Endocannabinoids limit excessive mast cell maturation and activation in human skin.
Mast cells (MCs) crucially contribute to many inflammatory diseases. However, the physiological controls preventing excessive activities of MCs in human skin are incompletely understood. Since endocannabinoids are important neuroendocrine MC modifiers, we investigated how stimulation/inhibition of cannabinoid 1 (CB1) receptors affect the biology of human skin MCs in situ. This was investigated in the MC-rich connective tissue sheath of organ-cultured human scalp hair follicles by quantitative (immuno)histomorphometry, ultrastructural, and quantitative PCR techniques with the use of CB1 agonists or antagonists, CB1 knockdown, or CB1 knockout mice. Kit+ MCs within the connective tissue sheath of human hair follicles express functional CB1 receptors, whose pharmacological blockade or gene silencing significantly stimulated both the degranulation and the maturation of MCs from resident progenitor cells in situ (ie, enhanced the number of tryptase+, FcεRIα, or chymase+ connective tissue sheath-MCs). This was, at least in part, stem cell factor-dependent. CB1 agonists counteracted the MC-activating effects of classical MC secretagogues. Similar phenomena were observed in CB1 knockout mice, attesting to the in vivo relevance of this novel MC-inhibitory mechanism. By using human hair follicle organ culture as an unconventional, but clinically relevant model system for studying the biology of MCs in situ, we show that normal skin MCs are tightly controlled by the endocannabinoid system. This limits excessive activation and maturation of MCs from resident progenitors via "tonic" CB1 stimulation by locally synthesized endocannabinoids. The excessive numbers and activation of MCs in allergic and other chronic inflammatory skin diseases may partially arise from resident intracutaneous MC progenitors, for example, because of insufficient CB1 stimulation. Therefore, CB1 stimulation is a promising strategy for the future management of allergy and MC-dependent skin diseases.


Lexical-semantic priming effects during infancy.
When and how do infants develop a semantic system of words that are related to each other? We investigated word-word associations in early lexical development using an adaptation of the inter-modal preferential looking task where word pairs (as opposed to single target words) were used to direct infants' attention towards a target picture. Two words (prime and target) were presented in quick succession after which infants were presented with a picture pair (target and distracter). Prime-target word pairs were either semantically and associatively related or unrelated; the targets were either named or unnamed. Experiment 1 demonstrated a lexical-semantic priming effect for 21-month olds but not for 18-month olds: unrelated prime words interfered with linguistic target identification for 21-month olds. Follow-up experiments confirmed the interfering effects of unrelated prime words and identified the existence of repetition priming effects as young as 18 months of age. The results of these experiments indicate that infants have begun to develop semantic-associative links between lexical items as early as 21 months of age.


Gene conversion as a source of nucleotide diversity in Plasmodium falciparum.
Examination of polymorphisms in the Plasmodium falciparum gene for falcipain 2 revealed that this gene is one of two paralogs separated by 10.8 kb in chromosome 11. We designate the annotated gene denoted chr11.gen_424 as encoding falcipain 2A and the annotated gene denoted chr11.gen_427 as encoding falcipain 2B. The paralogs are 96% identical at the nucleotide level and 93% identical at the amino acid level. The consensus sequences differ in 31/309 synonymous sites and 45/1140 nonsynonymous sites, including three amino acid replacements (V393I, A400P, and Q414E) that are near the catalytic site and that may affect substrate affinity or specificity. In six reference isolates, among 36 synonymous sites and 46 nonsynonymous sites that are polymorphic in the gene for falcipain 2A, falcipain 2B, or both, significant spatial clustering is observed. All but one of the polymorphisms appear to result from gene conversion between the paralogs. The estimated rate of gene conversion between the paralogs may be as many as 1,400 to 1,700 times greater than the rate of mutation. Owing to gene conversion, one of the falcipain 2A alleles is more similar to the falcipain 2B alleles than it is to other falcipain 2A alleles. Divergence among the synonymous sites suggests that the paralogous genes last shared a common ancestor 15.2 MYA, with a range of 8.8 to 20.6 MYA. During this period, the paralogs have acquired 0.10 synonymous substitutions per synonymous site in the coding region. The 5' and 3' flanking regions differ in 47.7% and 39.8% of the nucleotide sites, respectively. Hence synonymous sites and flanking regions are not conserved in sequence in spite of their high AT content and T skew.


Lessons from 11C-dihydrotetrabenazine imaging in a xenograft mouse model of rat insulinoma: is PET imaging of pancreatic beta cell mass feasible?
The feasibility of beta cell mass (BCM) imaging and quantification with positron emission tomography (PET) in the pancreas is controversial. In an effort to shed some light on this topic, we have used a xenograft model of rat insulinoma (RIN) in mice, mimicking an intramuscular islet transplantation situation. A total of 105 RIN cells were subcutaneously implanted in nude mice (N.=8). Tumor size and glycaemia levels were determined daily. Rat C-peptide was measured to demonstrate rat insulin production. PET imaging with 11C-(+)-α-dihydrotetrabenazine (11C-DTBZ) was done at 3 and 4 weeks and compared with 18F-FDG and 18F-DOPA studies in the same mice. Ex-vivo autoradiography with 11C-DTBZ was carried out in frozen sections of tumors. VMAT2 expression was measured by Western-blot and immunohistochemistry in tumors and RIN cells. Functional rat insulin production in mice was demonstrated by substantial decrease in glycaemia (<50 mg/dL by week 4) and rat C-peptide levels (7.2±2.6 ng/mL) similar to those measured in control rats. PET studies showed that tumor imaging with 11C-DTBZ at four (N.=8) and five (N.=5) weeks was negative; only bigger tumors could be seen with 18F-DOPA. In explanted tumors 11C-DTBZ autoradiography was negative, albeit VMAT2 expression measured by Western-blot and immunohistochemistry was lower than in cultured RIN cells. Although insulinomas are fully functional it does not seem feasible to use 11C-DTBZ for in-vivo measuring of BCM. This might either be due to inherent technical limitations of PET, decrease in VMAT2 expression in the tumors due to unknown reasons, or other biological limiting facts.


Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults.
The risk of Kaposi's sarcoma and non-Hodgkin's lymphoma is increased in people infected with the human immunodeficiency virus-1 (HIV). Highly active antiretroviral therapy (HAART) has been widely used by HIV-infected people in North America, Europe, and Australia since about 1997. Acquired immunodeficiency syndrome (AIDS) incidence and mortality rates have fallen markedly in association with the use of HAART, but its impact on the incidence of cancer in HIV-infected people is less clear. Cancer incidence data from 23 prospective studies that included 47 936 HIV-seropositive individuals from North America, Europe, and Australia were collated, checked, and analyzed centrally. Adjusted incidence rates (expressed as number of cancers per 1000 person-years) for Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, cervical cancer, and 20 other cancer types or sites were calculated. Rate ratios were estimated, comparing incidence rates from 1997 through 1999 with rates from 1992 through 1996, after adjustment for study, age, sex, and HIV transmission group. All statistical tests were two-sided. For the period from 1992 through 1999, 2702 incident cancers were reported in 138 148 person-years of observation, and more than 90% of them were either Kaposi's sarcoma or non-Hodgkin's lymphoma. The adjusted incidence rate for Kaposi's sarcoma declined from 15.2 in 1992 through 1996 to 4.9 in 1997 through 1999 (rate ratio = 0.32; 99% confidence interval [CI] = 0.26-0.40; based on 1489 and 190 cases, respectively; P<.0001). The incidence rates for non-Hodgkin's lymphoma also declined, from 6.2 to 3.6 (rate ratio = 0.58; 99% CI = 0.45-0.74; based on 623 and 134 cases, respectively; P<.0001). Among the lymphomas, the rate ratios were 0.42 (99% CI = 0.24-0.75) for cerebral lymphoma, 0.57 (99% CI = 0.39-0.85) for immunoblastic lymphoma, and 1.18 (99% CI = 0.48-2.88) for Burkitt's lymphoma (chi(2)(2) for heterogeneity = 6.2; P: =.05). There was no statistically significant change in the incidence rates for Hodgkin's disease (rate ratio = 0.77; 99% CI = 0.32-1.85; based on 38 and 12 cases, respectively; P =.4) or for cervical cancer (rate ratio = 1.87; 99% CI = 0.77-4.56; based on 19 and 17 cases, respectively; P =.07). The adjusted incidence rate for all other cancers combined was 1.7 in each time period (rate ratio = 0.96; 99% CI = 0.62-1.47; based on 126 and 54 cases, respectively). Since the widespread use of HAART, there have been substantial reductions in the incidence Kaposi's sarcoma and non-Hodgkin's lymphoma in HIV-infected people but, so far, no substantial change in the incidence of other cancers.


Antibacterial and antioxidant potency of floral honeys from different botanical and geographical origins.
In order to assess their physicochemical and antioxidant properties as well as their antimicrobial potency, four varieties of honey from different botanical and geographical origins were used. The agar incorporation method was used to determine the antimicrobial potency of honeys. The total phenol content was determined by a modified Folin-Ciocalteu method and the free radical scavenging activity by the Fe(3+)reducing power (FRAP) assay. Manuka honey was the most effective against Staphylococcus aureus Oxa R and S. aureus Oxa S with a Minimum Inhibitory Concentration (MIC) of 6% and 7%, respectively, whereas wild carrot honey was the most effective against Pseudomonas aeruginosa, with a MIC of 12%. Lavender honey was the least effective against all tested strains, even though was found to have the lowest pH and water content. Manuka honey had the highest content of polyphenols, with 899.09 ± 11.75 mg gallic acid/kg, whereas lavender honey had the lowest, with 111.42 ± 3.54 mg gallic acid/kg. A very significant correlation (r value was 0.9079 at P < 0.05) was observed between the total polyphenolic content and the Fe(2+) content formed in the presence of the honey antioxidants. The differences between honey samples in terms of antibacterial and antioxidant activity could be attributed to the natural variations in floral sources of nectar and the different locations.


Interferon-λ mediates oral tolerance and inhibits antigen-specific, T-helper 2 cell-mediated inflammation in mouse intestine.
Oral tolerance is an important component of gastrointestinal homeostasis, but mechanisms of its development are not fully understood. Loss of oral tolerance occurs during food allergen-related inflammation in the gastrointestinal tract. Interferon (IFN)-λ regulates immunity, but its role in oral tolerance is not clear. We investigated the role and the mechanism of IFN-λ in the development of oral tolerance and its effect on antigen-induced, T-helper (Th)-2 cell-mediated inflammation in the intestine. Expression of IFN-λ and its receptor were analyzed by immunohistochemical, flow cytometric, or immunoblot analyses. Tolerogenic dendritic cells (DCs) and regulatory T cells were examined in vitro and in vivo. A mouse model of antigen-induced, Th2 cell-mediated intestinal inflammation was used to examine the role of IFN-λ and T cells in oral tolerance in the intestine. CD3+ cells expressed the IFN-λ receptor, which was up-regulated following antigen-specific or nonspecific activation. Interaction between IFN-λ and its receptor induced apoptosis of T cells and their subsequent phagocytosis by DCs. This led to the generation of tolerogenic DCs and T regulatory cells in vitro and in vivo. Passive transfer of IFN-λ-primed CD3+ cells inhibited Th2 cell-mediated inflammation in the intestine. IFN-λ is involved in development and maintenance of oral tolerance in the intestines of mice; it might be used to suppress antigen-specific Th2 cell-mediated inflammation in patients.


