Converging influences from visual, auditory, and somatosensory cortices onto output neurons of the superior colliculus.
1. Physiological methods were used to examine the pattern of inputs from different sensory cortices onto individual superior colliculus neurons. 2. Visual, auditory, and somatosensory influences from anterior ectosylvian sulcus (AES) and visual influences from lateral suprasylvian (LS) cortex were found to converge onto individual multisensory neurons in the cat superior colliculus. An excellent topographic relationship was found between the different sensory cortices and their target neurons in the superior colliculus. 3. Corticotectal inputs were derived solely from unimodal neurons. Multisensory neurons in AES and LS were not antidromically activated from the superior colliculus. 4. Orthodromic and antidromic latencies were consistent with monosynaptic corticotectal inputs arising from LS and the three subdivisions of AES (SIV, Field AES, and AEV). 5. Superior colliculus neurons that received convergent cortical inputs formed a principal component of the tecto-reticulospinal tract. Thus there appears to be extensive cortical control over the output neurons through which the superior colliculus mediates attentive and orientation behaviors. 6. Two other multisensory circuits were identified. A population of multisensory superior colliculus neurons was found, which neither received convergent cortical input nor projected into the tecto-reticulo-spinal tract. In addition, multisensory neurons in AES and LS proved to be independent of the superior colliculus (i.e., they were not corticotectal). While it is likely that these three distinct multisensory neural circuits have different functional roles, their constituent neurons appear to integrate their various sensory inputs in much the same way.


Alterations in glia and axons in the brains of Binswanger's disease patients.
Although increasing attention is being paid to Binswanger's disease, a form of vascular dementia characterized by diffuse white matter lesions, only limited information is available on the pathological changes that occur in the glia and axons in the white matter. We therefore investigated the brains of patients with Binswanger's disease to gain further insight into its pathophysiology. Autopsied brains from patients with Binswanger's disease (group 3; n = 17) were compared with those of nonneurological controls (group 1; n = 5) and controls with large cortical infarcts but without significant white matter lesions (group 2; n = 5). Glial fibrillary acidic protein (GFAP) was used as an immunohistochemical marker for astroglia, leukocyte common antigen (LCA) was used as a marker for microglia, and HLA-DR was used as a marker for activated microglia. Axonal damage was assessed by the accumulation of proteins, which are transported by fast axonal flow, amyloid protein precursor (APP), synaptophysin, and chromogranin A. Although there was no difference in numerical density of GFAP-immunoreactive astroglia in each group, regressive astroglia were observed in 7 of 17 patients with Binswanger's disease. LCA-immunoreactive microglia were 1.7 times more numerous in Binswanger's disease than in group 1 (P < .05). HLA-DR-immunoreactive-activated microglia were 3.4 times and 2.1 times more numerous in Binswanger's disease as compared with group 1 (P < .01) and group 2 (P < .05), respectively. There was frequent perivascular lymphocyte cuffing, and clusters of macrophages with a decreased number of oligodendroglia were observed in the rarefied white matter. The grading scores for the number of axons immunoreactive for either APP, synaptophysin, or chromogranin A were significantly higher in Binswanger's disease than in group 1 or 2. The pathological alterations in Binswanger's diseased brains include regressive changes in the astroglia and activation of the microglia with a decrease in the oligodendroglia, which were associated with the degradation of both myelin and axonal components. These results indicate that an inflammatory reaction and compromised axonal transport, mediated by chronic ischemia, may play an important role in the pathophysiology of Binswanger's disease.


Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1.
Metallothioneins (MTs) are small cysteine-rich proteins that bind heavy metal ions such as zinc, cadmium and copper with high affinity, and have been functionally implicated in heavy metal detoxification and radical scavenging. Transcription of metallothioneins genes is induced by exposure of cells to heavy metals. This induction is mediated by metal-responsive promoter elements (MREs). We have previously cloned the cDNA of an MRE-binding transcription factor (MTF-1) from the mouse. Here we present the human cDNA equivalent of this metal-regulatory factor. Human MTF-1 is a protein of 753 amino acids with 93% amino acid sequence identity to mouse MTF-1 and has an extension of 78 amino acids at the C-terminus without counterpart in the mouse. The factors of both species have the same overall structure including six zinc fingers in the DNA binding domain. We have physically mapped the human MTF-1 gene to human chromosome 1 where it localizes to the short arm in the region 1p32-34, most likely 1p33. Both human and mouse MTF-1 when produced in transfected mammalian cells strongly bind to a consensus MRE of metallothionein promoters. However, human MTF-1 is more effective than the mouse MTF-1 clone in mediating zinc-induced transcription.


Akt Signaling in Macrophage Polarization, Survival, and Atherosclerosis.
The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications.


Neuro-immune abnormalities in autism and their relationship with the environment: a variable insult model for autism.
Autism spectrum disorder (ASD) is a heterogeneous condition affecting an individual's ability to communicate and socialize and often presents with repetitive movements or behaviors. It tends to be severe with less than 10% achieving independent living with a marked variation in the progression of the condition. To date, the literature supports a multifactorial model with the largest, most detailed twin study demonstrating strong environmental contribution to the development of the condition. Here, we present a brief review of the neurological, immunological, and autonomic abnormalities in ASD focusing on the causative roles of environmental agents and abnormal gut microbiota. We present a working hypothesis attempting to bring together the influence of environment on the abnormal neurological, immunological, and neuroimmunological functions and we explain in brief how such pathophysiology can lead to, and/or exacerbate ASD symptomatology. At present, there is a lack of consistent findings relating to the neurobiology of autism. Whilst we postulate such variable findings may reflect the marked heterogeneity in clinical presentation and as such the variable findings may be of pathophysiological relevance, more research into the neurobiology of autism is necessary before establishing a working hypothesis. Both the literature review and hypothesis presented here explore possible neurobiological explanations with an emphasis of environmental etiologies and are presented with this bias.


Staining of urinary leucocytes as an aid to the diagnosis of inflammation in the urinary tract.
Five hundred specimens of urine have been examined for pyuria and bacteriuria, the leucocytes being stained by the Sternheimer-Malbin method. Most urines contained either less than 1 or more than 10 leucocytes per cmm; a few specimens contained 1 to 10 cells per cmm, whatever their viable bacterial count. The presence of leucocytes in urine was usually related to the bacterial count, pyuria being commonest in urines showing ;significant bacteriuria'. However, urinary tract instrumentation caused pyuria in the absence of infection. Leucocytes with nuclei staining blue by the Sternheimer-Malbin technique were considered to be indicative of active inflammation, but the incidence of such cells appeared to be a reflection of the total leucocyte count of the specimen rather than of its viable bacterial count. In the majority of cases the diagnosis of infection can be made on the basis of the bacterial count and the degree of pyuria. The staining technique appears to have a limited use, restricted to the interpretation of cases in which the results of culture and conventional leucocyte counts are ambiguous.


Taxon ordering in phylogenetic trees by means of evolutionary algorithms.
In in a typical "left-to-right" phylogenetic tree, the vertical order of taxa is meaningless, as only the branch path between them reflects their degree of similarity. To make unresolved trees more informative, here we propose an innovative Evolutionary Algorithm (EA) method to search the best graphical representation of unresolved trees, in order to give a biological meaning to the vertical order of taxa. Starting from a West Nile virus phylogenetic tree, in a (1 + 1)-EA we evolved it by randomly rotating the internal nodes and selecting the tree with better fitness every generation. The fitness is a sum of genetic distances between the considered taxon and the r (radius) next taxa. After having set the radius to the best performance, we evolved the trees with (λ + μ)-EAs to study the influence of population on the algorithm. The (1 + 1)-EA consistently outperformed a random search, and better results were obtained setting the radius to 8. The (λ + μ)-EAs performed as well as the (1 + 1), except the larger population (1000 + 1000). The trees after the evolution showed an improvement both of the fitness (based on a genetic distance matrix, then close taxa are actually genetically close), and of the biological interpretation. Samples collected in the same state or year moved close each other, making the tree easier to interpret. Biological relationships between samples are also easier to observe.


A systematic review and meta-analysis of health care utilization outcomes in alcohol screening and brief intervention trials.
This systematic review and meta-analysis examines the effect of screening and brief intervention (SBI) on outpatient, emergency department (ED), and inpatient health care utilization outcomes. Much of the current literature speculates that SBI provides cost savings through reduced health care utilization, but no systematic review or meta-analysis examines this assertion. Publications were abstracted from online journal collections and targeted Web searches. The systematic review included any publications that examined the association between SBI and health care utilization. Each publication was rated independently by 2 study authors and assigned a consensus methodological score. The meta-analysis focused on those studies examined in the systematic review, but it excluded publications that had incomplete data, low methodological quality, or a cluster-randomized design. Systematic review results suggest that SBI has little to no effect on inpatient or outpatient health care utilization, but it may have a small, negative effect on ED utilization. A random effects meta-analysis using the Hedges method confirms the ED result for SBI delivered across settings (standardized mean difference = -0.06, I = 13.9%) but does not achieve statistical significance (confidence interval: -0.15, 0.03). SBI may reduce overall health care costs, but more studies are needed. Current evidence is inconclusive for SBI delivered in ED and non-ED hospital settings. Future studies of SBI and health care utilization should report the estimated effects and variance, regardless of the effect size or statistical significance.


Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity.
Our aim was to determine the molecular cause of autosomal dominant familial retinal arteriolar tortuosity (FRAT) in a family with three affected subjects. Ophthalmologic evaluation included determination of best-corrected visual acuity (BCVA), slit-lamp and dilated fundus inspection, applanation tonometry, fundus photography, and fluorescein retinal angiography (FA). Molecular methods included whole exome sequencing analysis and Sanger sequencing validation of putative causal mutation in DNA from affected individuals. Typical signs of familial retinal arteriolar tortuosity were observed in all three patients. Exome sequencing identified a heterozygous c.1528G > A (p. Gly510Arg) mutation in COL4A1. Sanger sequencing confirmed that all three patients harbored the same pathogenetic mutation in COL4A1. The p. Gly510Arg variant in COL4A1 was absent in DNA from an available unaffected daughter, from a set of control alleles, and from publicly available databases. The molecular basis of familial retinal arteriolar tortuosity was identified for the first time, thus expanding the human phenotypes linked to COL4A1 mutations. Interestingly, the COL4A1 p.Gly510Arg mutation has been previously identified in a family with HANAC (Hereditary Angiopathy with Nephropathy, Aneurysm and Cramps), a multisystemic disease featuring retinal arteriolar tortuosity. No cerebral, neurologic, renal, cardiac or vascular anomalies were recognized in the pedigree described here. These data indicate that identical mutations in COL4A1 can originate both eye-restricted and systemic phenotypes.


Sensory neuron lineage mapping and manipulation in the Drosophila olfactory system.
Nervous systems exhibit myriad cell types, but understanding how this diversity arises is hampered by the difficulty to visualize and genetically-probe specific lineages, especially at early developmental stages prior to expression of unique molecular markers. Here, we use a genetic immortalization method to analyze the development of sensory neuron lineages in the Drosophila olfactory system, from their origin to terminal differentiation. We apply this approach to define a fate map of nearly all olfactory lineages and refine the model of temporal patterns of lineage divisions. Taking advantage of a selective marker for the lineage that gives rise to Or67d pheromone-sensing neurons and a genome-wide transcription factor RNAi screen, we identify the spatial and temporal requirements for Pointed, an ETS family member, in this developmental pathway. Transcriptomic analysis of wild-type and Pointed-depleted olfactory tissue reveals a universal requirement for this factor as a switch-like determinant of fates in these sensory lineages.


Initial resuscitation after burn injury: therapies, strategies, and controversies.
Thermal injury disrupts normal hemostasis and sets off a cascade of events: cellular alterations and release of inflammatory mediators cause hypovolemic and cellular shock. Fluid resuscitation in burn injuries has been in use for more than a century, and much research has been devoted to development of resuscitation formulas and appropriate choice of fluid. Parameters for adequate monitoring of resuscitation are greatly debated. Current research efforts focus on minimizing burn edema through mediator modulation and on development of definitive endpoints of resuscitation monitoring.


Surface and structural effects of pitch and time on global melodic expectancies.
We investigated how the surface and structural information of pitch and time in melodies contribute to the perceived expectancy of melodic segments. The contour (pitch surface), tonality (pitch structure), rhythm (time surface) and metre (time structure) were preserved or altered in factorial fashion, either for the full length of a melody (Full condition) or only its last phrase (Last condition). Participants (N = 24) with a range of musical training received instructions to rate how expected the second portion of a melody was, having heard its first part. Additionally, instructions varied across blocks to attend selectively to pitch, time, or both. Expectancy ratings for the Last condition were lower than for the Full condition, indicating that ratings truly reflected expectancy (rather than overall goodness, which would predict the opposite). Interestingly, tonality and rhythm contributed to global expectancy ratings, but not contour or metre. Furthermore, listeners were unable to ignore entirely either dimension, but successfully attenuated their influence in accordance with instructions. These findings offer a unique insight into music perception by testing expectancies of melody segments (beyond single-note continuations), factorially varying both the surface and structure of pitch and time, and using a selective attention manipulation.


Molecular identification of two prophenoloxidase-activating proteases from the hemocytes of Plutella xylostella (Lepidoptera: Plutellidae) and their transcript abundance changes in response to microbial challenges.
The phenoloxidase (PO) activation system plays an important role in insect innate immunity, particularly in wound healing and pathogen defense. A key member of this system is prophenoloxidase-activating protease (PAP), which is the direct activator of prophenoloxidase (proPO). Despite their importance in the insect PO activation system, content of studies is limited. In this article, we identify two complementary DNAs (cDNAs), PxPAPa and PxPAPb, encoding possible PAPs, from immunized larval hemocytes of the diamondback moth, Plutella xylostella (L.), by RACE method. PxPAPa is 1,149-bp long and encodes a 382-residue open reading frame (ORF) with a predicted 17-residue signal peptide, a clip domain, and a Tryp_Spc domain. PxPAPb is 1,650-bp long and encodes a 440-residue ORF with a predicted 20-residue signal peptide, two clip domains, and a Tryp_Spc domain. PxPAPa and PxPAPb have a high sequence similarity to Manduca sexta (L.) PAP1 and PAP3, respectively. We also examined the transcript patterns of PxPAPa, PxPAPb, and pxPAP3, another clip-domain serine protease gene, response to different microbial challenges by using real-time quantitative polymerase chain reaction. The results show that the transcript abundance of PxPAPa is significantly increased by Micrococcus luteus and Escherichia coli but not Candida albicans. PxPAPb is induced only by Mi. luteus, whereas pxPAP3 could be induced by all the microbes in the test, but the transcript patterns of Mi. luteus, E. coli, and C. albicans are completely different. This study provides new insights into the molecular events that occur during the immune response, particularly melanization cascade that is involved in encapsulation and nodulation of pathogen or parasite invaders via hemocytes in host insects.


Modeling the terrestrial N processes in a small mountain catchment through INCA-N: A case study in Taiwan.
Riverine dissolved inorganic nitrogen (DIN) is an important indicator of trophic status of aquatic ecosystems. High riverine DIN export in Taiwan, ~3800kg-Nkm-2yr-1, which is ~18 times higher than the global average, urges the need of thorough understanding of N cycling processes. We applied INCA-N (Integrated Nitrogen Catchment Model) to simulate riverine DIN export and infer terrestrial N processes using weekly rainwater and streamwater samples collected at the Fushan Experimental Forest (FEF) of northern Taiwan. Results showed that the modeled discharge and nitrate export are in good agreement with observations, suggesting the validity of our application. Based on our modeling, the three main N removal processes, in the order of descending importance, were plant uptake, riverine N transport and denitrification at FEF. The high plant uptake rate, 4920kg-Nkm-2yr-1, should have led to accumulation of large biomass but biomass at FEF was relatively small compared to other tropical forests, likely due to periodic typhoon disruptions. The low nitrate concentration but high DIN export highlights the importance of hydrological control over DIN export, particularly during typhoons. The denitrification rate, 750kg-Nkm-2yr-1, at FEF was also low compared to other tropical forest ecosystems, likely resulting from quick water drainage through the coarse-loamy top soils. The high DIN export to atmospheric deposition ratio, 0.45, suggests that FEF may be in advanced stages of N excess. This simulation provides useful insights for establishing monitoring programs and improves our understanding N cycling in subtropical watersheds.


Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens.
The envelope spike of HIV is one of the most highly N-glycosylated structures found in nature. However, despite extensive research revealing essential functional roles in infection and immune evasion, the chemical structures of the glycans on the native viral envelope glycoprotein gp120--as opposed to recombinantly generated gp120--have not been described. Here, we report on the identity of the N-linked glycans from primary isolates of HIV-1 (clades A, B, and C) and from the simian immunodeficiency virus. MS analysis reveals a remarkably simple and highly conserved virus-specific glycan profile almost entirely devoid of medial Golgi-mediated processing. In stark contrast to recombinant gp120, which shows extensive exposure to cellular glycosylation enzymes (>70% complex type glycans), the native envelope shows barely detectable processing beyond the biosynthetic intermediate Man5GlcNAc2 (<2% complex type glycans). This oligomannose (Man5-9GlcNAc2) profile is conserved across primary isolates and geographically divergent clades but is not reflected in the current generation of gp120 antigens used for vaccine trials. In the context of vaccine design, we also note that Manalpha1-->2Man-terminating glycans (Man6-9GlcNAc2) of the type recognized by the broadly neutralizing anti-HIV antibody 2G12 are 3-fold more abundant on the native envelope than on the recombinant monomer and are also found on isolates not neutralized by 2G12. The Manalpha1-->2Man residues of gp120 therefore provide a vaccine target that is physically larger and antigenically more conserved than the 2G12 epitope itself. This study revises and extends our understanding of the glycan shield of HIV with implications for AIDS vaccine design.


