The evidence for Shiatsu: a systematic review of Shiatsu and acupressure.
Shiatsu, similar to acupressure, uses finger pressure, manipulations and stretches, along Traditional Chinese Medicine meridians. Shiatsu is popular in Europe, but lacks reviews on its evidence-base. Acupressure and Shiatsu clinical trials were identified using the MeSH term 'acupressure' in: EBM reviews; AMED; BNI; CINAHL; EMBASE; MEDLINE; PsycARTICLES; Science Direct; Blackwell Synergy; Ingenta Select; Wiley Interscience; Index to Theses and ZETOC. References of articles were checked. Inclusion criteria were Shiatsu or acupressure administered manually/bodily, published after January 1990. Two reviewers performed independent study selection and evaluation of study design and reporting, using standardised checklists (CONSORT, TREND, CASP and STRICTA). Searches identified 1714 publications. Final inclusions were 9 Shiatsu and 71 acupressure studies. A quarter were graded A (highest quality). Shiatsu studies comprised 1 RCT, three controlled non-randomised, one within-subjects, one observational and 3 uncontrolled studies investigating mental and physical health issues. Evidence was of insufficient quantity and quality. Acupressure studies included 2 meta-analyses, 6 systematic reviews and 39 RCTs. Strongest evidence was for pain (particularly dysmenorrhoea, lower back and labour), post-operative nausea and vomiting. Additionally quality evidence found improvements in sleep in institutionalised elderly. Variable/poor quality evidence existed for renal disease symptoms, dementia, stress, anxiety and respiratory conditions. Appraisal tools may be inappropriate for some study designs. Potential biases included focus on UK/USA databases, limited grey literature, and exclusion of qualitative and pre-1989 studies. Evidence is improving in quantity, quality and reporting, but more research is needed, particularly for Shiatsu, where evidence is poor. Acupressure may be beneficial for pain, nausea and vomiting and sleep.


Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes.
Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type 1 diabetes (T1D) in the NOD mouse are on chromosome 1. Idd5.1 is likely accounted for by a synonymous single nucleotide polymorphism in exon 2 of Ctla4: the B10-derived T1D-resistant allele increases the expression of the ligand-independent isoform of CTLA-4 (liCTLA-4), a molecule that mediates negative signaling in T cells. Idd5.2 is probably Nramp1 (Slc11a1), which encodes a phagosomal membrane protein that is a metal efflux pump and is important for host defense and Ag presentation. In this study, two additional loci, Idd5.3 and Idd5.4, have been defined to 3.553 and 78 Mb regions, respectively, on linked regions of chromosome 1. The most striking findings, however, concern the evidence we have obtained for strong interactions between these four disease loci that help explain the association of human CTLA4 with T1D. In the presence of a susceptibility allele at Idd5.4, the CTLA-4 resistance allele causes an 80% reduction in T1D, whereas in the presence of a protective allele at Idd5.4, the effects of the resistance allele at Ctla4 are modest or, as in the case in which resistance alleles at Idd5.2 and Idd5.3 are present, completely masked. This masking of CTLA-4 alleles by different genetic backgrounds provides an explanation for our observation that the human CTLA-4 gene is only associated with T1D in the subgroup of human T1D patients with anti-thyroid autoimmunity.


Bis(σ-B-H) complexes of copper(i): precursors to a heterogeneous amine-borane dehydrogenation catalyst.
A series of bis(σ-B-H) complexes of copper(i) have been prepared by displacement of arene solvent from a β-diketiminate copper(i) complex by four-coordinate boranes, H3B-L (L = NMe3, lutidine). In the presence of the same copper arene complex, the secondary amine-borane H3B-NMe2H undergoes dehydrogenation. We provide evidence for formation of a heterogengous catalyst from decomposition of the solution species.


Comparing the biological and cultural inheritance of personality and social attitudes in the Virginia 30,000 study of twins and their relatives.
Measures of four dimensions of personality (Psychoticism, Extraversion, Neuroticism, and Lie scores) and six aspects of social attitudes (to sex, taxation, militarism, politics, religion and a general conservatism scale) were obtained by mailed questionnaire from 29,691 US subjects including adult twins (n = 14,761) their parents (n = 2360), their spouses (n = 4391), siblings (n = 3184) and adult children (n = 4800). After correction for the average effects of age, sex and source of sample, familial correlations were computed for 80 distinct biological and social relationships. The data allow for the estimation of the additive and non-additive effects of genes, assortative mating, vertical cultural inheritance and other non-parental effects of the shared environment on differences in personality and social attitudes. The interaction of genetic and environmental effects with sex may also be analyzed. Model-fitting analyses show that personality and social attitude measures differ markedly in major features of family resemblance. Additive and dominant genetic effects contribute to differences in both personality and attitudes, but the effects of the family environment, including vertical cultural transmission from parent to child, are much more marked for social attitudes than for personality. There is substantial assortative mating for social attitudes and almost none for personality. The causes of family resemblance depend significantly on sex for almost every variable studied. These findings clarify and extend the more tentative findings derived from previous twin, family and adoption studies.


High-risk screening: multi-modality surveillance of women at high risk for breast cancer (proven or suspected carriers of a breast cancer susceptibility gene).
Familial breast cancer accounts for about 10% of all breast cancer cases. Subjects with mutations in one of the breast cancer susceptibility genes face an about 90% lifetime risk to develop breast cancer. In addition, more than half of the patients will develop breast cancer already before the age of 50, and a significant number even before the age of 35. Screening for familial breast cancer needs to start, therefore, at the age of 30. Detection and differential diagnosis of breast cancer in such a young patient cohort is difficult to achieve with mammography. Our experience with a multi-modality screening program tailored to the needs of these specific high-risk individuals are reviewed in this article. Our data suggest that the prospective use of breast MR imaging offers a substantial increase in tumor detection rates compared to the combined use of two-view mammography and state-of-the-art breast US. Interestingly, the considerable improvement in diagnostic sensitivity as offered by breast MRI was not traded off by a reduced specificity. On the contrary, MRI helped avoid many unnecessary biopsies that have been caused by false-positive high-frequency breast ultrasound findings.


Maternal renal and interlobar arteries waveforms evaluation with color Doppler ultrasound in pregnancy-induced hypertension.
The authors performed a color Doppler ultrasound examination of both renal and interlobar arteries of 15 pregnant women affected by pregnancy-induced hypertension. The pulsatility index (PI), the resistance index (RI) and the systolic/diastolic ratio (S/D) values were compared with those of 15 healthy pregnant women of the same gestational age and with those of 15 nonpregnant healthy women. The authors found a significant difference (p < 0.0001) for all parameters investigated in renal and interlobar arteries between healthy pregnant women and the other two groups. No difference was found between patients with pregnancy-induced hypertension and nonpregnant healthy women. In conclusion, color Doppler ultrasound examination of both renal and interlobar arteries seems to be important for understanding the etiopathogenesis of pregnancy-induced hypertension.


Cyclin A1 shows age-related expression in benign tonsils, HPV16-dependent overexpression in HNSCC and predicts lower recurrence rate in HNSCC independently of HPV16.
Promoter methylation of the tumor suppressor gene Cyclin A1 could be associated with Human Papillomavirus 16 (HPV16) induced Head and Neck Squamous Cell Carcinoma (HNSCC) and Cervical Carcinoma. There is disagreement about the impact of this epigenetic event on protein expression of Cyclin A1 in malignant and non-malignant tissue and there hardly exists any information about possible relationships between Cyclin A1 expression and clinicopathological characteristics in HNSCC. We analyzed protein expression of Cyclin A1 in 81 HNSCC and 74 benign tonsils by immunohistochemistry and correlated it to Cyclin A1 methylation status, presence of HPV16 infection and other clinicopathological characteristics. Overexpression of Cyclin A1 was more present in HNSCC than in tonsils (p < 0.001). In both entities, HNSCC and benign tonsils, expression of Cyclin A1 significantly correlated with the expression of Cyclin-dependent kinase-inhibitor p16 (p = 0.000672 and 0.00495). In tonsils, expression of Cyclin A1 was inversely proportional to age (p = 0.00000396), and further correlated with expression of tumor suppressor gene p53 (p = 0.000228). In HNSCC Cyclin A1 expression was associated with the presence of HPV16 DNA (p = 0.0014) and a lower recurrence rate in univariate and multivariate analysis (p = 0.002 and 0.013). Neither in HNSCC nor in tonsils Cyclin A1 expression correlated with promoter methylation. Cyclin A1 is an important cell cycle regulator with age-related increased expression in tonsils of children. HPV16 induces overexpression of Cyclin A1 in HNSCC despite promoter methylation. Overexpression of Cyclin A1 predicts a lower recurrence rate in HNSCC independently of HPV16.


Genetic variation of polygenic characters and the evolution of genetic degeneracy.
The classical model of mutation-selection balance for quantitative characters sums the effects of individual sites to determine overall character value. I develop an alternative version of this classical model in which character value depends on the averaging of the effects of the individual sites. In this new averaging model, the equilibrium patterns of variance in allelic effects and character values change with the number of sites that affect a character in a different way from the classical model of summing effects. Besides changing the patterns of variance, the averaging model favours the addition of loci to the control of character values, perhaps explaining in part the recent observation of widespread genetic degeneracy.