Oral and anal sex practices among high school youth in Addis Ababa, Ethiopia.
Understanding the full range of sexual behaviors of young people is crucial in developing appropriate interventions to prevent and control sexually transmitted infections including HIV. However, such information is meager in developing countries. The objective of this study was to describe oral and anal sex practices and identify associated factors among high school youth. A cross-sectional study was conducted among high school youth in Addis Ababa, Ethiopia. A multi-stage sampling procedure was followed to select a representative sample of school youth. The total sample size for this study was 3840. Data were collected using a self-administered questionnaire. Data analysis was guided by the ecological framework. The overall proportion of people who reported ever having oral sex was 5.4% (190) and that of anal sex was 4.3% (154). Of these 51.6% (98) had oral sex and 57.1% (87) had anal sex in the past 12 months. Multiple partnerships were reported by 61.2% of the respondents who had oral sex and 51.1% of students practicing anal sex. Consistent condom use was reported by 12.2% of those practicing oral sex and 26.1% of anal sex. Reasons for oral and anal sex included prevention of pregnancy, preserving virginity, and reduction of HIV and STIs transmission. Oral sex practice was strongly and significantly associated with perception of best friends engagement in oral sex (AOR = 5.7; 95% CI 3.6-11.2) and having illiterate mothers (AOR = 11.5; 95%CI 6.4-18.5). Similarly, anal sex practice was strongly and significantly associated with favorable attitude towards anal sex (AOR = 6.2; 95%CI 3.8-12.4), and perceived best friends engagement in anal sex (AOR = 9.7; 95%CI 5.4-17.7). Considerable proportion of adolescents had engaged in oral and anal sex practices. Multiple sexual partnerships were common while consistent condom use was low. Sexual health education and behavior change communication strategies need to cover a full range of sexual practices.


Exploring transcription regulation through cell-to-cell variability.
The regulation of cellular protein levels is a complex process involving many regulatory mechanisms, each introducing stochastic events, leading to variability of protein levels between isogenic cells. Previous studies have shown that perturbing genes involved in transcription regulation affects the amount of cell-to-cell variability in protein levels, but to date there has been no systematic characterization of variability in expression as a phenotype. In this research, we use single-cell expression levels of two fluorescent reporters driven by two different promoters under a wide range of genetic perturbations in Saccharomyces cerevisiae, to identify proteins that affect variability in the expression of these reporters. We introduce computational methodology to determine the variability caused by each perturbation and distinguish between global variability, which affects both reporters in a coordinated manner (e.g., due to cell size variability), and local variability, which affects the individual reporters independently (e.g., due to stochastic events in transcription initiation). Classifying genes by their variability phenotype (the effect of their deletion on reporter variability) identifies functionally coherent groups, which broadly correlate with the different stages of transcriptional regulation. Specifically, we find that most processes whose perturbation affects global variability are related to protein synthesis, protein transport, and cell morphology, whereas most processes whose perturbations affect local variability are related to DNA maintenance, chromatin regulation, and RNA synthesis. Moreover, we demonstrate that the variability phenotypes of different protein complexes provide insights into their cellular functions. Our results establish the utility of variability phenotype for dissecting the regulatory mechanisms involved in gene expression.


Characteristics of a gun exchange program, and an assessment of potential benefits.
To describe a gun exchange program and assess potential benefits for participants and host communities. Mail survey of participants in a Sacramento, California gun exchange program, August 1993; the response rate was 79%. Comparative data were obtained from nationwide polls of gun owners. Most (62%) respondents were men; 40% were more than 55 years old; none was less than 25. Concern that children might find and use the gun was the most frequently cited reason for participating (46% of respondents). Of 141 firearms exchanged, 72% were handguns; 23% of respondents indicated that the guns they turned in were not in working order. Of respondents who owned a gun at the time of the program (rather than those who owned no guns and turned in a gun owned by someone else), 41% owned no guns after participating; the prevalence of handgun ownership declined from 79% to 32%. Those who continued to own guns were as likely as gun owners nationwide to keep a gun loaded in the house (odds ratio (OR) 0.9, 95% confidence interval (CI) 0.4 to 1.7) or to carry a gun with them (OR 1.5, 95% CI 0.6 to 3.8). Gun exchange programs may reduce risk for firearm violence among some participants, but a number of factors limit their overall benefits to host communities.


Organochlorine pesticides in surface soils from obsolete pesticide dumping ground in Hyderabad City, Pakistan: contamination levels and their potential for air-soil exchange.
This study was conducted to examine organochlorine pesticides (OCPs) contamination levels in the surface soil and air samples together with air-soil exchange fluxes at an obsolete pesticide dumping ground and the associated areas from Hyderabad City, Pakistan. Among all the sampling sites, concentrations of OCPs in the soil and air samples were found highest in obsolete pesticide dumping ground, whereas dominant contaminants were dichlorodiphenyltrichloroethane (DDTs) (soil: 77-212,200 ng g(-1); air: 90,700 pg m(-3)) and hexachlorocyclohexane (HCHs) (soil: 43-4,090 ng g(-1); air: 97,400 pg m(-3)) followed by chlordane, heptachlor and hexachlorobenzene (HCB). OCPs diagnostic indicative ratios reflect historical use as well as fresh input in the study area. Moreover, the air and soil fugacity ratios (0.9-1.0) at the dumping ground reflecting a tendency towards net volatilization of OCPs, while at the other sampling sites, the fugacity ratios indicate in some cases deposition and in other cases volatilization. Elevated concentrations of DDTs and HCHs at pesticide dumping ground and its surroundings pose potential exposure risk to biological organisms, to the safety of agricultural products and to the human health. Our study thus emphasizes the need of spatio-temporal monitoring of OCPs at local and regional scale to assess and remediate the future adverse implications.


Emotions in Go/NoGo conflicts.
On the basis of current emotion theories and functional and neurophysiological ties between the processing of conflicts and errors on the one hand and errors and emotions on the other hand we predicted that conflicts between prepotent Go responses and occasional NoGo trials in the Go/NoGo task would induce emotions. Skin conductance responses (SCRs), corrugator muscle activity, and startle blink responses were measured in three experiments requiring speeded Go responses intermixed with NoGo trials of different relative probability and in a choice reaction experiment serving as a control. NoGo trials affected several of these emotion-sensitive indicators as SCRs and startle blinks were reduced whereas corrugator activity was prolonged as compared to Go trials. From the pattern of findings we suggest that NoGo conflicts are not aversive. Instead, they appear to be appraised as obstructive for the response goal and as less action relevant than Go trials.