Prolonged salivary cortisol recovery in second-trimester pregnant women and attenuated salivary alpha-amylase responses to psychosocial stress in human pregnancy.
The underlying biological mechanisms of stress-related pregnancy complications in humans are still poorly understood. Recent research on pharmacological or physical provocation procedures in pregnant women has resulted in inhomogeneous findings. Furthermore, no studies conducted so far have used a psychosocial stress paradigm at different stages of pregnancy. The aim of this study was to identify endocrine, autonomic, and psychological responses to standardized psychosocial stress at different stages of pregnancy. Ninety healthy women (aged 21-37 yr), including 30 pregnant women at the beginning of the second trimester and 30 women at the beginning of the third trimester, as well as 30 nonpregnant women in the follicular phase of their menstrual cycle, underwent a psychosocial stress test. Salivary free cortisol, alpha-amylase, heart rate, and psychological parameters were repeatedly measured. Salivary cortisol recovery was significantly prolonged in second-trimester pregnant women (P = 0.04). Cortisol and heart rate increases of both pregnant groups were shown to be comparable with those of the controls. alpha-Amylase increases of both pregnant groups were markedly attenuated compared with nonpregnant women (P = 0.008). From these data, we conclude that, in contrast to pregnancy in rats, pregnancy in women does not result in a restraint of the hypothalamic-pituitary-adrenal axis to psychosocial stress. Furthermore, attenuated alpha-amylase stress response might reflect protective processes within the autonomic nervous system during pregnancy, whereas prolonged cortisol recovery during the beginning of second-trimester pregnancy might be associated with the vulnerability to stress-related pregnancy complications during this period of time.


Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia.
HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10-8 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10-8 ) and IOMM-Lee (p = 4 × 10-9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10-6 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


The microbial flora associated with oral carcinomas.
Changes in the microbial flora on the oral mucosa after cancerous alteration may lead to both local and systemic infections. In this study, we assessed the microbial flora associated with the surfaces of oral squamous cell carcinoma. A comparative evaluation of these microbial contents was made with that of the contralateral healthy mucosa and control (healthy) mucosa. We also assessed the microbial flora from the saliva culture in subjects with oral squamous cell carcinoma and healthy controls. The case control study was made up of 30 subjects with oral squamous cell carcinoma as the study group; 30 healthy age-, sex-, habit-, and dentition-matched subjects served as the control group. In the study group, microbial samples were collected from the carcinoma site, contralateral healthy mucosa, and saliva, whereas in the control group, samples were collected from the healthy mucosa and saliva. These samples were stored on ice and subsequently transported to the laboratory in 2 mL of thioglycollate transport media, where the microbial cultures were carried out. Oral squamous cell carcinoma sites harbor significantly more microbial flora (bacteria and yeasts) compared to those of healthy mucosa (control group). The microbial flora predominantly isolated from the carcinoma site were Streptococcus species, Staphylococcus species, Moraxella species, Enterococcus feacalis, Aerobic spore bearers, Klebsiella species, Citrobacter species, Proteus species, Pseudomonas species, and Candida albicans. The median number of colony forming units (CFU)/mL at carcinoma sites (3.85 x 105 CFU/mL) was significantly higher than that of the healthy mucosa (0.571 x 105 CFU/mL; P = .0000, Wilcoxon nonparametric test). Similarly, in saliva of carcinoma subjects, the median number of CFU/mL (2.408 x 105 CFU/mL) was significantly higher than that of saliva in control subjects (0.78 x 105 CFU/mL; P = .0000, Wilcoxon nonparametric test). The present study clearly indicates that the subjects with oral squamous cell carcinoma harbor significantly more microbial flora. Emphasis has to be given to preventing microbial flora in the oral cavity and treating these patients with appropriate antimicrobial agents, thus reducing their morbidity.


Experimentally induced antipredator responses are mediated by social and environmental factors.
Nest predation is a common cause of reproductive failure for many bird species, and various antipredator defense behaviors have evolved to reduce the risk of nest predation. However, trade-offs between current reproductive duties and future reproduction often limit the parent's ability to respond to nest predation risk. Individual responses to experimentally increased nest predation risk can give insights into these trade-offs. Here, we investigate whether social and ecological factors affect individual responses to predation risk by experimentally manipulating the risk of nest predation using taxidermic mounts in the cooperative breeding Seychelles warbler (Acrocephalus sechellensis). Our results show that dominant females, but not males, alarm called more often when they confront a nest predator model alone than when they do so with a partner, and that individuals that confront a predator together attacked more than those that did so alone. Dominant males increased their antipredator defense by spending more time nest guarding after a presentation with a nest predator, compared with a nonpredator control, but no such effect was found for females, who did not increase the time spent incubating. In contrast to incubation by females, nest guarding responses by dominant males depended on the presence of other group members and food availability. These results suggest that while female investment in incubation is always high and not dependent on social and ecological conditions, males have a lower initial investment, which allows them to respond to sudden changes in nest predation risk.


Comparative genome analysis of the mouse imprinted gene impact and its nonimprinted human homolog IMPACT: toward the structural basis for species-specific imprinting.
Mouse Impact is a paternally expressed gene encoding an evolutionarily conserved protein of unknown function. Here we identified IMPACT, the human homolog of Impact, on chromosome 18q11. 2-12.1, a region syntenic to the mouse Impact locus. IMPACT was expressed biallelically in brain and in various tissues from two informative fetuses and in peripheral blood from an informative adult. To reveal the structural basis for the difference in allelic expression between the two species, we elucidated complete genome sequences for both mouse Impact ( approximately 38 kb) and human IMPACT ( approximately 30 kb). Sequence comparison revealed that the two genes share a well-conserved exon-intron organization but bear significantly different CpG islands. The mouse island lies in the first intron and contains characteristic tandem repeats. Furthermore, this island serves as a differentially methylated region (DMR) consisting of a hypermethylated maternal allele and an unmethylated paternal allele. Intriguingly, this intronic island is missing from the nonimprinted human IMPACT, whose sole CpG island spans the first exon, lacks any apparent repeats, and escapes methylation on both chromosomes. These results suggest that the intronic DMR plays a role in the imprinting of Impact.


Functional Consequences of Pravastatin Isomerization on OATP1B1-Mediated Transport.
Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3'α-iso-pravastatin acid (3αPVA) under acidic pH conditions. Previous studies reported interindividual differences in circulating concentrations of PVA and 3αPVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3αPVA inhibition of OATP1B1-mediated PVA uptake into human embryonic kidney 293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5, and *15). 3αPVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC50/Ki values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3αPVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (Vmax values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3αPVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3αPVA was higher (lower Km value) than for PVA. These data confirm that PVA conversion to 3αPVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. SIGNIFICANCE STATEMENT: 3'α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types; however, the IC50 values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3'α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant-expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin interindividual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.


The afferent connections of the posterior hypothalamic nucleus in the rat using horseradish peroxidase.
The posterior hypothalamic nucleus has been implicated as an area controlling autonomic activity. The afferent input to the nucleus will provide evidence as to its role in autonomic function. In the present study, we aimed to identify the detailed anatomical projections to the posterior hypothalamic nucleus from cortical, subcortical and brainstem structures, using the horseradish peroxidase (HRP) retrograde axonal transport technique in the rat. Subsequent to the injection of HRP into the posterior hypothalamic nucleus, extensive cell labelling was observed bilaterally in various areas of the cerebral cortex including the cingulate, frontal, parietal and insular cortices. At subcortical levels, labelled cells were observed in the medial and lateral septal nuclei, the bed nucleus of stria terminalis, and various thalamic and amygdaloid nuclei. Also axons of the vertical and horizontal limbs of the diagonal band were labelled and labelled cells were localised at the CA1 and CA3 fields of the hippocampus and the dentate gyrus. The brainstem projections were from the medial, lateral and parasolitary nuclei, the intercalated nucleus of the medulla, the sensory nuclei of the trigeminal nerve, and various reticular, vestibular, raphe and central grey nuclei. The posterior hypothalamic nucleus also received projections from the lateral and medial cerebellar nuclei and from upper cervical spinal levels. The results are discussed in relation to the involvement of the posterior hypothalamic nucleus in autonomic function and allows a better understanding of how the brain controls visceral function.


Preserving fertility in the hypogonadal patient: an update.
An increasing number of young and middle-aged men are seeking treatment for symptoms related to deficient levels of androgens (hypogonadism) including depression, loss of libido, erectile dysfunction, and fatigue. The increase in prevalence of testosterone supplementation in general and anabolic steroid-induced hypogonadism specifically among younger athletes is creating a population of young men who are uniquely impacted by the testicular end-organ negative consequences of exogenous steroid use. Exogenous testosterone therapy can alter the natural regulation of the hypothalamic-pituitary-gonadal axis leading to impaired spermatogenesis with azoospermia being a serious possible result, thus rendering the individual infertile. For men of reproductive age who suffer from hypogonadal symptoms, preservation of fertility is an important aspect of their treatment paradigm. Treatment with human chorionic gonadotropin (hCG) has shown the ability not only to reverse azoospermia brought on by testosterone supplementation therapy but also to help maintain elevated intratesticular testosterone levels. In addition, selective estrogen receptor modulators, often used with hCG have been shown both to elevate total testosterone levels and to maintain spermatogenesis in hypogonadal men.