Different approaches to relating genotype to phenotype in developmental disorders.
In this article, we discuss the complex problem of relating genotype to phenotype and challenge the simple mapping of genes to higher level cognitive modules. We examine various methods that have been used to investigate this relation including quantitative genetics, molecular genetics, animal models, and in-depth psychological and computational studies of developmental disorders. Both single gene and multiple gene disorders indicate that the relationship between genotype and phenotype is very indirect and that, rather than identifying mere snapshots of developmental outcomes, the process of ontogenetic development itself must be taken into account.


Effects of Genistein and Synergistic Action in Combination with Tamoxifen on the HepG2 Human Hepatocellular Carcinoma Cell Line
Introduction: The flavonoids comprise a diverse group of polyphenolic compounds with antioxidant activity that is present in edible plants like soybeans and soy products. In vivo studies have concentrated on the effects of flavonoids on cancer and genistein (GE), a soy-derived isoflavone, has been reported to reduce prostate, colon, hepatic and breast adenocarcinoma risk. Tamoxifen (TAM) is an important drug for cancer treatment worldwide, which can induce apoptosis in various cancers, including examples in the liver, breast and ovaries. The aim of the present study was to evaluate the effects of GE and TAM, alone and in combination, on proliferation and apoptosis in the human hepatocellular carcinoma (HCC) HepG2 cell line. Materials and Methods: HepG 2 cells were treated with GE, TAM and GE/TAM and then MTT and flow cytometry assays were conducted to determine effects on viability and apoptosis, respectively. Results: GE and TAM inhibited cell proliferation and induced apoptosis in the HepG 2 cell lines. Discussion: Our findings clearly indicated that GE and TAM may exert inhibitory and apoptotic effects in liver cancer cells. Conclusion: GE and TAM can significantly inhibit growth of HCC cells and play a significant role in apoptosis.


Toxin Degradation by Rumen Microorganisms: A Review.
Animal feeds may contain exogenous compounds that can induce toxicity when ruminants ingest them. These toxins are secondary metabolites originating from various sources including plants, bacteria, algae and fungi. Animal feed toxins are responsible for various animal poisonings which negatively impact the livestock industry. Poisoning is more frequently reported in newly exposed, naïve ruminants while 'experienced' ruminants are observed to better tolerate toxin-contaminated feed. Ruminants can possess detoxification ability through rumen microorganisms with the rumen microbiome able to adapt to utilise toxic secondary metabolites. The ability of rumen microorganisms to metabolise these toxins has been used as a basis for the development of preventative probiotics to confer resistance against the poisoning to naïve ruminants. In this review, detoxification of various toxins, which include plant toxins, cyanobacteria toxins and plant-associated fungal mycotoxins, by rumen microorganisms is discussed. The review will include clinical studies of the animal poisoning caused by these toxins, the toxin mechanism of action, toxin degradation by rumen microorganisms, reported and hypothesised detoxification mechanisms and identified toxin metabolites with their toxicity compared to their parent toxin. This review highlights the commercial potential of rumen inoculum derived probiotics as viable means of improving ruminant health and production.


Further support for the alignment of cattle along magnetic field lines: reply to Hert et al.
Hert et al. (J Comp Physiol A, 2011) challenged one part of the study by Begall et al. (PNAS 105:13451-13455, 2008) claiming that they could not replicate the finding of preferential magnetic alignment of cattle recorded in aerial images of Google Earth. However, Hert and co-authors used a different statistical approach and applied the statistics on a sample partly unsuitable to examine magnetic alignment. About 50% of their data represent noise (resolution of the images is too poor to enable unambiguous measurement of the direction of body axes, pastures are on slopes, near settlements or high voltage power-lines, etc.). Moreover, the authors have selected for their analysis only ~ 40% of cattle that were present on the pastures analyzed. Here, we reanalyze all usable data and show that cattle significantly align their body axes in North-South direction on pastures analyzed by Hert and co-authors. This finding thus supports our previous study. In addition, we show by using aerial Google Earth images with good resolution, that the magnetic alignment is more pronounced in resting than in standing cattle.


Cloning the mouse homolog of the human cystic fibrosis transmembrane conductance regulator gene.
The cystic fibrosis transmembrane conductance regulator is encoded by the gene known to be mutated in patients with cystic fibrosis. This paper reports the cloning and sequencing of cDNAs for the murine homolog of the human cystic fibrosis transmembrane conductance regulator gene. A clone that, by analogy to the human sequence, extends 3' from exon 9 to the poly(A) tail was isolated from a mouse lung cDNA library. cDNA clones containing exons 4 and 6b were also isolated and sequenced, but the remainder of the mRNA proved difficult to obtain by conventional cDNA library screening. Sequences spanning exons 1-9 were cloned by PCR from mouse RNA. The deduced mouse protein sequence is 78% identical to the human cystic fibrosis transmembrane regulator, with higher conservation in the transmembrane and nucleotide-binding domains. Amino acid sequences in which known cystic fibrosis missense mutations occur are conserved between man and mouse; in particular, the predicted mouse protein has a phenylalanine residue corresponding to that deleted in the most common human cystic fibrosis mutation (delta F508), which should allow the use of transgenic strategies to introduce this mutation in attempts to create a "cystic fibrosis mouse".


Transcriptomic analysis of Bama pig's liver in various nutritional states reveals a metabolic difference of fatty acids.
Both fasting and treatment with a high-fat diet (HFD) can dramatically change fat metabolism in the liver and, thus, are commonly used methods to investigate hepatic fat metabolism and related diseases. Here, the gene expression profiles of pig liver under both conditions were investigated and changes in hepatic triacylglycerol (TG) levels under different diet conditions were determined. In this study, both fasting and HFD conditions significantly increased hepatic TG levels and serum levels of cholesterol, TG, high-density lipoprotein, low-density lipoprotein, and apolipoprotein B. Transcriptome sequencing analysis identified 580 differentially expressed genes (DEGs) between the fasting group and the control group (F/C group) and 613 between the HFD group and the control group (H/C group). Kyoto Encyclopedia of Genes and Genomes enrichment analysis found that the DEGs of the F/C group were mainly enriched in the synthesis pathways of fatty acids (FAs) with less than 16 carbons, while the DEGs of the H/C group were mainly enriched in the synthesis pathways of FAs with more than 16 carbons. In order to verify whether changes in the expression levels of the DEGs caused changes in FA metabolism, the composition and saturation of the FAs in liver TG were analyzed, which showed that under fasting conditions, the contents of monounsaturated and polyunsaturated FAs had increased, while the proportion of saturated FAs had decreased. However, the content of polyunsaturated FAs decreased, while the contents of monounsaturated and saturated FAs increased under HFD conditions. These results will help clarify the differences in FA metabolism in the liver under different nutritional states and indicate that the proportion of unsaturated FAs had increased in hepatic fat under fasting conditions.


Dynamic balance of excitation and inhibition rapidly modulates spike probability and precision in feed-forward hippocampal circuits.
Feed-forward inhibitory (FFI) circuits are important for many information-processing functions. FFI circuit operations critically depend on the balance and timing between the excitatory and inhibitory components, which undergo rapid dynamic changes during neural activity due to short-term plasticity (STP) of both components. How dynamic changes in excitation/inhibition (E/I) balance during spike trains influence FFI circuit operations remains poorly understood. In the current study we examined the role of STP in the FFI circuit functions in the mouse hippocampus. Using a coincidence detection paradigm with simultaneous activation of two Schaffer collateral inputs, we found that the spiking probability in the target CA1 neuron was increased while spike precision concomitantly decreased during high-frequency bursts compared with a single spike. Blocking inhibitory synaptic transmission revealed that dynamics of inhibition predominately modulates the spike precision but not the changes in spiking probability, whereas the latter is modulated by the dynamics of excitation. Further analyses combining whole cell recordings and simulations of the FFI circuit suggested that dynamics of the inhibitory circuit component may influence spiking behavior during bursts by broadening the width of excitatory postsynaptic responses and that the strength of this modulation depends on the basal E/I ratio. We verified these predictions using a mouse model of fragile X syndrome, which has an elevated E/I ratio, and found a strongly reduced modulation of postsynaptic response width during bursts. Our results suggest that changes in the dynamics of excitatory and inhibitory circuit components due to STP play important yet distinct roles in modulating the properties of FFI circuits.


Prevalence and correlates of HIV and sexually transmitted infections among female sex workers and their non-commercial male partners in two Mexico-USA border cities.
Female sex workers (FSWs) acquire HIV and other sexually transmitted infections (STIs) through unprotected sex with commercial and non-commercial (intimate) male partners. Little research has focused on FSWs' intimate relationships, within which condom use is rare. We sought to determine the prevalence and correlates of HIV/STIs within FSWs' intimate relationships in Northern Mexico. From 2010 to 2011, we conducted a cross-sectional survey of FSWs and their non-commercial male partners in Tijuana and Ciudad Juárez, Mexico. Eligible FSWs and their verified male partners were aged ≥18 years; FSWs reported lifetime use of heroin, cocaine, crack, or methamphetamine and recently exchanged sex (past month). Participants completed baseline questionnaires and testing for HIV, chlamydia, gonorrhea, and syphilis. We determined the prevalence and correlates of individuals' HIV/STI positivity using bivariate probit regression. Among 212 couples (n = 424), prevalence of HIV was 2.6 % (n = 11). Forty-two (9.9 %) tested positive for any HIV/STIs, which was more prevalent among women than men (12.7 % vs. 7.1 %, p < 0.05). FSWs with regular sex work clients were less likely to test positive for HIV/STIs than those without regular clients. Similarly, male partners of FSWs who had regular clients were 9 % less likely to have HIV/STIs. Higher sexual decision-making power was protective against HIV/STIs for women. Men who recently used methamphetamine or reported perpetrating any conflict within steady relationships were more likely to test positive for HIV/STIs. Within FSWs' intimate relationships in two Mexican-US border cities, nearly one in ten partners tested positive for HIV/STIs. Couple-based prevention interventions should recognize how intimate relationship factors and social contexts influence HIV/STI vulnerability.


