearing M2 mutation. The second part of our study regards the question of the genetic relationships between Western and Eastern Pygmies. Our results favour the pre-Bantu hypothesis which suggests that the two Pygmy groups separated in ancient times (at least 18,000 years ago), whereas they do not support the recent divergence and differential admixture hypothesis which posits their separation as a consequence of the Bantu expansion (2,000-3,000 years ago).