The attribution of human infections with antimicrobial resistant Salmonella bacteria in Denmark to sources of animal origin.
Based on the Danish Salmonella surveillance in 2000-2001, we developed a mathematical model for quantifying the contribution of each major animal-food sources to human salmonellosis caused by antimicrobial resistant bacteria. Domestic food products accounted for 53.1% of all cases, mainly caused by table eggs (37.6%). A large proportion (19%) of cases were travel related, while 18% could not be associated with any source. Imported food products accounted for 9.5% of all cases; the most important source being imported chicken. Multidrug and quinolone resistance was rarely found in cases acquired from Danish food, but was common in cases related to imported products (49.7% and 35.6% of attributable cases) and travelling (26.5% and 38.3% of attributable cases). For most serovars, the quinolone-resistant isolates were found to be associated with relatively more human infections than that of resistant isolates, which in turn was higher than that of susceptible isolates. This may be due to quinolone-resistant isolates having a higher ability to survive food processing and/or cause disease. This study showed domestic food to be the most important source of Salmonella infections in Denmark, but infections with multidrug- and quinolone-resistant isolates were more commonly caused by imported food products and travelling, emphasizing the need for a global perspective on food safety and antimicrobial usage.


Measurement and real-time cancellation of vibration-induced phase noise in a cavity-stabilized laser.
We demonstrate a method to measure and actively reduce the coupling of vibrations to the phase noise of a cavity-stabilized laser. This method uses the vibration noise of the laboratory environment rather than active drive to perturb the optical cavity. The laser phase noise is measured via a beat note with a second unperturbed ultra-stable laser while the vibrations are measured by accelerometers positioned around the cavity. A Wiener filter algorithm extracts the frequency and direction dependence of the cavity response function. Once the cavity response function is known, real-time noise cancellation can be implemented by use of the accelerometer measurements to predict and then cancel the laser phase fluctuations. We present real-time noise cancellation that results in a 25 dB reduction of the laser phase noise power spectral density.


Strengthening Mentoring in Low- and Middle-Income Countries to Advance Global Health Research: An Overview.
Mentoring is a proven path to scientific progress, but it is not a common practice in low- and middle-income countries (LMICs). Existing mentoring approaches and guidelines are geared toward high-income country settings, without considering in detail the differences in resources, culture, and structure of research systems of LMICs. To address this gap, we conducted five Mentoring-the-Mentor workshops in Africa, South America, and Asia, which aimed at strengthening the capacity for evidence-based, LMIC-specific institutional mentoring programs globally. The outcomes of the workshops and two follow-up working meetings are presented in this special edition of the American Journal of Tropical Medicine and Hygiene. Seven articles offer recommendations on how to tailor mentoring to the context and culture of LMICs, and provide guidance on how to implement mentoring programs. This introductory article provides both a prelude and executive summary to the seven articles, describing the motivation, cultural context and relevant background, and presenting key findings, conclusions, and recommendations.


The effect of chitosan bead encapsulating calcium sulfate as an injectable bone substitute on consolidation in the mandibular distraction osteogenesis of a dog model.
The purpose of this project was to study the effect of chitosan bead encapsulating calcium sulfate, which provides a sustained release of chitosan and calcium sulfate after implantation, on early bony consolidation in distraction osteogenesis of a dog model. Forty-five dogs were used for this study. An external distraction device was applied to the mandibular body after a vertical osteotomy and mandibular distraction was initiated 5 days after the operation at a rate of 1 mm/day up to a 10-mm distraction. The experimental group was divided into a control group (I), hyaluronic acid group (II), chitosan group (III), calcium sulfate group (IV), and chitosan bead encapsulating calcium sulfate group (V). Normal saline was injected in group I. In group II, 1 mL of hyaluronic acid solution was injected into the distracted region. In group III, 1 mL of injectable solution of chitosan mixed with hyaluronic acid was implanted. In group IV, 1 mL of injectable solution of calcium sulfate mixed with hyaluronic acid was implanted. In group V, an injectable form of powdered chitosan bead encapsulating calcium sulfate mixed with 1 mL volume of hyaluronic acid was implanted. Bone mineral density was 12% of the contralateral normal mandible at 3 weeks, 23.4% at 6 weeks in group I, 15% at 3 weeks, 29.1% at 6 weeks in group II, 16% at 3 weeks and 32% at 6 weeks in group III, 30.4% at 3 weeks and 52.8% at 6 weeks in group IV, and 33.6% at 3 weeks and 55% at 6 weeks in group V with statistical significance (P < .005). The mean 3-point failure load was compared with the intact contralateral mandible and noted to be 12% in the control group, 16% in group II, 18% in group III, 34.3% in group IV, and 31.7% in group V. Difference of mean percentages between one group and another was statistically significant (P < .005). In the histologic findings, new bone was generated in all groups. In groups IV and V, the formation of active woven bone was observed throughout the distracted region at 6 weeks. The amount of new bone formation in the distracted zone was in the order of group IV and V, III and II, and the control group. These findings suggest that chitosan bead encapsulating calcium sulfate appears to facilitate early bony consolidation in distraction osteogenesis.


Adenoma detection rate and risk of colorectal cancer and death.
The proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death. Using data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions. We evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98). The adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.).


A History of the Council of State Neurosurgical Societies.
As neurological surgery evolved into its own subspecialty early in the 20th century, a need arose to create an environment for communication and education among those surgeons working in this burgeoning surgical discipline. As the socioeconomic climate in health care began to change in the United States, an unforeseen need arose that was outside the scope of the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Society of Neurological Surgeons. The capacity to understand and address the evolving socioeconomic landscape and to offer a platform for advocacy required a new entity. Grassroots efforts of neurosurgeons at the state level ultimately yielded a formal organization of state neurosurgical societies to fill this void by recognizing, understanding, and addressing socioeconomic factors affecting the practice of neurological surgery. This formal organization became the Council of State Neurosurgical Societies (CSNS). The CSNS provides a forum in which state societies can meet to identify, understand, and advocate for policies on behalf of organized neurosurgery. The purpose of this paper is to detail the history of the formation of the CSNS. By understanding this history and the need for the development of the CSNS, it is hoped that its evolving role as a voice for neurological surgeons in the modern era of health care will be made clear.


Ageing of the enteric nervous system.
The intrinsic neurones of the enteric nervous system (ENS) play a fundamental role in the regulation of gastrointestinal functions. Although much remains to be learnt about the changes that take place in intestinal nerves during ageing, evidence suggests that selective neurodegeneration may occur in the ageing ENS. Age-associated changes in intestinal innervation may contribute to the gastrointestinal disorders that increase in incidence in the elderly, such as dysphagia, gastrointestinal reflux and constipation. A number of other factors, such as immobility, co-morbidity, and side effects of therapeutic medication for other disorders however, are also likely to contribute to the aetiology of these conditions. An important finding in rodents is that the neuronal losses that take place in the ENS during ageing may be prevented by calorie restriction; an indication that diet may influence gastrointestinal ageing. Thus, it is of importance to understand not only how the ENS changes during 'normal' ageing, but also how external factors contribute to these changes. Here, current knowledge of how intestinal innervation is affected during normal ageing and how these changes may impact upon gastrointestinal physiology are reviewed.


Common elements of parent management training programs for preschool children with autism spectrum disorder.
Parent management training is a general set of interventions used as a part of a variety of clinical approaches to reduce behavioral problems of children. These behavioral problems in children with special needs (such as autism spectrum disorder) take a more complex form. The objective is to present elements, needed to develop parent management training program to reduce behavioral problems in preschool children with autism spectrum disorder. At first, all parent management training programs for reducing behavioral problems of preschool children were collected. Subsequently, all programs were reviewed from the perspective of having a systematic review or meta-analysis, confirming the effectiveness of this program at preschool age. After that, interviews with experts and parents were conducted to identify effective elements on development of this program. In the next step, a set of components was obtained using information about parent management training programs as well as items obtained from interviews with experts and parents. At this stage, 10 experts were asked to rate the items according to their importance using the Delphi method. The items that achieved the required scores were introduced as main items. The number of them was 13 and included items such as full assessment of the child and appropriate communication with the child. Considering the characteristics of children with autism spectrum disorder will require changes in some parts of parent management training program, therefore, it is necessary to develop a specific program for these children to cover all of their characteristics.


Public provision of emergency obstetric care: a case study in two districts of Pakistan.
Pakistan is one out of five countries where together half of the global neonatal deaths occur. As the provision of services and facilities is one of the key elements vital to reducing this rate as well as the maternal mortality rate, this study investigates the status of the delivery of essential obstetric care provided by the public health sector in two districts in Khyber Pakhtunkhwa in 2015 aiming to highlight areas where critical improvements are needed. We analysed data from a survey of 22 primary and secondary healthcare facilities as well as 85 community midwives (CMWs) in Haripur and Nowshera districts. Using a structured questionnaire we evaluated the performance of emergency obstetric care (EmOC) signal functions and patient statistics in public health facilities. Also, 102 CMWs were interviewed about working hours, basic and specialised delivery service provision, referral system and patient statistics. We investigate the public provision of emergency obstetric care using seven key medical services identified by the United Nations (UN). Deliveries by public health cadres account for about 30% of the total number of births in these districts. According to the UN benchmark, only a small fraction of basic EmOC (2/18) and half of the comprehensive EmOC (2/4) facilities of the recommended minimum number were available to the population in both districts. Only a minority of health facilities and CMWs carry out several signal functions. Only 8% of the total births in one of the study districts are performed in public EmOC health facilities. Both districts show a significant shortage of available public EmOC service provisions. Development priorities need to be realigned to improve the availability, accessibility and quality of EmOC service provisions by the public health sector alongside with existing activities to increase institutional births.