Hydrogen-rich saline protects against small-scale liver ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress.
Our research investigated the role of Hydrogen-rich saline (HRS) on the Endoplasmic reticulum stress (ERS) pathway and the effect of HRS on tissue injury in small Bama pig model of hepatic ischemia-reperfusion combined with partial hepatectomy. Eighteen healthy Bama miniature pigs were randomly divided equally into three groups: Sham, IRI, and HRS. Laparoscopic technique was employed to establish the model of hepatic ischemia-reperfusion combined with partial hepatectomy. HRS (10mL/kg) was injected into the portal vein 10min before perfusion. Histological examinations of the liver tissues were performed after HE staining. Additionally, transmission electron microscopy was performed to detect liver cell microstructure. Real-time PCR, Western blotting, and immunohistochemical staining were performed to analyze various ERS molecules including GRP78, p-eIF2α, XBP-1s, Full-length ATF6α, p-JNK, ATF4, and CHOP. We observed that HRS visibly improved ischemia-reperfusion injury (IRI) by reducing various parameters of ERS stress as evidenced by down-regulation of the mRNA as well as protein levels of GRP78, p-eIF2α, XBP-1s, p-JNK, and CHOP, and reducing the cleavage of Full-length ATF6α. Our study demonstrates that HRS protects the liver from IRI by inhibiting ERS.


Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects.
The closure of the neural tube (NT) in the human embryo has generally been described as a continuous process that begins at the level of the future cervical region and proceeds both rostrally and caudally. On the other hand, multiple initiation sites of NT closure have been demonstrated in mice and other animals. In humans, based on the study of neural tube defects (NTD) in clinical cases, van Allen et al. (1993) proposed a multisite NT closure model in which five closure sites exist in the NT of human embryos. In the present study, we examined human embryos in which the NT was closing (Congenital Anomaly Research Center, Kyoto University) grossly and histologically, and found that NT closure in human embryos initiates at multiple sites but that the mode of NT closure in humans is different from that in many other animal species. In addition to the future cervical region that is widely accepted as an initiation site of NT closure (Site A), the mesencephalic-rhombencephalic boundary was found to be another initiation site (Site B). The second closure initiating at Site B proceeds bidirectionally and its caudal extension meets the first closure from Site A over the rhombencephalon, and the rostral extension of the second closure meets another closure extending from the rostral end of the neural groove (Site C) over the prosencephalon, where the anterior neuropore closes. The caudal extension of the first closure initiating at Site A was found to proceed all the way down to the caudal end of the neural groove where the posterior neuropore is formed, indicating that in humans, NT closure does not initiate at the caudal end of the neural groove to proceed rostrally. Since there is a considerable species difference in the mode of NT closure, we should be careful when extrapolating the data from other animals to the human. It seems that the type of NTD affects the intrauterine survival of abnormal embryos. Almost all the embryos with total dysraphism appear to die by 5 weeks of gestation, those with an opening over the rhombencephalon by 6.5 weeks, and those with a defect at the frontal and parietal regions survive beyond 7 weeks.


Enzymatic generation of hydrogen peroxide shows promising antifouling effect.
The antifouling (AF) potential of hydrogen peroxide (H(2)O(2)) produced enzymatically in a coating containing starch, glucoamylase, and hexose oxidase was evaluated in a series of laboratory tests and in-sea field trials. Dissolved H(2)O(2) inhibited bacterial biofilm formation by eight of nine marine Proteobacteria, tested in microtiter plates. However, enzymatically produced H(2)O(2) released from a coating did not impede biofilm formation by bacteria in natural seawater tested in a biofilm reactor. A field trial revealed a noticeable effect of the enzyme system: after immersion in the North Sea for 97 days, the reference coating without enzymes had 35-40 barnacles, 10% area coverage by diatoms and 15% area coverage by tunicates. The enzyme containing coating had only 6-12 barnacles, 10% area coverage by diatoms and no tunicates. The enzyme system had a performance similar to a copper-based commercial coating and thus appears to have potential as a non-persistent AF agent.


Short day transcriptomic programming during induction of dormancy in grapevine.
Bud dormancy in grapevine is an adaptive strategy for the survival of drought, high and low temperatures and freeze dehydration stress that limit the range of cultivar adaptation. Therefore, development of a comprehensive understanding of the biological mechanisms involved in bud dormancy is needed to promote advances in selection and breeding, and to develop improved cultural practices for existing grape cultivars. The seasonally indeterminate grapevine, which continuously develops compound axillary buds during the growing season, provides an excellent system for dissecting dormancy, because the grapevine does not transition through terminal bud development prior to dormancy. This study used gene expression patterns and targeted metabolite analysis of two grapevine genotypes that are short photoperiod responsive (Vitis riparia) and non-responsive (V. hybrid, Seyval) for dormancy development to determine differences between bud maturation and dormancy commitment. Grapevine gene expression and metabolites were monitored at seven time points under long (LD, 15 h) and short (SD, 13 h) day treatments. The use of age-matched buds and a small (2 h) photoperiod difference minimized developmental differences and allowed us to separate general photoperiod from dormancy specific gene responses. Gene expression profiles indicated three distinct phases (perception, induction and dormancy) in SD-induced dormancy development in V. riparia. Different genes from the NAC DOMAIN CONTAINING PROTEIN 19 and WRKY families of transcription factors were differentially expressed in each phase of dormancy. Metabolite and transcriptome analyses indicated ABA, trehalose, raffinose and resveratrol compounds have a potential role in dormancy commitment. Finally, a comparison between V. riparia compound axillary bud dormancy and dormancy responses in other species emphasized the relationship between dormancy and the expression of RESVERATROL SYNTHASE and genes associated with C3HC4-TYPE RING FINGER and NAC DOMAIN CONTAINING PROTEIN 19 transcription factors.


In vivo cortical diffusion imaging relates to Alzheimer's disease neuropathology.
There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed. Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.


Inward rectification in KATP channels: a pH switch in the pore.
Inward-rectifier potassium channels (Kir channels) stabilize the resting membrane potential and set a threshold for excitation in many types of cell. This function arises from voltage-dependent rectification of these channels due to blockage by intracellular polyamines. In all Kir channels studied to date, the voltage-dependence of rectification is either strong or weak. Here we show that in cardiac as well as in cloned KATP channels (Kir6.2 + sulfonylurea receptor) polyamine-mediated rectification is not fixed but changes with intracellular pH in the physiological range: inward-rectification is prominent at basic pH, while at acidic pH rectification is very weak. The pH-dependence of polyamine block is specific for KATP as shown in experiments with other Kir channels. Systematic mutagenesis revealed a titratable C-terminal histidine residue (H216) in Kir6.2 to be the structural determinant, and electrostatic interaction between this residue and polyamines was shown to be the molecular mechanism underlying pH-dependent rectification. This pH-dependent block of KATP channels may represent a novel and direct link between excitation and intracellular pH.


[Complement terminal fraction deficiency revealed at first invasive meningococcal infection].
Prevalence of complement protein deficiency in the general population is rare and its association with an increased risk of meningococcal infection is well established. However, management of these patients with potentially serious infections and indications warranting a search for such a deficiency have not met with consensus. We report the case of a 3-year-old child with no significant medical history who consulted in an emergency department for a fever after a stay in Senegal. Medical explorations concluded in septicemia and meningococcal W meningitis with a favorable outcome. Secondarily, we highlighted a complete deficiency of complement component C6. We diagnosed the same deficit in his twin sister who presented no infection. A long-term prophylactic antibiotic therapy and a meningococcal conjugate vaccine A,C,Y,W were set up for the twins. Recurrent invasive meningococcal infections and highlighting certain meningococcal serogroups are currently indications for complement protein exploration. We suggest expanding the search criteria for a complement protein deficiency after a single event of invasive meningococcal infection. This is an easy, rapid, and cost-effective screening system by dosage of CH50, C3, C4, and AP50. The arrival of the new meningococcal B vaccine will contribute to improving these patients' care. Family screening is necessary for prophylactic therapy.