Exploring the roots of antagony in the safe male circumcision partnership in Botswana.
Partnerships in global health and development governance have been firmly established as a tool to achieve effective outcomes. Botswana implements Safe Male Circumcision (SMC) for HIV prevention through a North-South partnership comprising the local Ministry of Health, US Centers for Disease Control and Prevention (funded by PEPFAR) and Africa Comprehensive HIV/AIDS Partnership (funded by the Bill and Melinda Gates Foundation). The SMC partnership experienced significant antagony and the aim of this paper is to illuminate the actions and processes in the SMC program that contributed to that antagony. Methods used to gather data include observation of the partners' planning and strategic meeting in 2012, in-depth interviews with lead officers at national level, focus group discussions with district officers and implementers, younger male officers and old community members as recipients of the service. The findings reveal that the partnership experienced antagony during operational processes and as the ultimate outcome. Target setting, financial power of the North, superficial ownership given to the South, ignoring local traditional realities results in antagony. Three roots of antagony have been identified: 1. therapeutic domination-medical expertise given with arrogance; 2.iatrogenic violence-good intentions that cause unintended harm; 3. the Trojan horse-Reckless acceptance of the gift as well as deceptive power positioned under the pretext of benevolence. The three roots of antagony; therapeutic domination, iatrogenic violence and the Trojan horse, constitute attitudes, hidden intentions and unintended consequences that influence program implementation and cause harm at different levels. Examples of therapeutic domination and the Trojan horse have highlighted the need for vigilance at the stage of establishing a partnership, to prevent more powerful partners from developing and applying hidden agendas and to strengthen accountability from the local partner. Iatrogenic violence has highlighted the need for partnership interventions to prevent good partner intentions accidentally producing bad outcomes.


Clinical experience with mixed chimerism to induce transplantation tolerance.
Lymphohematopoietic chimerism was first shown to be associated with donor-specific allograft tolerance more than 60 years ago. However, early clinical experience with bone marrow transplantation soon revealed that conventional, myeloablative approaches were far too toxic and the risk of graft-versus-host disease too great to justify using this technology for the purpose of organ allograft tolerance induction in the absence of malignant disease. In this review, we discuss a step-wise approach that has been applied by several centers to establish less toxic approaches to using hematopoietic cell transplantation (HCT) for tolerance induction. These steps include (i) feasibility and efficacy data for tolerance induction in large animal models; (ii) safety data in clinical trials for patients with hematologic malignancies; and (iii) pilot trials of combined HCT and kidney transplantation for tolerance induction. Thus far, only one published trial conducted at the Massachusetts General Hospital in Boston has achieved long-term acceptance of human leukocyte antigen-mismatched kidney allografts without chronic immunosuppressive therapy. Alternative protocols have been successful in large animals, but long-term organ allograft tolerance has not been reported in patients. Thus, proof-of-principle that nonmyeloablative induction of mixed chimerism can be used intentionally to induce organ allograft tolerance has now been achieved. Directions for further research to make this approach applicable for a broader patient population are discussed.


The bacteriophage P1 hot gene product can substitute for the Escherichia coli DNA polymerase III {theta} subunit.
The theta subunit (holE gene product) of Escherichia coli DNA polymerase (Pol) III holoenzyme is a tightly bound component of the polymerase core. Within the core (alpha-epsilon-theta), the alpha and epsilon subunits carry the DNA polymerase and 3' proofreading functions, respectively, while the precise function of theta is unclear. holE homologs are present in genomes of other enterobacteriae, suggestive of a conserved function. Putative homologs have also been found in the genomes of bacteriophage P1 and of certain conjugative plasmids. The presence of these homologs is of interest, because these genomes are fully dependent on the host replication machinery and contribute few, if any, replication factors themselves. To study the role of these theta homologs, we have constructed an E. coli strain in which holE is replaced by the P1 homolog, hot. We show that hot is capable of substituting for holE when it is assayed for its antimutagenic action on the proofreading-impaired dnaQ49 mutator, which carries a temperature-sensitive epsilon subunit. The ability of hot to substitute for holE was also observed with other, although not all, dnaQ mutator alleles tested. The data suggest that the P1 hot gene product can substitute for the theta subunit and is likely incorporated in the Pol III complex. We also show that overexpression of either theta or Hot further suppresses the dnaQ49 mutator phenotype. This suggests that the complexing of dnaQ49-epsilon with theta is rate limiting for its ability to proofread DNA replication errors. The possible role of hot for bacteriophage P1 is discussed.


Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population.
Urine cadmium concentrations were associated with all-cause and cardiovascular mortality in men in the 1988-1994 U.S. National Health and Nutrition Examination Survey (NHANES) population. Since 1988, cadmium exposure has decreased substantially in the United States. The associations between blood and urine cadmium and cardiovascular disease (CVD) mortality at more recent levels of exposure are unknown. We evaluated the prospective association of blood and urine cadmium concentrations with all-cause and CVD mortality in the 1999-2004 U.S. population. We followed 8,989 participants who were ≥ 20 years of age for an average of 4.8 years. Hazard ratios for mortality end points comparing the 80th to the 20th percentiles of cadmium distributions were estimated using Cox regression. The multivariable adjusted hazard ratios [95% confidence intervals (CIs)] for blood and urine cadmium were 1.50 (95% CI: 1.07, 2.10) and 1.52 (95% CI: 1.00, 2.29), respectively, for all-cause mortality, 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for CVD mortality, 1.98 (95% CI: 1.11, 3.54) and 2.53 (95% CI: 1.54, 4.16) for heart disease mortality, and 1.73 (95% CI: 0.88, 3.40) and 2.09 (95% CI: 1.06, 4.13) for coronary heart disease mortality. The population attributable risks associated with the 80th percentile of the blood (0.80 μg/L) and urine (0.57 μg/g) cadmium distributions were 7.0 and 8.8%, respectively, for all-cause mortality and 7.5 and 9.2%, respectively, for CVD mortality. We found strongly suggestive evidence that cadmium, at substantially low levels of exposure, remains an important determinant of all-cause and CVD mortality in a representative sample of U.S. adults. Efforts to further reduce cadmium exposure in the population could contribute to a substantial decrease in CVD disease burden.