Asthma, airflow limitation and mortality risk in the general population.
Asthma and chronic obstructive pulmonary disease co-exist in a significant proportion of patients. Whether asthma increases mortality risk among subjects with airflow limitation remains controversial. We used data from 2121 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease cohort. At enrolment (1972-1973), participants completed questionnaires and lung function tests. Participants were categorised into four groups based on the combination of airflow limitation (AL; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%) and physician-confirmed asthma at baseline. Vital status as of January 2011 was assessed through the National Death Index. Cox proportional hazards models were used to test differences in mortality risk across the four airflow limitation/asthma groups. In multivariate Cox models, the AL+/asthma+ group had a 114% increased mortality risk during follow-up compared with the AL-/asthma- group (adjusted HR 2.14; 95% CI 1.64-2.79). The corresponding hazard ratios were 1.09 (95% CI 0.89-1.34) and 1.34 (95% CI 1.14-1.57) for the AL-/asthma+ and AL+/asthma- groups, respectively. Among subjects with airflow limitation, asthma was associated with increased mortality risk (HR 1.58, 95% CI 1.17-2.12). However, this increased risk was substantially reduced and no longer significant after further adjustment for baseline FEV1 levels. Similar results were obtained when airflow limitation was defined as FEV1/FVC less than the lower limit of normal. In a population-based cohort, subjects with concomitant airflow limitation and asthma had an increased risk of dying, which was mainly related to their baseline lung function deficits.


Voreloxin, a first-in-class anticancer quinolone derivative, in relapsed/refractory solid tumors: a report on two dosing schedules.
Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity. Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history. In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m(2)). At 60 mg/m(2), four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m(2), two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m(2) (HP patients) and 60 mg/m(2) (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m(2)). At 18 mg/m(2), two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m(2). Voreloxin exhibited low clearance (2 L/h/m(2)), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria. Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia.


Different clinical spectrum of leptospirosis.
Leptospirosis is a prevalent zoonotic disease. Human infection usually occurs through exposure to environmental sources. Clinical course of leptospirosis is variable. We presented five patients, aged between 4-14 years, having a history of contact with rodents and symptoms 7-10 days after contact. The first three cases were relatives and had contact with dead rats after applying insecticides to bakery across from their house. The first case diagnosed as isolated meningitis, others as flu-like illness. The fourth case had a contact history with a rat inundate in the canalization and diagnosed as acute hepatitis. The last case, living in a village with poor sanitation, developed secondary hemophagocytic syndrome. ELISA was performed for diagnosis. High dose penicillin and additional immunosuppressive drugs for the last case were used. All cases showed recovery within 10 days. Leptospirosis should be considered in any patient presenting with an abrupt onset or prolonged fever, myalgia, headache and jaundice.


Naturalistic observations of beer drinking among college students.
We observed the beer drinking behavior of 308 university students in several bar and party settings. The following relationships were found: males drinking beer in bars consumed 0.92 oz per min; females drank less beer than males, and stayed in a bar for a longer time period; patrons drank significantly more beer when drinking in groups and when purchasing beer in pitchers versus cups or bottles; and intervals between party arrival and first drink and between party departure and last drink varied inversely with blood alcohol concentration. We discuss these findings with regard to developing interventions to prevent alcohol-impaired driving.


Antibody recognition of a highly conserved influenza virus epitope.
Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.


"We shall count it as a part of kyogero": acceptability and considerations for scale up of single dose chlorhexidine for umbilical cord care in Central Uganda.
Cleansing the umbilical cord with chlorhexidine reduces neonatal morbidity and mortality, particularly in communities where newborn deaths and home births are common. As a result, the World Health Organization and national authorities are advocating the scale up of this intervention. In order for such a scale up to be effective, it has to be acceptable to the targeted population. With the overall aim to clarify conditions for scale-up, this study explored the acceptability of single dose chlorhexidine solution for umbilical cord care among health workers and infant care providers in the districts of Kampala and Mukono in Central Uganda. This was a qualitative study that involved mothers of neonates enrolled in a chlorhexidine trial, nurses implementing the trial, key community members and opinion leaders in childcare. We conducted 30 in depth interviews (IDIs) with mothers (18), health workers (8), traditional birth attendants (2), a father (1) and a grandmother (1) and 4 focus group discussions (FGDs), 3 with mothers and 1 with health workers. We used qualitative content analysis to analyze our findings and borrow upon Sekhon's model when presenting our findings. Cognitive and emotional responses to chlorhexidine use included ease of use, and a perception that chlorhexidine reduced smell and abdominal colic. We also found that wider social and cultural factors were important to chlorhexidine use. These included cultural value put on quick separation of the umbilical cord as well as the practice of bathing the baby in a herbal mixture called kyogero. We also found that older relatives were key decision makers in umbilical cord care for newborns, but were seldom present during health workers' counseling of mothers about hygienic care of the cord. The application of chlorhexidine on the umbilical cord stump at birth was acceptable as an addition rather than a total replacement of traditional substances. The scale up of chlorhexidine should consider how to accommodate local beliefs and practices in a way that does not compromise the effect of the intervention; encouraging mothers to delay the bathing of babies in kyogero could be one way of doing this.


The Dundee coronary risk-disk for management of change in risk factors.
To devise a simplified system for grading and monitoring modifiable coronary risk in primary care, to be used with an action plan. The risk equation came from 5203 men aged 40-59 in the United Kingdom heart disease prevention project, who had 331 coronary events over five years; the population rank (reading 1-100) was obtained by scoring 10,359 participants in the Scottish heart health study. Calculation of rank was embodied in the Dundee coronary risk-disk; the formula was tested against the Whitehall study; disk and action plan were evaluated in primary care. The system measures modifiable coronary risk from smoking, blood pressure, and blood cholesterol concentration by a sex and age related rank running from 1 (high risk, priority action) to 100 (low risk, general advice). The formula predicted outcome acceptably in the Whitehall study and is built into a circular slide rule. Only eight (11%) of 76 general practitioners and practice nurses surveyed already used risk factor scores. After evaluation most thought they should use one and proposed to incorporate the Dundee coronary risk-disk and the associated action plan into their routines. The Dundee coronary risk-disk readout of Dundee rank, standardised on a scale of 1 to 100 by age and sex, is a simple, valid means of assessing and monitoring modifiable coronary risk. It puts single risk factors (such as cholesterol concentration) in perspective and can aid selective testing. Understood by medical staff and patients, it should improve the efficiency and effectiveness of the high risk approach to coronary prevention.


A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes.
During development, extracellular signaling molecules interact with intracellular gene networks to control the specification, pattern and size of organs. One such signaling molecule is Hedgehog (Hh). Hh is known to act as a morphogen, instructing different fates depending on the distance to its source. However, how Hh, when signaling across a cell field, impacts organ-specific transcriptional networks is still poorly understood. Here, we investigate this issue during the development of the Drosophila ocellar complex. The development of this sensory structure, which is composed of three simple eyes (or ocelli) located at the vertices of a triangular patch of cuticle on the dorsal head, depends on Hh signaling and on the definition of three domains: two areas of eya and so expression--the prospective anterior and posterior ocelli--and the intervening interocellar domain. Our results highlight the role of the homeodomain transcription factor engrailed (en) both as a target and as a transcriptional repressor of hh signaling in the prospective interocellar region. Furthermore, we identify a requirement for the Notch pathway in the establishment of en maintenance in a Hh-independent manner. Therefore, hh signals transiently during the specification of the interocellar domain, with en being required here for hh signaling attenuation. Computational analysis further suggests that this network design confers robustness to signaling noise and constrains phenotypic variation. In summary, using genetics and modeling we have expanded the ocellar gene network to explain how the interaction between the Hh gradient and this gene network results in the generation of stable mutually exclusive gene expression domains. In addition, we discuss some general implications our model may have in some Hh-driven gene networks.


Dual-wavelength emission from optically cascaded intersubband transitions.
Dual-wavelength intersubband emission at 8 and 10 microm is reported in a three-level quantum-well system in which one electronic state is at the same time the lower level of the first optical transition and the upper level of the second. Results are presented for two different AlInAs/GaInAs quantum cascade structures featuring single-well active regions with two vertical transitions or double-well active regions with one diagonal and one vertical transition. Laser action has been achieved between the excited states of the single-well device and on the diagonal transition of the double-well structure. In the latter case the wavelength can be electric-field tuned by means of the Stark effect also above threshold.