Improvement strategies in ovine artificial insemination.
Artificial insemination in ram is scarcely widespread comparing with other domestic species. This has been due not only to fertility results being irregular and low but also because of the difficulty in the application of enhancements such as the use of frozen-thawed sperm. Although there is a lot of information on the use of different options to improve these AI results (such as transcervical application, the use of thawed sperm, etc.) commercial programmes can be classified on two general categories: those using refrigerated semen (15 degrees C) by superficial intracervical deposition (vaginal), and, more restricted, those using thawed sperm by intrauterine deposition (laparoscopy). In the present work, we have summarized our viewpoint on three general research lines for the improvement of AI results in sheep: semen preservation, AI procedures and semen assessment. Briefly, in ram it is necessary to develop a medium term methodology of sperm refrigeration (3-5 days), which would allow the distribution of sperm doses to a widespread area. Nevertheless, it is also necessary to develop an intrauterine transcervical AI technique, which allows thawed semen to be applied by vaginal insemination. Besides, the low predictive value of classic assessment techniques limits the ability to adjust the number of spermatozoa per dose according to its actual fertility.


Current practices in the use of sildenafil for pulmonary arterial hypertension in Brazilian hospitals.
Sildenafil is a cyclic guanosine monophosphate-specific phosphodiesterase-5 inhibitor used for treating pulmonary hypertension. Although the use of sildenafil in patients under 18 years old is off-label, this inhibitor has been widely prescribed for children treatment at hospitals in Brazil. In this work we evaluated the current practices in using sildenafil in the three main reference hospitals of Rio de Janeiro to design a clinical trial. Then we analyzed the content of sildenafil in powder paper preparations used in these institutions. We assessed the data about the use of sildenafil in three reference hospitals including Instituto Nacional de Cardiologia - INC, Instituto Estadual de Cardiologia Aloysio de Castro - IECAC and Hospital Pro-Cardíaco - HPC. The pharmacy records were analyzed from April 1st, 2008 to April 30th, 2008 and interviews with the pharmacists were also performed. Our results showed that INC used the greatest amount of sildenafil in: treatment of pulmonary arterial hypertension (PAH), management of transient PAH during surgery, preparation for cardiac transplantation and haemodynamic studies during cardiac catheterization. Meanwhile IECAC and HPC used sildenafil only for treating PAH in few patients during the period evaluated. In INC and IECAC, sildenafil was available in tablets, and powder papers prepared by two private pharmacies and one public hospital pharmacy. In contrast all patients of HPC received sildenafil in tablets with no external manipulation. Our quantification analysis results using reverse-phase high performance liquid chromatography method showed that powder papers prepared by the private pharmacies from the sildenafil tablets presented only 58.5 to 89.3% of the declared concentration in contrast to samples from the public hospital pharmacy (104.4 to 105.3%). Few patients received the prescribed sildenafil dose at the reference hospitals evaluated in Rio de Janeiro, which may importantly compromise this inhibitor effect in the current treatment. This study reinforced the need of checking the practices of preparing and administering sildenafil continually.


Cyclic di-adenosine monophosphate (c-di-AMP) is required for osmotic regulation in Staphylococcus aureus but dispensable for viability in anaerobic conditions.
Cyclic di-adenosine monophosphate (c-di-AMP) is a recently discovered signaling molecule important for the survival of Firmicutes, a large bacterial group that includes notable pathogens such as Staphylococcus aureus However, the exact role of this molecule has not been identified. dacA, the S. aureus gene encoding the diadenylate cyclase enzyme required for c-di-AMP production, cannot be deleted when bacterial cells are grown in rich medium, indicating that c-di-AMP is required for growth in this condition. Here, we report that an S. aureus dacA mutant can be generated in chemically defined medium. Consistent with previous findings, this mutant had a severe growth defect when cultured in rich medium. Using this growth defect in rich medium, we selected for suppressor strains with improved growth to identify c-di-AMP-requiring pathways. Mutations bypassing the essentiality of dacA were identified in alsT and opuD, encoding a predicted amino acid and osmolyte transporter, the latter of which we show here to be the main glycine betaine-uptake system in S. aureus. Inactivation of these transporters likely prevents the excessive osmolyte and amino acid accumulation in the cell, providing further evidence for a key role of c-di-AMP in osmotic regulation. Suppressor mutations were also obtained in hepS, hemB, ctaA, and qoxB, coding proteins required for respiration. Furthermore, we show that dacA is dispensable for growth in anaerobic conditions. Together, these findings reveal an essential role for the c-di-AMP signaling network in aerobic, but not anaerobic, respiration in S. aureus.


Spatial pattern of myosin phosphorylation in contracting smooth muscle cells: evidence for contractile zones.
We have purified a polyclonal antibody by affinity chromatography which binds specifically to the phosphorylated form of the regulatory light chain (Mr = 20,000) of smooth muscle myosin. This antibody does not stain relaxed, permeabilized smooth muscle cells isolated from guinea pig taenia coli. However, when these cells were stimulated to contract with CaCl2 (100 microM) and ATP (1 mM), the immunofluorescence staining was localized in a series of transverse bands. This distribution of activated myosin appears to reflect an underlying structural organization of the smooth muscle cell cytoskeleton into mechanically coupled contractile zones.


Disorders of puberty.
Normal puberty begins between eight and 14 years of age in girls and between nine and 14 years of age in boys. Pubic hair distribution is used to stage puberty, along with breast size and contour in girls and testicular volume in boys. Some children experience constitutional sexual precocity, but precocity is likely to be pathologic if it occurs in very young children, if there is contrasexual development or if the sequence of normal pubertal milestones is disrupted. Delayed puberty may be constitutional, but pathologic causes should be considered. The etiology of a pubertal disorder can often be determined with the use of a focused medical history, a directed physical examination and appropriate diagnostic tests. Treatment for disorders of puberty is determined by the underlying cause.


Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks.
C1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation. To assess the effect of time to treatment (<6 vs ≥6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy. A post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open-label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies. In IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment. Early treatment with C1-INH (<6 hours) provides a better treatment response than late treatment (≥6 hours), supporting the international recommendation to treat HAE attacks as early as possible. ClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981.


Mitotic regulation of the human anaphase-promoting complex by phosphorylation.
The anaphase-promoting complex (APC) or cyclosome is a ubiquitin ligase that initiates anaphase and mitotic exit. APC activation is thought to depend on APC phosphorylation and Cdc20 binding. We have identified 43 phospho-sites on APC of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7. In vitro, at least 15 of the mitotic phospho-sites can be generated by cyclin-dependent kinase 1 (Cdk1), and 3 by Polo-like kinase 1 (Plk1). APC phosphorylation by Cdk1, but not by Plk1, is sufficient for increased Cdc20 binding and APC activation. Immunofluorescence microscopy using phospho-antibodies indicates that APC phosphorylation is initiated in prophase during nuclear uptake of cyclin B1. In prometaphase phospho-APC accumulates on centrosomes where cyclin B ubiquitination is initiated, appears throughout the cytosol and disappears during mitotic exit. Plk1 depletion neither prevents APC phosphorylation nor cyclin A destruction in vivo. These observations imply that APC activation is initiated by Cdk1 already in the nuclei of late prophase cells.


Genetic and Environmental Contributions to the Association Between Cannabis Use and Psychotic-Like Experiences in Young Adult Twins.
To investigate contributions of genetic and environmental risk factors and possible direction of causation for the relationship between symptoms of cannabis use disorders (CUD) and psychotic-like experiences (PLEs), a population-based sample of 2793 young adult twins (63.5% female, mean [range] age 28.2 [19-36] y) were assessed for symptoms of CUD and PLEs using the Composite International Diagnostic Interview. Latent risk of having symptoms of CUD or PLEs was modeled using Item Response Theory. Co-twin control analysis was performed to investigate effect of familiar confounding for the association between symptoms of CUD and PLEs. Biometric twin models were fitted to estimate the heritability, genetic and environmental correlations, and direction for the association. Lifetime use of cannabis was reported by 10.4 % of the twins, and prevalence of PLEs ranged from 0.1% to 2.2%. The incidence rate ratio of PLEs due to symptoms of CUD was 6.3 (95% CI, 3.9, 10.2) in the total sample and 3.5 (95% CI, 1.5, 8.2) within twin pairs. Heritability estimates for symptoms of CUD were 88% in men and women, and for PLEs 77% in men and 43% in women. The genetic and environmental correlations between symptoms of CUD and PLEs were 0.55 and 0.52, respectively. The model allowing symptoms of CUD to cause PLEs had a better fit than models specifying opposite or reciprocal directions of causation. The association between symptoms of CUD and PLEs is explained by shared genetic and environmental factors and direct effects from CUD to risk for PLEs.


Hepatitis C virus: molecular and epidemiological evidence of male-to-female transmission.
There is general consensus that hepatitis C virus is efficiently transmitted by the parenteral route, whereas data on viral transmission by sexual or non-sexual intrafamilial contact are conflicting. The aim of this study was to investigate the transmission of hepatitis C virus in nine heterosexual couples. The mean age of the couples was 43.7 years. When interviewed, all of the women denied the presence of risk factors for acquisition of the infection, whereas the cause of infection in the nine husbands could be attributed to blood transfusions in two of them (22.2%), use of intravenous and inhaled drugs in six (66.7%), acupuncture in one (11.1%), and tattooing in one (11.1%). All men and none of the women reported sexual relations with sex professionals. The mean homology score (Non Structural 5b-hepatitis C virus) was 98.4%. Among the nine couples with matching subtypes, one (11.1%) was infected with subtype 1a, three (33.3%) with subtype 1b, and five (55.5%) with subtype 3a. Shared personal hygiene items showed a much higher correlation with the possible route of transmission and were better supported by the sequence homology data than the other associated risk factors. Three (33.3%) couples shared toothbrushes, seven (77.8%) shared razor blades, eight (88.8%) shared nail clippers, and six (66.7%) shared manicure cutters. Sharing of personal hygiene items was a confounding factor in the discussion of sexual hepatitis C virus transmission and the hypothesis of male-to-female transmission was supported in this study.