The effect of community-based programs on diabetes prevention in low- and middle-income countries: a systematic review and meta-analysis.
The increasing prevalence of type 2 diabetes mellitus (T2DM) can have a substantial impact in low- and middle-income countries (LMICs). Community-based programs addressing diet, physical activity, and health behaviors have shown significant benefits on the prevention and management of T2DM, mainly in high-income countries. However, their effects on preventing T2DM in the at-risk population of LMICs have not been thoroughly evaluated. The Cochrane Library (CENTRAL), MEDLINE, EMBASE and two clinical trial registries were searched to identify eligible studies. We applied a 10 years limit (from 01 Jan 2008 to 06 Mar 2018) on English language literature. We included randomized controlled trials (RCTs) with programs focused on lifestyle changes such as weight loss and/or physical activity increase, without pharmacological treatments, which aimed to alter incidence of diabetes or one of the T2DM risk factors, of at least 6 months duration based on follow-up, conducted in LMICs. Six RCTs randomizing 2574 people were included. The risk of developing diabetes in the intervention groups reduced more than 40%, RR (0.57 [0.30, 1.06]), for 1921 participants (moderate quality evidence), though it was not statistically significant. Significant differences were observed in weight, body mass index, and waist circumference change in favor of community-based programs from baseline, (MD [95% CI]; - 2.30 [- 3.40, - 1.19], p < 0.01, I2 = 87%), (MD [95% CI]; - 1.27 [- 2.10, - 0.44], p < 0.01, I2 = 96%), and (MD [95% CI]; - 1.66 [- 3.17, - 0.15], p = 0.03, I2 = 95%), respectively. The pooled effect showed a significant reduction in fasting blood glucose and HbA1C measurements in favor of the intervention (MD [95% CI]; - 4.94 [- 8.33, - 1.55], p < 0.01, I2 = 62%), (MD [95% CI]; - 1.17 [- 1.51, - 0.82], p < 0.01, I2 = 46%), respectively. No significant difference was observed in 2-h blood glucose values, systolic or diastolic blood pressure change between the two groups. Based on available literature, evidence suggests that community-based interventions may reduce the incidence rate of T2DM and may positively affect anthropometric indices and HbA1C. Due to the heterogeneity observed between trials we recommend more well-designed RCTs with longer follow-up durations be executed, to confirm whether community-based interventions lead to reduced T2DM events in the at-risk population of LMIC settings.


Inhibition of apoptosis by gamma interferon in cells and mice infected with Chlamydia muridarum (the mouse pneumonitis strain of Chlamydia trachomatis).
The effect of gamma interferon (IFN-gamma) on apoptosis due to infection by Chlamydia muridarum (the mouse pneumonitis strain of Chlamydia trachomatis) was studied in epithelial cells in culture and in the genital tracts of mice. IFN-gamma concentrations that induce the formation of aberrant, persistent chlamydiae inhibit apoptosis due to C. muridarum infection. In cells treated with an IFN-gamma concentration that leads to the development of a heterogenous population of normal and aberrant Chlamydia vacuoles, apoptosis was inhibited preferentially in cells that contained the aberrant vacuoles. The inhibitory effect of IFN-gamma appears to be due in part to expression of host cell indoleamine 2,3-dioxygenase activity, since inhibition of apoptosis could be partially reversed through coincubation with exogenous tryptophan. Apoptotic cells were observed in the genital tracts of wild-type mice infected with C. muridarum, and a significantly larger number of apoptotic cells was detected in infected IFN-gamma-deficient mice. These results suggest that IFN-gamma may contribute to pathogenesis of persistent Chlamydia infections in vivo by preventing apoptosis of infected cells.


Absorbance of opaque microstructures in optically diffuse media.
In this study experimental measurements are used to determine that the observed absorbance of opaque microstructures in optically diffuse media correlates with the total surface area rather than the attenuation as calculated in a nonscattering environment. The data suggest that it may be possible to use remote measurements of optical diffuse transmission to quantify surface areas of microcapillaries that are highly absorbing or larger blood vessels that can have high intrinsic attenuation because of hematocrit alone. Results obtained in a transmission geometry are insensitive to the position of the microstructure along the line between source and detector, whereas those collected in a remission geometry are highly sensitive to the depth at which the structure is located. These types of measurement involving microscopic structures embedded in diffuse media have potential application in quantifying blood vessel surface areas that contain contrast agents or other microparticles within tissue.


Mechanism of action of anticancer titanocene derivatives: an insight from quantum chemical calculations.
Titanocene derivatives exhibit high potential in the treatment of cisplatin-resistant tumor types. Density functional theory calculations were performed on the hydrated form of five drug candidates differing in the pendant arms attached to the aromatic rings. A qualitative correlation has been found between the experimentally measured anticancer activity of alkylammonium-functionalized titanocene derivatives and the computed free energy change of the proton-induced dissociation reaction of these compounds. The results indicate that differences in the cytotoxic activities could be related to the solvation properties of the protolysis products, whereas no correlation was found with gas-phase properties of these molecules. Contrary to the free energy change of the protolysis reaction, other molecular properties, such as the geometrical parameters or the binding energies of the cyclopentadienyl rings in solution, do not correlate with the in vitro cytotoxic activity of these drug candidates.