Behavioral and physiological effects of deep pressure on children with autism: a pilot study evaluating the efficacy of Grandin's Hug Machine.
One symptom common to many persons with autism is a high arousal or anxiety level. This study investigated the effects of deep pressure on arousal and anxiety reduction in autism with Grandin's Hug Machine, a device that allows self-administration of lateral body pressure. Twelve children with autism were randomly assigned to either an experimental group (receiving deep pressure) or a placebo group (not receiving deep pressure but in the disengaged Hug Machine). All children received two 20-min sessions a week over a 6-week period. Arousal was measured behaviorally with the Conners Parent Rating Scale and physiologically with galvanic skin response (GSR) readings. Behavioral results indicated a significant reduction in tension and a marginally significant reduction in anxiety for children who received the deep pressure compared with the children who did not. Additionally, children in the experimental group, whose GSR measures decreased, on average, after deep pressure, were somewhat more likely to have higher GSR arousal a priori. These preliminary findings support the hypothesis that deep pressure may have a calming effect for persons with autism, especially those with high levels of arousal or anxiety.


Cardiac Intensive Care Unit Admissions during COVID-19 Pandemic-A Single Center Experience.
The impact of coronavirus disease 2019 (COVID-19) lockdown on cardiac emergency admissions to hospitals has been reported previously. We aimed to study the emergency room (ER) admissions to cardiac intensive care unit (CICU) at a tertiary care center during that period and compare this with admissions during the same time frame in the previous years. This is a retrospective observational study of patients admitted to the CICU during the pandemic period from March 22 to August 1 (inclusive) of 2020 and compared this with CICU admissions in the same time frame in the previous 2 years (2018 and 2019). During the study period in 2020, a total of 216 patients (age 59 ± 14 years) were admitted via ER, which is a 33% and 30% decline in admissions compared to 2019 (n = 322, age 63 ± 12 years) and 2018 (n = 307, age 62 ± 13), respectively. The decline in admissions with the primary diagnosis of acute coronary syndrome (ACS), acute decompensated heart failure, arrhythmia, and other diagnoses during the study period in 2020 were 27%, 38%, 62%, and 59%, respectively, while there was a 50% increase in acute pulmonary embolism admission compared to the mean admission in 2018 and 2019. Weekly admission rates gradually increased from less than 10 per week in the first 3 weeks to >15 by eighth week of the study period in 2020, while the trend was same throughout the study period in the previous 2 years. The CICU mortality rate in 2020 study period was 4.6% compared to 3.9% in 2018 (p = 0.83) and 5.6% in 2019 (p = 0.70). The in-hospital mortality of these patients was also similar in all 3 years (6.5%, 7.8%, and 7.9% in 2018, 2019, and 2020, respectively; p = 0.61). Our study showed that CICU admissions during COVID-19 lockdown had declined compared to the previous years in a large tertiary center in India. Government and health organizations should educate the public early on during the pandemic about the consequences of ignoring other acute medical problems such as ACS, provide various measures for them to reach hospital early, and give reassurance with the best practices adopted in hospitals to avoid contracting the virus from the hospital environment. Yalamanchi R, Dasari BC, Narra L, Oomman A, Kumar P, Nayak R, et al. Cardiac Intensive Care Unit Admissions during COVID-19 Pandemic-A Single Center Experience. Indian J Crit Care Med 2020;24(11):1103-1105.


Effect on Down syndrome screening performance of adjusting for marker levels in a previous pregnancy.
In prenatal screening for Down syndrome, serum marker values can be adjusted using values from a previous pregnancy to avoid the problem of women having a high chance of recurrent false-positive results. We investigate the effect of such adjustment on overall screening performance. Monte Carlo simulation was used to investigate the effect of this adjustment on five widely used screening tests for Down syndrome (Triple, Quadruple, Combined, serum Integrated, Integrated tests). Adjustment for screening marker values (expressed in multiples of the median, (MoM)) in a previous pregnancy improved screening performance. The detection rate for a 1% false-positive rate (FPR) increased from 54 to 59% with the Triple test, from 63 to 68% with the Quadruple test, from 70 [corrected] to 75% for the Combined test, from 70 [corrected] to 76% for the serum Integrated test, and from 85 to 88% for the Integrated test. The FPR for an 85% detection rate decreased from 10 to 7.9%, 7.1 to 4.9%, 4.9 to 3.7%, 4.7 to 2.9% and 1.1 to 0.7% respectively for the five tests. Among women who have had a false-positive result in a previous pregnancy, adjustment substantially lowers the false-positive rate, for example, from 18 [corrected] to 7.3% with the Combined test using a 1 in 250 risk cut-off. MoM adjustment for values in a previous pregnancy improves overall screening performance and substantially reduces the high recurrent false-positive rate. This adjustment can be routinely applied in screening programmes through the screening software used to interpret a woman's screening results.


Mechanical stretch increases the proliferation while inhibiting the osteogenic differentiation in dental pulp stem cells.
Dental pulp stem cells (DPSCs), which can differentiate into several types of cells, are subjected to mechanical stress by jaw movement and occlusal forces. In this study, we evaluated how the uniaxial mechanical stretch influences proliferation and differentiation of DPSCs. DPSCs were isolated and cultured from male Sprague-Dawley rats. Cultured DPSCs were identified by surface markers and the differentiation capabilities as adipocytes or osteoblasts. To examine the response to mechanical stress, uniaxial stretch was exposed to cultured DPSCs. We evaluated the impact of stretch on the intracellular signaling, proliferation, osteogenic differentiation, and gene expressions of DPSCs. Stretch increased the phosphorylation of Akt, ERK1/2, and p38 MAP kinase as well as the proliferation of DPSCs. The stretch-induced proliferation of DPSCs was abolished by the inhibition of the ERK pathway. On the other hand, stretch significantly decreased the osteogenic differentiation of DPSCs, but did not affect the adipogenic differentiation. We also confirmed mRNA expressions of osteocalcin and osteopontin were significantly suppressed by stretch. In conclusion, uniaxial stretch increased the proliferation of DPSCs, while suppressing osteogenic differentiation. These results suggest a crucial role of mechanical stretch in the preservation of DPSCs in dentin. Furthermore, mechanical stretch may be a useful tool for increasing the quantity of DPSCs in vitro for regenerative medicine.


Professional toothbrushing as a method for diagnosing gingivitis in 3- to 6-year-old preschool children.
The aim of the present crossover study was to evaluate professional toothbrushing as a method for diagnosing gingivitis in children. Thirty-four preschool children who had gingival bleeding > or = 10% and without proximal restorations/carious lesions were included in the study. Examinations comprised two gingival indices recorded at a 15-min interval, in the following sequences: the Ainamo and Bay gingival bleeding index (GBI1) followed by the brushing index (BI2) and vice versa (BI1-GBI2). Half of the children started the study in the first sequence and the other half in the second. After a 3- to 4-day washout period, the indices were again recorded with individuals changing the sequences. Data analysis considered GBI as the gold standard, and sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) were also calculated. The overall mean value of gingival bleeding at the first examination was 18.85 +/- 9.24%. Validation of toothbrushing performed after GBI (BI2) resulted in values for SE, SP, PPV and NPV of 0.59 (95% CI, 0.55 to 0.63), 0.92 (95% CI, 0.91 to 0.93), 0.64 (95% CI, 0.60 to 0.69) and 0.90 (95% CI, 0.89 to 0.92), respectively. BI performed before GBI (BI1) resulted in similar SE, SP, PPV and NPV. Percentage agreement of GBI1-BI2 and BI1-GBI2 was 83.5% and 85.9%, respectively. Professional toothbrushing can be suggested as a method for the diagnosis of gingival inflammatory status in children, especially as an indicator of gingival health.


Human herpes virus 8 in solid organ transplantation.
Human herpes virus 8 (HHV-8) is a geographically limited virus that causes neoplastic and nonneoplastic diseases predominantly in endemic regions. Primary HHV-8 infection, which is usually asymptomatic in immunocompetent individuals, result in lifelong latency. When the equilibrium between virus and host immunity is disturbed, such as after organ transplantation, HHV-8 may activate molecular pathways that drive oncogenesis. Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease are the major malignancies associated with HHV-8. The incidences of these neoplastic pathologies mirror the geographic HHV-8 seroprevalence, and certain groups of patients are at higher risk. In this context, the risk of HHV-8 and its clinical disease is highest in immunocompromised patients, including transplant recipients. Solid organ transplant recipients from HHV-8 endemic regions may develop HHV-8 reactivation or primary infection and manifest with Kaposi's sarcoma or less commonly primary effusion lymphoma and Castleman's disease; these neoplastic diseases are reported much less commonly in low-prevalent areas. There is currently no standard method of screening for HHV-8 infection in the transplant setting, although HHV-8 polymerase chain reaction is available to confirm clinical suspicion of infection. Management of HHV-8-associated diseases entails primarily a reduction in the degree of pharmacologic immunosuppression and, in some cases, chemotherapy may be required. The mammalian target of rapamycin inhibitor sirolimus may have the potential for management because of its antiproliferative properties. The role of antiviral drugs for HHV-8 prevention and treatment is yet to be defined.