Epidemiology of invasive meningococcal disease in France in 2003.
National surveillance of invasive meningococcal disease (IMD) is based on mandatory reporting. The case definition for surveillance notification was changed in mid-2002 to include cases without microbiological confirmation. The IMD alert detection system was enhanced in 2003 with daily reporting and weekly analysis by district, serogroup, and age. Evaluation of the exhaustivity of the surveillance with capture-recapture analysis allowed correcting for underreporting. In 2003, 803 cases were reported. After correction for under-reporting, the estimated incidence was 1.78 / 100 000. After excluding 'new' cases reported with new definition criteria, the 2002-2003 increase was 4%. Incidence decreased with age, with the highest values in infants less than 1 year (20/100 000), children aged between 1 and 2 years (11/100 000) and in teenagers of 17 years old(7/100 000). The overall case fatality rate was 12%. Fifty nine per cent of cases were due to serogroup B, 32% to C, 5% to W135, and 4% to Y and non-groupable meningococci. Patients with purpura fulminans treated with intravenous antibiotics before admission to hospital were shown to have lower fatality rates than those not treated. In 2001-2003, 5 situations required particular attention: two clusters of serogroup B IMD had set off mass prophylaxis, one outbreak due to a specific B IMD clonal complex with high case fatality rate, and two districts crossed the alert threshold for serogroup C IMD, 2/100 000, and mass vaccination was recommended.


Physician communication about the cost and acquisition of newly prescribed medications.
To describe the frequency and content of physician discussions about the cost and acquisition of new medications. Qualitative and quantitative study combining patient and physician surveys with transcribed audiotaped office visits from 185 outpatient encounters with 15 family physicians, 18 internists, and 11 cardiologists in 2 Sacramento healthcare systems between January and November 1999, in which 243 new medications were prescribed. Transcripts were qualitatively analyzed to describe conversations concerning the cost and acquisition of new medication prescriptions, frequencies of discussions were described, and multivariate logistic regression was used to examine the predictors of cost discussions. For one third of newly prescribed medications, physicians discussed an aspect of acquisition, including cost and insurance coverage for 12%, logistics of obtaining medications for 18%, and medication supply for 9%. Patients initiated cost or insurance concerns for fewer than 2% of the new medications prescribed. There were 5 discussions about patient out-of-pocket costs and 7 discussions offering tips for cost savings. In multivariate analysis, cost discussions were more likely to occur with patients earning less than 20,000 dollars per year compared with those earning more than 60,000 dollars per year, were less likely to occur with medications prescribed by family physicians or internists compared with cardiologists, and were less likely with medications prescribed to older patients. Physician-patient discussions about new medication cost and other acquisition issues, especially medication affordability, occur infrequently. Because physicians may not recognize patients' financial impediments to acquiring medications, this issue should be raised when prescribing new medications.


Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus.
Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare ( ≤ 0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.


Localization and characterization of STRO-1 cells in the deer pedicle and regenerating antler.
The annual regeneration of deer antlers is a unique developmental event in mammals, which as a rule possess only a very limited capacity to regenerate lost appendages. Studying antler regeneration can therefore provide a deeper insight into the mechanisms that prevent limb regeneration in humans and other mammals, and, with regard to medical treatments, may possibly even show ways how to overcome these limitations. Traditionally, antler regeneration has been characterized as a process involving the formation of a blastema from de-differentiated cells. More recently it has, however, been hypothesized that antler regeneration is a stem cell-based process. Thus far, direct evidence for the presence of stem cells in primary or regenerating antlers was lacking. Here we demonstrate the presence of cells positive for the mesenchymal stem cell marker STRO-1 in the chondrogenic growth zone and the perivascular tissue of the cartilaginous zone in primary and regenerating antlers as well as in the pedicle of fallow deer (Dama dama). In addition, cells positive for the stem cell/progenitor cell markers STRO-1, CD133 and CD271 (LNGFR) were isolated from the growth zones of regenerating fallow deer antlers as well as the pedicle periosteum and cultivated for extended periods of time. We found evidence that STRO-1(+) cells isolated from the different locations are able to differentiate in vitro along the osteogenic and adipogenic lineages. Our results support the view that the annual process of antler regeneration might depend on the periodic activation of mesenchymal progenitor cells located in the pedicle periosteum. The findings of the present study indicate that not only limited tissue regeneration, but also extensive appendage regeneration in a postnatal mammal can occur as a stem cell-based process.


Therapy may explain recent deficits in AIDS incidence.
Since the middle of 1987, fewer consistently defined AIDS cases have been reported than expected among homosexual and bisexual men in the United States. This "AIDS deficit" was greater among homosexual and bisexual men in New York City, San Francisco, and Los Angeles, but was also striking among all homosexual and bisexual men in the United States. Deficits were virtually absent among intravenous drug users (IVDUs) in the United States. Three independent sources of data--placebo-controlled trials, pharmaceutical company reports, and the San Francisco Men's Health Study--were used to demonstrate that the amounts of zidovudine (AZT) given prophylactically to those at highest risk of AIDS since March 1987 have been sufficient to account for most of the observed AIDS deficits. Other advances in the medical care of pre-AIDS patients may have combined with AZT to produce the deficits. Other hypothesized explanations were examined and found insufficient to account for the observed AIDS deficits, including: (a) a sudden halt in new human immunodeficiency virus (HIV) infections during the early or mid-1980s; (b) misspecification of the distribution of AIDS incubation times following HIV infection; (c) increasing delays in the reporting of AIDS cases; (d) changes in the surveillance definition of AIDS in 1987; and (e) evolution of attenuated HIV strains. The hypothesis that therapy is affecting national AIDS rates has important implications. Failure to take the effects of therapy into account can lead to serious underestimates by back-calculation of the cumulative numbers infected with HIV and of AIDS incidence over the longer term. Moreover, it appears that AIDS incidence could be retarded in underserved groups, such as IVDUs, by making AZT and other state-of-the-art treatments readily available to AIDS-free patients with advanced immunodeficiency.


First record of soybean stem fly Melanagromyza sojae (Diptera: Agromyzidae) in Paraguay confirmed by molecular evidence.
We provided the first scientific record of Melanagromyza sojae (Zehntner, 1900), through molecular characterization of partial mtDNA COI gene, that confirms the occurrence of this pest in Paraguay. Previously reported in Brazil, an outbreak of larvae of M. sojae known as the soybean stem fly (SSF) that belongs to the family Agromyzidae, was also noted in soybean fields from the Canindeyú, Alto Paraná and Itapúa Departments in Paraguay. This pest is highly polyphagous, attacking various host plant species from the family Fabaceae, such as soybean and other beans. The implications of SSF detection in Paraguay are discussed in relation to the current soybean cultivation practices from this agriculturally important South American region, including Brazil.


3D pediatric cranial bone imaging using high-resolution MRI for visualizing cranial sutures: a pilot study.
There is an unmet need to perform imaging in young children and obtain CT-equivalent cranial bone images without subjecting the patients to radiation. In this study, the authors propose using a high-resolution fast low-angle shot golden-angle 3D stack-of-stars radial volumetric interpolated breath-hold examination (GA-VIBE) MRI sequence that is intrinsically robust to motion and has enhanced bone versus soft-tissue contrast. Patients younger than 11 years of age, who underwent clinical head CT scanning for craniosynostosis or other cranial malformations, were eligible for the study. 3D reconstructed images created from the GA-VIBE MRI sequence and the gold-standard CT scan were randomized and presented to 3 blinded reviewers. For all image sets, each reviewer noted the presence or absence of the 6 primary cranial sutures and recorded on 5-point Likert scales whether they recommended a second scan be performed. Eleven patients (median age 1.8 years) underwent MRI after clinical head CT scanning was performed. Five of the 11 patients were sedated. Three clinicians reviewed the images, and there were no cases, either with CT scans or MR images, in which a reviewer agreed a repeat scan was required for diagnosis or surgical planning. The reviewers reported clear imaging of the regions of interest on 99% of the CT reviews and 96% of the MRI reviews. With CT as the standard, the sensitivity and specificity of the GA-VIBE MRI sequence to detect suture closure were 97% and 96%, respectively (n = 198 sutures read). The 3D reconstructed images using the GA-VIBE sequence in comparison to the CT scans created clinically acceptable cranial images capable of detecting cranial sutures. Future directions include reducing the scan time, improving motion correction, and automating postprocessing for clinical utility.


Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives.
Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.