[Traumatic spinal cord injury: neurologic and functional recovery].
A retrospective study was conducted. Evaluate the neurologic and functional recovery in patients with Traumatic Spinal Cord Injury (TSCI). A retrospective study was conducted, including the 93 patients with a diagnosis of TSCI admitted for rehabilitation in the Physical and Rehabilitation Medicine Department, Santo António General Hospital, between January 1993 and December 2002. Demographic and clinical data were collected from the hospital charts. The patients were evaluated at admission for rehabilitation, before discharging, 1 year and 3 years after injury. Neurologic status was registered according to the standards of the American Spinal Injury Association (ASIA) and functional status by the Functional Independence Measure (FIM). The sample population was 87% men, with a mean age of 40 years. Motor vehicle accidents and falls were the commonest mechanism of injury. The majority sustained dorsal and cervical lesions (45% and 42% respectively). The initial management included: intravenous high dose methylprednisolone, administered within eight hours after injury in 54% of the sample; early surgical stabilization, performed on 77%. Incomplete cord injury carried a better prognosis of motor improvement, especially the patients classified as C on the ASIA Impairment Scale (AIS). A significant statistical association was found between the outcomes obtained during the initial rehabilitation, and the ones achieved on the 3 year followup period. The neurologic recovery was not related with the patient's age, injury level, high dose steroid administration or surgery performed in the first 24 hours after injury (p >0.05). The FIM scores demonstrated the favourable functional outcomes achieved, especially during the inpatient rehabilitation. The results of this study further demonstrate the considerable potential for neurologic recovery after TSCI, emphasizing the importance of the rehabilitation investment continuity, especially for the ones with incomplete cord injury.


Methods for monitoring and measurement of protein translation in time and space.
Regulation of protein translation constitutes a crucial step in control of gene expression. In comparison to transcriptional regulation, however, translational control has remained a significantly under-studied layer of gene expression. This trend is now beginning to shift thanks to recent advances in next-generation sequencing, proteomics, and microscopy based methodologies which allow accurate monitoring of protein translation rates, from single target messenger RNA molecules to genome-wide scale studies. In this review, we summarize these recent advances, and discuss how they are enabling researchers to study translational regulation in a wide variety of in vitro and in vivo biological systems, with unprecedented depth and spatiotemporal resolution.


The evolution of early hearing detection and intervention programs in the United States.
Identifying and treating children with congenital hearing loss during the first few months of life is a relatively new concept. To assist states in the development of statewide Early Hearing Detection and Intervention programs, the federal government provides grants and/or cooperative agreements to almost all states and has established "National Goals, Program Objectives and Performance Measures" to guide the development and implementation of those systems. This article reviews the history of newborn hearing screening programs in the United States, summarizes the content of legislation and regulations passed by states related to universal newborn hearing screening, and describes how well each National Goal has been addressed. Although substantial progress has been made in the percentage of infants screened for hearing loss before hospital discharge, significant improvement is needed with respect to the availability of pediatric audiologists, implementation of effective tracking and data management systems, program evaluation and quality assurance, availability of appropriate early intervention programs, and linkages with medical home providers.


Nuclear data for reactor production of 131Ba and 133Ba.
The newest radioisotope for brachytherapy treatment of prostate cancer is 131Cs (t1/2 = 9.69 d, 100% EC). Generated via electron capture decay of 131Ba (t1/2 = 11.6 d, 100% EC), 131Cs has been used in brachytherapy for prostate cancer since 2004. The 131Ba parent is produced through neutron capture of enriched 130Ba in a nuclear reactor. For large-scale production of 131Ba, an accurate knowledge of production and burnup cross sections of 131Ba are essential. In this paper, we report two group cross sections (thermal and resonance integrals) for 130Ba and 131Ba and a new measure of the half-life of 131Ba. Targets consisting of milligram quantities of enriched 130Ba (∼35%) were irradiated in Oak Ridge National Laboratory's High Flux Isotope Reactor at thermal and resonance neutron fluxes of (1.9-2.1) × 1015 and (5.8-7.0) × 1013 neutrons·cm-2 s-1, respectively, for durations ranging from 3 to 26 days. In addition, cadmium covered samples of 130Ba were irradiated for 1 hour at 12.6% full reactor power (10.7 MW). The yield of 131Ba approaches a saturation value of ∼60 GBq (∼1.6 Ci) per mg of 130Ba for 20 days irradiation at a thermal neutron flux of 1.8 × 1015 n·s-1·cm-2, with a thermal/epithermal ratio of ∼30. Under the above experimental conditions, the two group cross sections of 130Ba are 6.9 ± 0.5 b (thermal, σ0) and 173 ± 7 b (resonance, I0). These values represent the sum of cross sections to metastable and ground states of 131Ba. For 131Ba, the empirically measured thermal cross section is 200 ± 50 b assuming an I0/σ0 of 10. This cross section is reported for the first time. Further, the half-life of 131Ba was remeasured to be 11.657 ± 0.008 d. Lastly, this study also resulted in the co-production of 133Ba (t1/2 = 10.52 y, 100% EC). The experimental yield of 133Ba is ∼370 MBq (∼10 mCi) per mg of 132Ba (thin target) for one cycle irradiation in the High Flux Isotope Reactor, and measured two-group 132Ba cross sections are 7.2 ± 0.2 b and 39.9 ± 1.3 b. These values also represent the sum of cross sections to metastable and ground states of 133Ba.


Negative regulatory elements are present in the human LMO2 oncogene and may contribute to its expression in leukemia.
Ectopic expression of LMO2 occurs in approximately 45% of T-lineage acute lymphoblastic leukemias (T-ALL), sometimes in association with chromosomal translocations. Recently, a lymphoproliferative disorder developed in two participants in a gene therapy trial due to LMO2 activation via integration of the retroviral vector. To investigate these regulatory disruptions, we analyzed the promoter region and identified a tissue-specific repressor. The fragment containing this element could also produce tissue-specific suppression of transcription from the SV40 promoter. This suppression involves histone acetylation which can be relieved with Trichostatin A (TSA). The negative element is in a region consistently removed from LMO2 in the known chromosomal translocations.