Geminin is required for Hox gene regulation to pattern the developing limb.
Development of the complex structure of the vertebrate limb requires carefully orchestrated interactions between multiple regulatory pathways and proteins. Among these, precise regulation of 5' Hox transcription factor expression is essential for proper limb bud patterning and elaboration of distinct limb skeletal elements. Here, we identified Geminin (Gmnn) as a novel regulator of this process. A conditional model of Gmnn deficiency resulted in loss or severe reduction of forelimb skeletal elements, while both the forelimb autopod and hindlimb were unaffected. 5' Hox gene expression expanded into more proximal and anterior regions of the embryonic forelimb buds in this Gmnn-deficient model. A second conditional model of Gmnn deficiency instead caused a similar but less severe reduction of hindlimb skeletal elements and hindlimb polydactyly, while not affecting the forelimb. An ectopic posterior SHH signaling center was evident in the anterior hindlimb bud of Gmnn-deficient embryos in this model. This center ectopically expressed Hoxd13, the HOXD13 target Shh, and the SHH target Ptch1, while these mutant hindlimb buds also had reduced levels of the cleaved, repressor form of GLI3, a SHH pathway antagonist. Together, this work delineates a new role for Gmnn in modulating Hox expression to pattern the vertebrate limb.


Subcortical surgical anatomy of the lateral frontal region: human white matter dissection and correlations with functional insights provided by intraoperative direct brain stimulation: laboratory investigation.
Recent neuroimaging and surgical results support the crucial role of white matter in mediating motor and higher-level processing within the frontal lobe, while suggesting the limited compensatory capacity after damage to subcortical structures. Consequently, an accurate knowledge of the anatomofunctional organization of the pathways running within this region is mandatory for planning safe and effective surgical approaches to different diseases. The aim of this dissection study was to improve the neurosurgeon's awareness of the subcortical anatomofunctional architecture for a lateral approach to the frontal region, to optimize both resection and postoperative outcome. Ten human hemispheres (5 left, 5 right) were dissected according to the Klingler technique. Proceeding lateromedially, the main association and projection tracts as well as the deeper basal structures were identified. The authors describe the anatomy and the relationships among the exposed structures in both a systematic and topographical surgical perspective. Structural results were also correlated to the functional responses obtained during resections of infiltrative frontal tumors guided by direct cortico-subcortical electrostimulation with patients in the awake condition. The eloquent boundaries crucial for a safe frontal lobectomy or an extensive lesionectomy are as follows: 1) the motor cortex; 2) the pyramidal tract and premotor fibers in the posterior and posteromedial part of the surgical field; 3) the inferior frontooccipital fascicle and the superior longitudinal fascicle posterolaterally; and 4) underneath the inferior frontal gyrus, the head of the caudate nucleus, and the tip of the frontal horn of the lateral ventricle in the depth. Optimization of results following brain surgery, especially within the frontal lobe, requires a perfect knowledge of functional anatomy, not only at the cortical level but also with regard to subcortical white matter connectivity.


Feeling the future: experimental evidence for anomalous retroactive influences on cognition and affect.
The term psi denotes anomalous processes of information or energy transfer that are currently unexplained in terms of known physical or biological mechanisms. Two variants of psi are precognition (conscious cognitive awareness) and premonition (affective apprehension) of a future event that could not otherwise be anticipated through any known inferential process. Precognition and premonition are themselves special cases of a more general phenomenon: the anomalous retroactive influence of some future event on an individual's current responses, whether those responses are conscious or nonconscious, cognitive or affective. This article reports 9 experiments, involving more than 1,000 participants, that test for retroactive influence by "time-reversing" well-established psychological effects so that the individual's responses are obtained before the putatively causal stimulus events occur. Data are presented for 4 time-reversed effects: precognitive approach to erotic stimuli and precognitive avoidance of negative stimuli; retroactive priming; retroactive habituation; and retroactive facilitation of recall. The mean effect size (d) in psi performance across all 9 experiments was 0.22, and all but one of the experiments yielded statistically significant results. The individual-difference variable of stimulus seeking, a component of extraversion, was significantly correlated with psi performance in 5 of the experiments, with participants who scored above the midpoint on a scale of stimulus seeking achieving a mean effect size of 0.43. Skepticism about psi, issues of replication, and theories of psi are also discussed.


Dual-modal imaging-guided highly efficient photothermal therapy using heptamethine cyanine-conjugated hyaluronic acid micelles.
Targeted phototherapy and multi-modal imaging can effectively improve the therapeutic efficacy and reduce the side effects of theranostics. Herein, we constructed novel biocompatible cyanine dye IR808-conjugated hyaluronic acid nanoparticles (HAIR NPs) for photothermal therapy (PTT) with near-infrared fluorescence (FL) and photoacoustic (PA) dual-modal imaging. The nanoparticles formed stable nanostructures under aqueous conditions with uniform size distribution. The HAIR NPs were rapidly taken up by the human lung cancer cells A549 via CD44 (the hyaluronic acid receptor on the surface of tumor cells) receptor-mediated endocytosis. Upon laser irradiation, the HAIR NPs enabled good near-infrared fluorescence imaging and photoacoustic imaging in tumor-bearing mice. In addition, the tight nanostructure arising from the covalent link between HA and IR808 could significantly improve the light-thermal conversion efficiency of IR808. Under a low dose of laser power, the HAIR NPs presented more effective photothermal therapy for the suppression of tumor growth than free IR808 in vitro and in vivo. Overall, these results indicate that the HAIR NPs may be an extremely promising nanoplatform in cancer theranostics for targeted PTT under FL and PA dual-modal imaging.


Seasonal variation of genotype-specific fertility and adaptation to endemic diseases: a study in past malarial areas of Italy.
Cyclic seasonal variation of genotype-specific fertility could interact with endemic diseases characterized by seasonal variation of severity resulting in changes of gene frequencies in the course of generations. Assuming that a given allele A has a frequency pw in infants conceived in the cold season and a frequency of ps in those conceived in the warm season and assuming that general fertility is the same in the two seasonal periods, the gene frequency in the population is pm = (pw + ps)/2; this frequency remains constant over the course of generations. The introduction of an endemic disease bearing negatively on general fertility and characterized by a seasonal pattern of severity could result in variations of the A allele frequency. If the maximum of endemicity coincides with the maximum value of the allele A frequency, the frequency of allele A will progressively decrease. A simple mathematical algorithm has been applied to two polymorphic enzymes (ACP1 and G6PD) correlated with past malarial morbidity in Sardinia and the Po River delta. The two systems show differences in gene frequency in relation to season of conception. The theoretical changes fit quite well with the data observed in Sardinian and Po delta populations, thus suggesting a mechanism that is an alternative to or concurrent with the classical mechanism that assumes a direct connection between the genetic systems and the biology of the malarial parasite.


Cytotoxic and apoptotic effects of chalcone derivatives of 2-acetyl thiophene on human colon adenocarcinoma cells.
Recent studies report that chalcones exhibit cytotoxicity to human cancer cell lines. Typically, the form of cell death induced by these compounds is apoptosis. In the context of the discovery of new anticancer agents and in light of the antitumour potential of several chalcone derivatives, in the present study, we synthesized and tested the cytotoxicity of six chalcone derivatives on human colon adenocarcinoma cells. Six derivatives of 3-phenyl-1-(thiophen-2-yl) prop-2-en-1-one were prepared and characterized on the basis of their (1) H and (13) C NMR spectra. HT-29 cells were treated with synthesized chalcones on two concentrations by three different incubation times. Cells were evaluated by cell morphology, Tetrazolium dye (MTT) colorimetric assay, live/dead, flow cytometry (annexin V) and gene expression analyses to determine the cytotoxic way. Chalcones 3-(4-bromophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C06) and 3-(2-nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C09) demonstrated higher cytotoxicity than other chalcones as shown by cell morphology, live/dead and MTT assays. In addition, C06 induced apoptosis on flow cytometry annexin V assay. These data were confirmed by a decreased expression of anti-apoptotic genes and increased pro-apoptotic genes. Our findings indicate in summary that the cytotoxic activity of chalcone C06 on colorectal carcinoma cells occurs by apoptosis.


Enhancing nonmass lesions in the breast: evaluation with proton (1H) MR spectroscopy.
To prospectively evaluate the sensitivity and specificity of proton (hydrogen 1 [1H]) magnetic resonance (MR) spectroscopy for diagnosing malignant enhancing nonmass lesions identified at breast MR imaging, with histologic examination as the reference standard. In this HIPAA-compliant, institutional review board-approved study, in which all participants gave written informed consent, proton (1H) MR spectroscopy of the breast was performed in suspicious or biopsy-proved malignant lesions that were 1 cm or larger at MR imaging. Single-voxel proton (1H) MR spectroscopic data were collected. MR spectroscopic findings were defined as positive if the signal-to-noise ratio of the choline resonance peak was 2 or greater and as negative in all other cases. MR spectroscopic results were then compared with histologic findings, and statistical analysis was performed. In 32 women (median age, 48.5 years [range, 20-63 years]) with enhancing nonmass lesions, the median lesion size at MR imaging was 2.8 cm (range, 1.2-9.0 cm). At histologic analysis, 12 (37%) of 32 lesions were malignant and 20 (63%) were benign. Positive choline findings were present in 15 of 32 lesions, including all 12 (100%) cancers and three (15%) of 20 benign lesions, giving proton (1H) MR spectroscopy a sensitivity of 100% (95% confidence interval [CI]: 74%, 100%) and a specificity of 85% (95% CI: 62%, 97%) for detection of enhancing nonmass lesions. For 25 lesions with unknown histologic features, proton (1H) MR spectroscopy would have significantly (P<.01) increased the positive predictive value of biopsy from 20% to 63%. If biopsy had been performed for only those lesions with positive choline findings at proton (1H) MR spectroscopy, biopsy might have been avoided for 17 (68%) of 25 lesions, and no cancers would have been missed. Proton (1H) MR spectroscopy had 100% sensitivity and 85% specificity for the detection of malignancy in enhancing nonmass lesions.