CD4 function in thymocyte differentiation and T cell activation.
The ectodomains of the T cell surface glycoproteins CD4 and CD8 bind to membrane-proximal domains of MHC class II and class I molecules, respectively, while both cytoplasmic domains interact with the protein tyrosine kinase (PTK) p56lck (lck) through a shared cysteine-containing motif. Function of CD4 and CD8 requires their binding to the same MHC molecule as that recognized by the T cell antigen receptor (TCR). In vitro studies indicate that CD4-associated lck functions even in the absence of kinase activity. In vivo experiments show that, whereas helper T cell development is impaired in CD4-deficient mice, high level expression of a transgenic CD4 that cannot bind lck rescues development of this T cell subset. These studies suggest that CD4 is an adhesion molecule whose localization is regulated through protein-protein interactions of the associated PTK and whose function is to increase the stability of the TCR signalling complex by binding to the relevant MHC. The function of CD4 in development has been further studied in the context of how double positive (CD4+CD8+) thymocytes mature into either CD4+ T cells with helper function and TCR specificity for class II or into CD8+ T cells with cytotoxic function and specificity for class I. Studies using CD4-transgenic mice indicate that development of single positive T cells involves stochastic downregulation of either CD4 or CD8, coupled to activation of a cytotoxic or helper program, respectively, and subsequent selection based on the ability of the TCR and remaining co-receptor to engage the same MHC molecule.


Bioassay of methyl parathion for possible carcinogenicity.
A bioassay of methyl parathion for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered methyl parathion at one of two doses, initially either 62.5 or 125 ppm. These doses were maintained for 102 weeks for the females; however, due to decreased mean body weight gain in the dosed males, the low and high doses for the males were reduced after 37 weeks to 20 and 50 ppm, respectively, and administration at the lowered doses was continued for 65 weeks. The time-weighted average doses for the male mice were 35 and 77 ppm, respectively, for the low- and high-dose groups. Matched controls consisted of 20 untreated mice of each sex. All surviving mice were killed at the end of administration of the test chemical. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout the bioassay and were dose related. Survival was unaffected in both species except for an increase in mortality in the high-dose female rats, in which 46% of the animals were alive at the end of the study. No tumors occurred in any of the groups of rats or mice of either sex at incidences that were significantly higher in the dosed groups than in the corresponding control groups. It is concluded that under the conditions of this bioassay, methyl parathion was not carcinogenic for F344 rats or B6C3F1 mice of either sex.


Male circumcision for HIV prevention in sub-Saharan Africa: who, what and when?
Male circumcision (circumcision) reduces HIV incidence in men by 50-60%. The United Nations Joint Programme on HIV/AIDS (UNAIDS) recommends the provision of safe circumcision services in countries with high HIV and low circumcision prevalence, prioritizing 12-30 years old HIV-uninfected men. We explore how the population-level impact of circumcision varies by target age group, coverage, time-to-scale-up, level of risk compensation and circumcision of HIV infected men. An individual-based model was fitted to the characteristics of a typical high-HIV-prevalence population in sub-Saharan Africa and three scenarios of individual-level impact corresponding to the central and the 95% confidence level estimates from the Kenyan circumcision trial. The simulated intervention increased the prevalence of circumcision from 25 to 75% over 5 years in targeted age groups. The impact and cost-effectiveness of the intervention were calculated over 2-50 years. Future costs and effects were discounted and compared with the present value of lifetime HIV treatment costs (US$ 4043). Initially, targeting men older than the United Nations Joint Programme on HIV/AIDS recommended age group may be the most cost-effective strategy, but targeting any adult age group will be cost-saving. Substantial risk compensation could negate impact, particularly if already circumcised men compensate. If circumcision prevalence in HIV uninfected men increases less because HIV-infected men are also circumcised, this will reduce impact in men but would have little effect on population-level impact in women. Circumcision is a cost-saving intervention in a wide range of scenarios of HIV and initial circumcision prevalence but the United Nations Joint Programme on HIV/AIDS/WHO recommended target age group should be widened to include older HIV-uninfected men and counselling should be targeted at both newly and already circumcised men to minimize risk compensation. To maximize infections-averted, circumcision must be scaled up rapidly while maintaining quality.


The Safety and Efficacy of Cryolipolysis: A Systematic Review of Available Literature.
In the past decade, the practice of body contouring using cryolipolysis has increased tremendously. While numerous anecdotal reports extol the efficacy of this product, the majority of these studies are small, retrospective case-series that lack control groups. The authors aim to systematically review available literature to better illustrate the efficacy and safety of this new procedure. A systematic literature review performed using MEDLINE, Embase, PubMed, and Cochrane databases identified all published studies evaluating cryolipolysis for body contouring. A total of 34 articles up to February 2015 were identified. Nineteen articles matched the selection criteria and were included in the analysis. Sixteen were evaluated in the final analysis. A total of 1445 patients had reportable data for analysis of the safety profile. Twelve patients (0.82%) reported complications with the most common being diminished sensation lasting greater than 4 weeks. An aggregate total of 295 patients had objective data for evaluation of tissue reduction. The mean time from procedure to objective outcome evaluation was 3.83 months. The mean reduction of subcutaneous tissue was 19.55% with respect to a designated control site. Selective cryolipolysis appears, at short-term follow-up, to reliably decrease subcutaneous tissue deposits. Reported complications are uncommon and appear to resolve without intervention. Future studies should aim to optimize patient selection and treatment characteristics while obtaining long-term follow-up data.


Understanding heterogeneity among elderly consumers: an evaluation of segmentation approaches in the functional food market.
It is beneficial for both the public health community and the food industry to meet nutritional needs of elderly consumers through product formats that they want. The heterogeneity of the elderly market poses a challenge, however, and calls for market segmentation. Although many researchers have proposed ways to segment the elderly consumer population, the elderly food market has received surprisingly little attention in this respect. Therefore, the present paper reviewed eight potential segmentation bases on their appropriateness in the context of functional foods aimed at the elderly: cognitive age, life course, time perspective, demographics, general food beliefs, food choice motives, product attributes and benefits sought, and past purchase. Each of the segmentation bases had strengths as well as weaknesses regarding seven evaluation criteria. Given that both product design and communication are useful tools to increase the appeal of functional foods, we argue that elderly consumers in this market may best be segmented using a preference-based segmentation base that is predictive of behaviour (for example, attributes and benefits sought), combined with a characteristics-based segmentation base that describes consumer characteristics (for example, demographics). In the end, the effectiveness of (combinations of) segmentation bases for elderly consumers in the functional food market remains an empirical matter. We hope that the present review stimulates further empirical research that substantiates the ideas presented in this paper.


How to open the treasure chest? Optimising DNA extraction from herbarium specimens.
Herbarium collections are potentially an enormous resource for DNA studies, but the use of herbarium specimens in molecular studies has thus far been slowed down by difficulty in obtaining amplifiable DNA. Here we compare a set of commercially available DNA extraction protocols and their performance in terms of DNA purity and yield, and PCR amplification success as measured by using three differentially sized markers, the rbcL barcoding marker (cpDNA), the LEAFY exon 3 (nrDNA), and the trnL((UAA)) P6 loop (cpDNA). Results reveal large differences between extraction methods, where DNA purity rather than yield is shown to be strongly correlated with PCR success. Amplicon size shows similarly strong correlation with PCR success, with the shortest fragment showing the highest success rate (78%, P6 loop, 10-143 base pairs (bp)) and the largest fragment the lowest success (10%, rbcL, 670 bp). The effect of specimen preparation method on PCR success was also tested. Results show that drying method strongly affects PCR success, especially the availability of fragments longer than 250 bp, where longer fragments are more available for PCR amplification in air dried material compared to alcohol dried specimens. Results from our study indicate that projects relying on poor-quality starting material such as herbarium or scat samples should focus on extracting pure DNA and aim to amplify short target regions (<200-300 bp) in order to maximise outcomes. Development of shorter barcoding regions, or mini-barcodes within existing ones should be of high importance as only a few options are currently available; this is particularly important if we hope to incorporate the millions of herbarium samples available into barcoding initiatives and other molecular studies.


Building capacity in health and education systems to deliver interventions that strengthen early child development.
Building capacity within health and education systems of low- and middle-income countries in order to deliver high-quality early childhood services requires coordinated efforts across sectors, effective governance, sufficient funding, an adequate workforce, reliable data systems, and continuous monitoring, evaluation, and improvement cycles; it also requires partnerships with the private sector, communities, and parents. In addition, building capacity requires leadership, innovation of strategies to fit into existing structures, evidence-based intervention models, and effective partnerships that help make interventions more culturally relevant, help finance them, and help create institutional long-term support and sustainability for them. In this article, we focus on identifying eight critical aspects of enabling systemic support for early childhood services. Every action that strengthens these critical aspects should be seen as necessary, but insufficient, steps toward a national strong governance structure for delivering a locally relevant and comprehensive early child development program that promotes children's developmental potentials.


[Organic aciduria: diagnosis in high-risk Brazilian patients]
OBJECTIVE: To determine the prevalence of organic acidurias in high-risk Brazilian patients. METHODS: Laboratory techniques for the detection and quantification of organic acids by gas chromatography/mass spectrometry were implemented in Porto Alegre, Brazil. We investigated 1,480 patients suspected of organic aciduria between January 1994 and June 2000. RESULTS: Seventy three (4.9%) cases of organic acidemias (acidurias) were diagnosed among the tested individuals. In most of these patients, prompt therapy resulted in rapid symptom improvement; these results are completely different from our previous cases diagnosed in other laboratories in Europe and the United States, where several patients died before any measures could be taken. CONCLUSIONS: These results demonstrate the importance of diagnosing organic acidurias in loco even in developing countries, in spite of the extra costs involved.