Nuclear factor-kappaB: the enemy within.
Numerous lines of investigation suggest that nuclear factor NF-kappaB, a proinflammatory transcription factor, could promote tumorigenesis. Various inflammatory agents, carcinogens, tumor promoters, and the tumor microenvironment activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by it have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis, and metastasis. Constitutively activated NF-kappaB is common in wide variety of tumors. Furthermore, there exists genetic evidence that NF-kappaB mediates tumorigenesis. Thus, suppression of NF-kappaB activation should be effective in the prevention and treatment of cancer.


Residents' experiences of encounters with relatives and significant persons: a hermeneutic study.
The aim of this study was to explore and interpret the meaning of residents' experiences of encounters with their relatives and other significant persons in nursing homes. Twelve residents in three different nursing homes in a western Sweden municipality were interviewed. The method used was hermeneutical text analysis. Three themes emerged in the interpretation of the text: being pleased, being someone, and being inconvenient. These themes were also described through seven subthemes: to be happy to have someone, to make someone else happy, going back in life, to be together in a community, not being alone, to be disconnected, and to be a burden. The study concludes that it is important for nurses in nursing homes to develop a deeper insight into what various social contacts can mean for residents. To develop this knowledge, it is important that nurses in nursing homes can be educated, and supported by clinical supervision, in relation to residents' experiences of encounters with relatives and other significant persons.


Transgenerational effects of historic radiation dose in pale grass blue butterflies around Fukushima following the Fukushima Dai-ichi Nuclear Power Plant meltdown accident.
Low dose radiation effects have been investigated in Chernobyl for many years but there is uncertainty about initial doses received by many animal species. However, the Fukushima Dai-ichi Nuclear Power Plant accident opens an opportunity to study the effects of the initial low historic dose on directly exposed species and their progeny during a time where the contaminating radionuclides are decaying. In this paper, it is proposed that historic acute exposure and its resulting non-targeted effects (NTEs) may be partially involved in the high mortality/abnormality rates seen across generations of pale grass blue butterflies (Zizeeria maha) around Fukushima. Data from Hiyama et al. (2012) on the morphological abnormality frequencies in Z. maha collected around Fukushima and their progeny were used in this paper. Two dose reconstruction methods based on the Gaussian plume model were used to determine the external absorbed dose to the first exposed generation from both ground shine and plume shine. One method involved the use of the dose rate recorded at the time of collection and only took Cs-137 into account. The other involved using release rates and atmospheric conditions to determine the doses and considered Cs-137 and Cs-134. The reconstructed doses were plotted against the mortality rates and abnormality frequencies across generations. The mortality rates of the progeny from irradiated progenitors increased linearly with the increasing historic radiation doses reconstructed using both Cs-137 and Cs-134 sources. Additionally, a higher level of morphological abnormalities was observed in progeny than in the progenitors. The mean abnormality frequencies also increased throughout generations. As these results are a sign of NTEs being involved, it can be suggested that increasing mutation levels across generations may result, in part, from NTEs induced by the initial low dose received by the first exposed generation. However, continual accumulation of mutations over generations in their natural contaminated habitats remains a likely contributor into the observed outcome.


A novel HLA-A*3303-restricted minor histocompatibility antigen encoded by an unconventional open reading frame of human TMSB4Y gene.
Female-to-male hemopoietic stem cell transplantation (HSCT) elicits T cell responses against male-specific minor histocompatibility (H-Y) Ags encoded by the Y chromosome. All previously identified H-Y Ags are encoded by conventional open reading frames, but we report in this study the identification of a novel H-Y Ag encoded in the 5'-untranslated region of the TMSB4Y gene. An HLA-A*3303-restricted CD8(+) CTL clone was isolated from a male patient after an HSCT from his HLA-identical sister. Using a panel of cell lines carrying Y chromosome terminal deletions, a narrow region controlling the susceptibility of these target cells to CTL recognition was localized. Minigene transfection and epitope reconstitution assays identified an 11-mer peptide, EVLLRPGLHFR, designated TMSB4Y/A33, whose first amino acid was located 405 bp upstream of the TMSB4Y initiation codon. Analysis of the precursor frequency of CTL specific for recipient minor histocompatibility Ags in post-HSCT peripheral blood T cells revealed that a significant fraction of the total donor CTL response in this patient was directed against the TMSB4Y epitope. Tetramer analysis continued to detect TMSB4Y/A33-specific CD8(+) T cells at least up to 700 days post-HSCT. This finding underscores the in vivo immunological relevance of minor histocompatibility Ags derived from unconventional open reading frame products.


Inflamed-HLH, MAS, or something else?
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive and maladaptive inflammation. Primary HLH is most frequently encountered in young children, and, without timely recognition and therapy, can lead to multiorgan failure and death. It is most often diagnosed using the HLH-2004 criteria and by identifying pathological mutations. However, the HLH-2004 criteria are not specific for HLH, and patients can easily fulfill these diagnostic criteria in other proinflammatory states in which HLH-therapy would not be indicated, including hematologic malignancies, infections, and rheumatologic disease. Therefore, great care must be taken to ensure that the specific disease associated with features of HLH is accurately recognized, as consequences of improper treatment can be catastrophic. We propose a diagnostic pathway for patients for whom HLH is on the differential (visual abstract). Importantly, in situations in which the initial diagnostic workup is equivocal or unrevealing, reevaluation for occult malignancy, infection, or rheumatologic disease would be prudent, as occult presentations may be missed on primary evaluation. Temporizing medications can be used in critically ill patients while awaiting secondary evaluation. By using this framework, clinicians will be able to more reliably discern primary HLH from other pro-inflammatory states and thus provide timely, appropriate disease-specific therapy.