Automated measurement of nitrogen trifluoride in ambient air.
We present an analytical method for the in situ measurement of atmospheric nitrogen trifluoride (NF(3)), an anthropogenic gas with a 100-year global warming potential of over 16,000. This potent greenhouse gas has a rising atmospheric abundance due to its emission from a growing number of manufacturing processes and an expanding end-use market. Here we present a modified version of the "Medusa" preconcentration gas chromatography/mass spectrometry (GC/MS) system of Miller, B. R.; Weiss, R. F.; Salameh, P. K.; Tanhua, T.; Greally, B. R.; Mühle, J.; Simmonds, P. G. Anal. Chem.2008, 80 (5), 1536-1545. By altering the techniques of gas separation and chromatography after initial preconcentration, we are now able to make atmospheric measurements of NF(3) with relative precision <2% (1σ) for current background clean air samples. Importantly, this method augments the currently operational Medusa system, so that the quality of data for species already being measured is not compromised and NF(3) is measured from the same preconcentrated sample. We present the first in situ measurements of NF(3) from La Jolla, California made 11 times daily, illustrating how global deployment of this technique within the AGAGE (Advanced Global Atmospheric Gases Experiment) network could facilitate estimation of global and regional NF(3) emissions over the coming years.


Cancer incidence and mortality in workers exposed to fluoride.
Although a recent bioassay showed increased frequency of bone cancer in rats with high oral intake of fluoride, the data are reported as equivocal evidence of carcinogenicity. In humans, occupational fluoride exposure may cause skeletal fluorosis, and our earlier follow-up of fluoride-exposed workers showed increased incidence of respiratory cancers. To further evaluate occupational fluoride exposure as a carcinogenic risk factor, we extended by approximately one decade the follow-up of a cohort of 425 men and 97 women employed for at least 6 months in the period 1924-1961 at the Copenhagen cryolite processing plant. Cryolite ore contains about 50% fluoride. Cancer mortality was determined for the period 1941-1989, and incidence for 1943-1987. For comparison, we used national mortality rates and cancer incidence rates for the Copenhagen area. Among the men, 300 deaths occurred; 223 were expected. Respiratory (lung and laryngeal) cancers and violent death were responsible for most of this excess; rates for mortality from cardiovascular disease were close to the rates expected. Of the 423 male workers, 119 developed cancers; 103.6 were expected. There was excess incidence of cancers of the lungs (35 men; standard incidence ratio [SIR] = 1.35), larynx (5 men; SIR = 2.29), and urinary bladder (17 men; SIR = 1.84). Maximum incidence occurred after 10-19 years of employment, but otherwise, no stable relationship between cancer incidence and duration of employment was observed. The incidence of respiratory and urinary cancers was particularly high in men less than 35 years old at first employment. Cancers in female workers were too few to allow detailed evaluation. The increased incidence of respiratory cancers suggests that cigarette smoking was frequent in this cohort, despite the unremarkable cardiovascular mortality, but the disproportionate increase in the incidence of bladder cancer is difficult to explain by smoking habits alone. Because this industrial cohort was exposed to high concentrations of fluoride dust, heavy respiratory exposure to fluoride may have contributed to the increased cancer risk. If these workers inhaled a carcinogenic substance partly excreted in the urine, an increased incidence of respiratory and bladder cancers would not be inconceivable. The potential role of fluoride as a cause of bladder cancer needs to be explored.


Prevalence of Mental Disorder and Service Use by Immigrant Generation and Race/Ethnicity Among U.S. Adolescents.
To examine differences in lifetime prevalence of mental disorder and service use among U.S. adolescents by both immigrant generation and race/ethnicity. A total of 6,250 adolescents aged 13 to 18 years in the National Comorbidity Survey Replication Adolescent Supplement were assessed for lifetime prevalence of mood and/or anxiety disorders, behavior disorders, and mental health service use. Twelve groups defined by self-identified race/ethnicity (non-Hispanic white, Hispanic, non-Hispanic black, Asian) and immigrant generation (first, second, third, or more) were compared. Differences in prevalence of lifetime mental disorder were most apparent when immigrant generation and race/ethnicity were considered jointly. Compared to third+generation non-Hispanic white adolescents, the odds of mood/anxiety disorder were increased among second-generation Asian (adjusted odds ratio [AOR] = 2.51; 95% CI = 1.22-5.17) and third+generation Hispanic (AOR = 1.28; 95% CI = 1.00-1.63) but reduced among first-generation Asian (AOR = 0.27; 95% CI = 0.10-0.71) and second-generation non-Hispanic white adolescents (AOR = 0.50; 95% CI = 0.30-0.81). The odds of behavior disorder were lower among first-generation Asian (AOR = 0.26; 95% CI = 0.09-0.71) and all generations of non-Hispanic black adolescents (AOR range 0.43-0.55). Adjusting for lifetime disorder, first-generation Hispanic and non-Hispanic white adolescents and all generations of non-Hispanic black adolescents were less likely to receive mental health services (AOR range 0.24-0.55). Variation in risk of disorder by immigrant generation and race/ethnicity underscores the importance of considering social, economic, and cultural influences in etiologic and treatment studies of adolescent psychopathology. Lower rates of service use, particularly among first-generation immigrant adolescents, highlight the need to identify and address barriers to recognition and treatment of mental disorders among adolescents from immigrant and racial/ethnic minority backgrounds.


Acidification and starch behaviour during co-fermentation of cassava (Manihot esculenta Crantz) and soybean (Glycine max Merr) into gari, an African fermented food.
Changes in acidification and starch behaviour were investigated during co-fermentation of cassava and soybean into gari, an African fermented product. Non-volatile acidity, pH and starch content were evaluated using standard analytical methods. Starch breakdown and pasting characteristics were also analysed using a Brabender viscoamylograph. Fermentation caused significant variations in the pH, non-volatile acidity and starch concentration. The pH decreased with concomitant increases in non-volatile acidity during co-fermentation of the cassava dough. Soy fortification up to 20% caused only minimal effects on the pH, titratable acidity and starch content during the fermentation period. Starch content decreased from 69.8% to 60.4% within the 48 h fermentation time in the unfortified sample, with similar trends noted at all levels of fortification. Starch pasting characteristics showed varied trends in pasting temperature, peak viscosity, viscosity at 95 degrees C and at 50 degrees C-hold with increasing fermentation time and soybean concentration. Cassava could be co-fermented with soybean up to 20% concentration during gari processing without significant effect on its process and product quality characteristics.


Investigating attentional control sets: Evidence for the compilation of multi-feature control sets.
Top-down control over stimulus-driven attentional capture, as postulated by the contingent capture hypothesis, has been a topic of lively scientific debate for a number of years now. According to the latter hypothesis, a stimulus has to match the feature of a top-down established control set in order to be selected automatically. Today, research on the topic of contingent capture has focused mostly on the manipulation of only a single feature separating the target from the distractors (the selection feature). The research presented here examined the compilation of top-down attentional control sets having multiple selection features. We report three experiments in which the feature overlap between the distractor and the top-down sets was manipulated on different perceptual features (e.g., colour, orientation and location). Distractors could match three, two or one of the features of the top-down sets. In line with our hypotheses, the strength of the distractor interference effects decreased linearly as the feature overlap between the distractor and the participants' top-down sets decreased. These results therefore suggest a decline in the efficiency with which distractors involuntarily capture attention as the target-similarity decreases. The data support the idea of multi-feature attentional control sets and are discussed in light of prominent contemporary theories of visual attention.


Death by Suicide in the First Year After Irregular Discharge From Inpatient Hospitalization.
Single-site studies indicate irregular hospital discharges are associated with elevated suicide risk. As part of ongoing analytics in the Veterans Affairs (VA) health system, the authors evaluated associations between irregular discharge and suicide over a 15-year period. All inpatient discharges and discharge types from 2001 through 2014 were identified using VA administrative data. Mortality and cause-of-death data were drawn from comprehensive VA searches of the Centers for Disease Control and Prevention National Death Index. Suicide risk following regular versus irregular discharge was compared by using survival analysis and adjusting for age, gender, and VA facility. Among 5,051,051 discharges, 2.1% (103,995) were irregular. Adjusted suicide risk was higher following irregular discharge compared with regular discharge (hazard ratio [HR]=2.02, 95% confidence interval [CI]=1.78-2.29). Stratified analyses by unit type showed that the association was nonsignificant for psychiatric discharges but significant for general medical discharges (HR=3.01, CI=2.54-3.57). Patients were at increased suicide risk after irregular hospital discharges.