Effects of the vasopeptidase inhibitor, omapatrilat, in 723 patients with coronary heart disease.
Among individuals with a history of myocardial infarction (MI), higher levels of blood pressure (BP) are associated with increased long-term risks of death from coronary heart disease. Treatment with a BP-lowering regimen, based on omapatrilat may result in greater clinical benefits than treatment with a regimen based on a regular angiotensin-converting enzyme (ACE) inhibitor because of more favourable effects on the renin-angiotensin-aldosterone system. Seven hundred and twenty-three clinically stable patients with a history of MI or unstable angina, and a mean entry BP of 134/77 mmHg, were randomised to six months treatment with omapatrilat 40 mg, omapatrilat 20 mg, or matching placebo. After six months, mean BP levels (systolic/diastolic) in the omapatrilat 40 mg group were reduced by 4.3/2.9 mmHg (95% confidence interval 1.3 to 7.2/1.2 to 4.6). Mean BP levels in the omapatrilat 20 mg group were reduced by 4.6/1.0 mmHg (1.6 to 7.6/ 0.7 to 2.6) in comparison with the placebo group. Both doses of omapatrilat also produced significant decreases in plasma ACE activity and significant increases in levels of plasma renin activity, atrial natriuretic peptide, endothelin and homocysteine (p<0.05 for all). Premature discontinuations were more frequent with omapatrilat than with placebo (p<0.001 for 20 mg and 40 mg). Omapatrilat produced changes in BP, neurohormone and biochemical parameters that were similar for the two doses. The long-term clinical implications of the observed effects are uncertain and a large-scale randomised trial would be required to reliably establish the effects of omapatrilat on the risks of major vascular disease events among patients with coronary heart disease.


Basal forebrain cholinergic lesions disrupt increments but not decrements in conditioned stimulus processing.
Magnocellular neurons in the basal forebrain provide the major cholinergic innervation of cortex. Recent research suggests that this cholinergic system plays an important role in the regulation of attentional processes. The present study examined the ability of rats with selective immunotoxic lesions of these neurons (made with 192 IgG-saporin) to modulate attention within an associative learning framework. Each rat was exposed to conditioned stimuli (CS) that were either consistent or inconsistent predictors of subsequent cues. Intact control rats showed increased CS associability when that cue was an inconsistent predictor of a subsequent cue, whereas lesioned rats were impaired in increasing attention to the CS when its established relation to another cue was modified. In a separate experiment designed to test latent inhibition, it was shown that removal of the corticopetal cholinergic neurons spared a decrement in associability that occurs when rats are extensively preexposed to a CS prior to conditioning. These data indicate that the cholinergic innervation of cortex is critical for incrementing, but not for decrementing attentional processing. The specific behavioral tests used to assess the role of the basal forebrain cholinergic system in the present study were previously used to identify a role for the amygdala central nucleus in attention (Holland and Gallagher, 1993b). Those studies, together with the results in this report, indicate that regulation of attentional processes during associative learning may be mediated by projections from the amygdala to the basal forebrain cholinergic system.


CDC growth charts: United States.
This report presents the revised growth charts for the United States. It summarizes the history of the 1977 National Center for Health Statistics (NCHS) growth charts, reasons for the revision, data sources and statistical procedures used, and major features of the revised charts. Data from five national health examination surveys collected from 1963 to 1994 and five supplementary data sources were combined to establish an analytic growth chart data set. A variety of statistical procedures were used to produce smoothed percentile curves for infants (from birth to 36 months) and older children (from 2 to 20 years), using a two-stage approach. Initial curve smoothing for selected major percentiles was accomplished with various parametric and nonparametric procedures. In the second stage, a normalization procedure was used to generate z-scores that closely match the smoothed percentile curves. The 14 NCHS growth charts were revised and new body mass index-for-age (BMI-for-age) charts were created for boys and girls (http://www.cdc.gov/growthcharts). The growth percentile curves for infants and children are based primarily on national survey data. Use of national data ensures a smooth transition from the charts for infants to those for older children. These data better represent the racial/ethnic diversity and the size and growth patterns of combined breast- and formula-fed infants in the United States. New features include addition of the 3rd and 97th percentiles for all charts and extension of all charts for children and adolescents to age 20 years. Created with improved data and statistical curve smoothing procedures, the United States growth charts represent an enhanced instrument to evaluate the size and growth of infants and children.


Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study.
Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. Novartis Vaccines and Diagnostics.


1991 Gulf War exposures and adverse birth outcomes.
We studied 1991 Gulf War (GW)-related environmental exposures and adverse birth outcomes in Iraqis. A random cross-sectional sample of 307 Iraqi families that immigrated to the United States responded to a structured interview covering socioeconomics, lifestyle, environmental exposures, and birth outcome. Data per each family was collected either from the man or the woman in the respective family. The respondents were divided into those that resided in Iraq during and following the GW (post-GW, n=185) and those that had left before (pre-GW, n=122). The primary outcome was lifetime prevalence of adverse birth outcomes, ie, congenital anomalies, stillbirth, low birth weight, and preterm delivery and its relationship to GW exposures. Mean number of adverse birth outcomes increased from 3.43 (SD=2.11) in the pre-GW to 4.63 (SD=2.63) in the post-GW group (P<.001). Mean chemical (Ch) and nonchemical (NCh) environmental exposure scores increased from pre-GW scores of 0.38 units (SD=1.76) and 0.43 (SD=1.86), respectively, to post-GW scores of 5.65 units (SD=6.23) and 7.26 (SD=5.67), P<.001 between groups for both exposures. There was a significant dose-response relationship between Ch environmental exposure (P=.001), but not NCh exposure, and number of adverse birth outcomes. Exposure to burning oil pits and mustard gas increased the risks for specific adverse birth outcomes by 2 to 4 times. Results indicate that Gulf War Ch, but not NCh exposures are related to adverse birth outcomes. Pregnancies in women with a history of war exposures might benefit from more intensive observation.


Impact of Spirulina Supplementation on Semen Parameters in Patients with Idiopathic Male Infertility: A Pilot Randomized Trial.
To evaluate the efficacy of therapy with spirulina supplement on semen parameters in patients with idiopathic male infertility. A total of 40 men with idiopathic infertility were randomly assigned into two groups. Group A received 2 g spirulina supplement as well as conventional regimen for the treatment of infertility selected by their physician (220 mg/day zinc sulfate, 500mg/day L-carnitine, and 50 mg/day clomiphene) during 12 weeksof the study, while group B received placebo plus conventional therapy during the study period. Semen parameters were analyzed at baseline and at the end of the study as a primary endpoint. The secondary endpoint was the rate of pregnancy occurring in the patients. wives. No significant differences in semen parameters were observed between the spirulina and control groups [count (16.43 vs. 46.00, P = .164), motility (51.00 vs. 48.7, P = .008), and morphology (47.50 vs. 15.00, P = NA)]. Our results showed a pregnancy rate of 5% in the spirulina group versus 0% in the control group. This pilot randomized trial provides initial evidence on the possible beneficial effects of spirulina mainly in patients with impaired sperm motility or morphology. Due to the limited sample size, further larger randomized trials not only at the level of semen parameters but at the scope of paternity are required to confirmthese potential benefits.


Traumatic Brain Injury Update.
Traumatic brain injury is a devastating, life-changing event in most cases. After the primary brain insult, it is helpful to use evidence-based monitoring techniques to guide implementation of essential interventions to minimize secondary injury and thereby improve patient outcomes. An update on multimodal neuromonitoring is provided in this narrative review, with discussion of tools and techniques currently used in the treatment of patients with brain injury. Neuroprotective treatments, from the well-studied targeted temperature management to new potential therapeutics under investigation, such as glyburide, also are presented.


Erythromycin for persistent or recurrent nongonococcal urethritis. A randomized, placebo-controlled trial.
To evaluate the efficacy of a 3-week regimen of erythromycin for treatment of persistent or recurrent nongonococcal urethritis in men. A prospective, randomized, double-blind trial with follow-up at 2, 4, and 8 weeks after enrollment. Seventy-seven evaluable men with objective evidence of nongonococcal urethritis (36 in the erythromycin group and 41 in the placebo group) with a mean age of 28 years, a median duration of urethritis of 3 months, and a median number of three previous antimicrobial regimens. Erythromycin, 500 mg, or placebo four times daily for 3 weeks. After 2 weeks of treatment, urethral symptoms resolved in 13 of 25 erythromycin-treated patients compared with 8 of 34 placebo-treated patients (P = 0.03). Erythromycin also resulted in more frequent resolution of urethral discharge and leukocytosis at all visits compared with placebo but these differences were not statistically significant. First-voided urine leukocyte counts decreased, however, by a median of 89% (95% CI, -96% to -67%) in the erythromycin group compared with 23% (CI, -73% to 83%) in the placebo group after treatment (P = 0.02 for the difference in changes). Further, in men with prostatic inflammation, urinary leukocyte counts decreased by a median of 94% (CI, -99% to -83%) after treatment in erythromycin-treated patients compared with a 46% increase (CI, -57% to 290%) in placebo-treated patients (P = 0.0003 for the difference in changes). A 3-week regimen of erythromycin was more effective than placebo in improving symptoms and in reducing pyuria in men with persistent or recurrent nongonococcal urethritis, especially among men with prostatic inflammation.


Exploring the Notion of Literacy Within Physical Literacy: A Discussion Paper.
The concept of physical literacy is continuing to gain traction internationally. This increasing interest has also given rise to concerns about the use, interpretation and meaning of the term "literacy" within the context of physical literacy. This paper explores the development of the terms literate, illiterate, literacy, and illiteracy identifying their historical origin and contemporary meaning. This provides the backdrop to explore the use of the term literacy within the context of physical literacy. In the final part of this introductory section the recent popularity of the literacies movement is explored. Our discussion identifies key intersections and areas of tension associated with the use, interpretation and meaning of literacy in the context of physical literacy. We adopt Whitehead's philosophy of physical literacy and discussion is informed further by Derrida's notion of differance, and Barad's challenge to singular representations of concepts. Once harnessing these concepts, we reach a juncture of an in-between space; entry points of nonidentity (sameness) and points where multiple effects of difference are created. Key discussion topics include: discourse, language and interpretations of literacy; in/tangibility of literacy; capturing literacy; literacy as a process or a product; connotations of the terms literate and illiterate; neoliberalism and literacy and finally literacy as learning. We believe that when understood as the productive and meaningful interaction with/in/through the world, literacy is still the appropriate term within the context of physical literacy. Our discussion leads us to conclude that as embodied individuals, physical literacy is often the literacy through which other literacies have to pass. Through physical activity individuals can not only nurture their own physical literacy but also contribute toward a global or holistic literacy that helps us navigate, connect and make sense of ourselves, others and the world around us. However, the paper acknowledges that this meaning is not always grasped with the historical understanding of literacy as well as it's translations into other languages presenting challenges in articulating the intended use, meaning and connotations of the contemporary understanding of physical literacy.


Fever and survival in rabbits infected with Pasteurella multocida.
1. Fever and survival rate of New Zealand white rabbits, injected with two doses of live Pasteurella multocida, were compared to determine if the relation between fever and survival observed in reptiles is also seen in a mammal. Since it is known that fever is beneficial in infected reptiles, our experiments were viewed as an initial step in the investigation of a similar potentially beneficial effect in mammals.2. There was a statistically significant correlation between the fever magnitude and survival. As fever increased up to 2.25 degrees C, the survival rate increased. Fevers above this level were associated with a decreased survival rate.3. Antipyretic drugs were administered to half the rabbits. The drugs were ineffective in reducing the fevers produced by injections of large doses of bacteria. Rabbits infused with antipyretics had a decreased mortality rate. The decreased mortality rate may be due to some action of the drugs other than their antipyretic effect.4. In vitro growth of P. multocida at normal (39 degrees C) and febrile (42 degrees C) temperatures was not significantly different. This suggests that the increased survival rate associated with higher fevers was not due to a direct inhibition of the growth of the bacteria by the increased temperature. It may be due to an enhancement of some aspect of the rabbits' immunological defences.5. It remains to be determined whether fever causes a higher survival rate or whether fever is only correlated with survival rate.


Resident macrophages influence stem cell activity in the mammary gland.
Macrophages in the mammary gland are essential for morphogenesis of the ductal epithelial tree and have been implicated in promoting breast tumor metastasis. Although it is well established that macrophages influence normal mammopoiesis, the mammary cell types that these accessory cells influence have not been determined. Here we have explored a role for macrophages in regulating mammary stem cell (MaSC) activity, by assessing the ability of MaSCs to reconstitute a mammary gland in a macrophage-depleted fat pad. Two different in vivo models were used to deplete macrophages from the mouse mammary fat pad, allowing us to examine the effect of macrophage deficiency on the mammary repopulating activity of MaSCs. Both the Csf1op/op mice and clodronate liposome-mediated ablation models entailed transplantation studies using the MaSC-enriched population. We show that mammary repopulating ability is severely compromised when the wild-type MaSC-enriched subpopulation is transplanted into Csf1op/op fat pads. In reciprocal experiments, the MaSC-enriched subpopulation from Csf1op/op glands had reduced regenerative capacity in a wild-type environment. Utilizing an alternative strategy for selective depletion of macrophages from the mammary gland, we demonstrate that co-implantation of the MaSC-enriched subpopulation with clodronate-liposomes leads to a marked decrease in repopulating frequency and outgrowth potential. Our data reveal a key role for mammary gland macrophages in supporting stem/progenitor cell function and suggest that MaSCs require macrophage-derived factors to be fully functional. Macrophages may therefore constitute part of the mammary stem cell niche.


Exact complex-wave reconstruction in digital holography.
We address the problem of exact complex-wave reconstruction in digital holography. We show that, by confining the object-wave modulation to one quadrant of the frequency domain, and by maintaining a reference-wave intensity higher than that of the object, one can achieve exact complex-wave reconstruction in the absence of noise. A feature of the proposed technique is that the zero-order artifact, which is commonly encountered in hologram reconstruction, can be completely suppressed in the absence of noise. The technique is noniterative and nonlinear. We also establish a connection between the reconstruction technique and homomorphic signal processing, which enables an interpretation of the technique from the perspective of deconvolution. Another key contribution of this paper is a direct link between the reconstruction technique and the two-dimensional Hilbert transform formalism proposed by Hahn. We show that this connection leads to explicit Hilbert transform relations between the magnitude and phase of the complex wave encoded in the hologram. We also provide results on simulated as well as experimental data to validate the accuracy of the reconstruction technique.


Substitution of Re7+ into CaMnO3: an efficient free electron generation dopant for tuning of thermoelectric properties.
Highly dense CaMn1-xRexO3 (0 ≤ x ≤ 0.04) samples were prepared by solid-state synthesis. The effect of Re doping was assessed by the characterisation of crystal structure, oxygen content, and electrical and thermal transport properties. The oxidation state of the substituted Re was determined by X-ray absorption near edge spectra to be Re7+, and led to expansion of the lattice and an increase in electron carrier concentration due to the formation of Mn3+. The thermal behaviour of the electrical conductivity and the thermopower over a wide temperature range allowed identification of different conduction mechanisms: (1) below 110 K, 3D variable range hopping, (2) between 110 and 650 K, small polaron transport, and (3) above 650 K, activation of carriers over a mobility edge. Evaluation of the power factor expected for different dopant oxidation states as a function of dopant concentration shows that the doping strategy using a heavy heptavalent ion allows accessibility of the peak power factor at lower dopant concentrations, lowering the amount of non-ionised impurities, and therefore improves the electronic substitution efficiency, the ratio of activated carriers over the nominal doping concentration, compared to previously studied dopants. An increased power factor and a reduced lattice thermal conductivity are obtained with a peak figure of merit ZT = 0.16(3) at 947 K for CaMn0.98Re0.02O3. This is an approximately two-fold increase compared to undoped CaMnO3, and is comparable to the highest values reported for highly dense B-site doped CaMnO3.


Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host-pathogen conflict.
DNA viruses in the family Poxviridae encode poxin enzymes that degrade the immune second messenger 2'3'-cGAMP to inhibit cGAS-STING immunity in mammalian cells. The closest homologs of poxin exist in the genomes of insect viruses suggesting a key mechanism of cGAS-STING evasion may have evolved outside of mammalian biology. Here we use a biochemical and structural approach to discover a broad family of 369 poxins encoded in diverse viral and animal genomes and define a prominent role for 2'3'-cGAMP cleavage in metazoan host-pathogen conflict. Structures of insect poxins reveal unexpected homology to flavivirus proteases and enable identification of functional self-cleaving poxins in RNA-virus polyproteins. Our data suggest widespread 2'3'-cGAMP signaling in insect antiviral immunity and explain how a family of cGAS-STING evasion enzymes evolved from viral proteases through gain of secondary nuclease activity. Poxin acquisition by poxviruses demonstrates the importance of environmental connections in shaping evolution of mammalian pathogens.


Measurements of absolute CH concentrations by cavity ring-down spectroscopy and linear laser-induced fluorescence in laminar, counterflow partially premixed and nonpremixed flames at atmospheric pressure.
We report quantitative, spatially resolved measurements of methylidyne concentration ([CH]) in laminar, counterflow partially premixed and nonpremixed flames at atmospheric pressure by using both cavity ring-down spectroscopy (CRDS) and linear laser-induced fluorescence (LIF) in the A-X (0, 0) band. Three partially premixed (phiB = 1.45, 1.6, 2.0) flames plus a single nonpremixed methane-air flame are investigated at a global strain rate of 20 s(-1). These quantitative measurements are compared with predictions from an opposed-flow flame code when utilizing two GRI chemical kinetic mechanisms (versions 2.11 and 3.0). The LIF measurements of [CH] are corrected for variations in the electronic quenching rate coefficient by using predicted major species concentrations and temperatures along with quenching cross sections for CH that are available in the literature. The peak CH concentration obtained by CRDS is used to calibrate the quenching-corrected LIF measurements. Excellent agreement is obtained between CH concentration profiles measured by using the CRDS and LIF techniques. The spatial location of the CH layer is very well predicted by GRI 3.0; moreover, the measured and predicted CH concentrations are in good agreement for all the flames of this study.