Two-criteria dental aging method applied to a Bosnian population: comparison of formulae for each tooth group versus one formula for all teeth.
The purpose of this study was to obtain age estimation formulae using the length of periodontosis, transparency of the root and root height in each tooth group for the current male population in Bosnia and Herzegovina and to compare these formulae with Lamendin's and Prince's formulae. The research was undertaken on 847 single rooted teeth from 200 identified deceased persons, individuals who died between the ages of 23 and 85 years. Periodontosis, transparency and root height were measured according to Lamendin's procedure. All teeth were grouped in two ways: according to the tooth groups and to the age groups. The highest coefficients of correlation are obtained for maxillary canines (R = 0,731) and mandibular canines (R = 0,706) and the maxillary lateral incisors showed the lowest mean error (ME = 6,63 years). In age groups, the lowest mean error was obtained in the 40-49 years age group (ME = 5,15 years). Equations developed in this study give statistically significantly better age estimations in comparison to the original Lamendin and Prince formulae for the whole sample as well as for each tooth group, except for mandibular central incisors. Age estimation with models developed for each tooth group (except for mandibular lateral incisors) was statistically significantly better than models based on the whole sample.


mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein.
The mdm-2 gene encodes a 90-kDa polypeptide that binds specifically to the p53 tumor suppressor protein. This physical interaction results in the inhibition of the transcriptional functions of p53 (J. Chen, J. Lin, and A. J. Levine, Mol. Med. 1:142-152, 1995, and J. Momand, G. P. Zambetti, D. C. Olson, D. George, and A. J. Levine, Cell 69:1237-1245, 1992). Experiments are described that demonstrate the ability of mdm-2 to abrogate both the p53-mediated cell cycle arrest and the apoptosis functions. In addition, the results presented here suggest that mdm-2 binding to p53 and the resultant inhibition of p53 transcription functions are critical for reversing p53-mediated cell cycle arrest. The N-terminal half or domain of the mdm-2 protein is sufficient to regulate these biological activities of p53, consistent with the possibility that the highly conserved central acidic region and the C-terminal putative zinc fingers of mdm-2 may encode other functions.


The safety of flexible endoscopic evaluation of swallowing with sensory testing (FEESST): an analysis of 500 consecutive evaluations.
We assessed the safety of a new office or bedside method of evaluating both the motor and sensory components of swallowing called flexible endoscopic evaluation of swallowing with sensory testing (FEESST). FEESST combines the established endoscopic evaluation of swallowing with a technique that determines laryngopharyngeal sensory discrimination thresholds by endoscopically delivering air-pulse stimuli to the mucosa innervated by the superior laryngeal nerve. Endoscopic assessment of laryngopharyngeal sensory capacity followed by endoscopic visualization of deglutition was prospectively performed 500 times in 253 patients with dysphagia over a 2.5-year period in a tertiary care center. The patients had a variety of underlying diagnoses, with stroke and chronic neurological disease predominating (n = 155). To determine the safety of FEESST, the presence of epistaxis, airway compromise, and significant changes in heart rate before and after the evaluation were assessed. Patients were also asked to rate the level of discomfort of the examination; 498 evaluations were completed. There were three instances of epistaxis that were self-limited. There were no cases of airway compromise. There were no significant differences in heart rate between pre- and posttest measurements (p > 0.05). Eighty-one percent of patients noted either no discomfort or mild discomfort as a result of the examination. In conclusion, FEESST is a safe method of evaluating dysphagia in the tertiary care setting and may also have application for the chronic care setting.


Factors affecting DNA-DNA interstrand cross-links in the antiparallel 3'-3' sense: a comparison with the 5'-5' directional isomer.
Reported herein is a study of the unusual 3'-3' 1,4-GG interstrand cross-link (IXL) formation in duplex DNA by a series of polynuclear platinum anticancer complexes. To examine the effect of possible preassociation through charge and hydrogen-bonding effects the closely related compounds [{trans-PtCl(NH(3))(2)}(2)(mu-trans-Pt(NH(3))(2){NH(2)(CH(2))(6)NH(2)}(2))](4+) (BBR3464, 1), [{trans-PtCl(NH(3))(2)}(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (BBR3005, 2), [{trans-PtCl(NH(3))(2)}(2)(mu-H(2)N(CH(2))(3)NH(2)(CH(2))(4))](3+) (BBR3571, 3) and [{trans-PtCl(NH(3))(2)}(2){mu-H(2)N(CH(2))(3)-N(COCF(3))(CH(2))(4)}](2+) (BBR3571-COCF(3), 4) were studied. Two different molecular biology approaches were used to investigate the effect of DNA template upon IXL formation in synthetic 20-base-pair duplexes. In the "hybridisation directed" method the monofunctionally adducted top strands were hybridised with their complementary 5'-end labelled strands; after 24 h the efficiency of interstrand cross-linking in the 5'-5' direction was slightly higher than in the 3'-3' direction. The second method involved "postsynthetic modification" of the intact duplex; significantly less cross-linking was observed, but again a slight preference for the 5'-5' duplex was present. 2D [(1)H, (15)N] HSQC NMR spectroscopy studies of the reaction of [(15)N]-1 with the sequence 5'-d{TATACATGTATA}(2) allowed direct comparison of the stepwise formation of the 3'-3' IXL with the previously studied 5'-5' IXL on the analogous sequence 5'-d(ATATGTACATAT)(2). Whereas the preassociation and aquation steps were similar, differences were evident at the monofunctional binding step. The reaction did not yield a single distinct 3'-3' 1,4-GG IXL, but numerous cross-linked adducts formed. Similar results were found for the reaction with the dinuclear [(15)N]-2. Molecular dynamics simulations for the 3'-3' IXLs formed by both 1 and 2 showed a highly distorted structure with evident fraying of the end base pairs and considerable widening of the minor groove.


Physiological Signal Variability in hMT+ Reflects Performance on a Direction Discrimination Task.
Our ability to perceive visual motion is critically dependent on the human motion complex (hMT+) in the dorsal visual stream. Extensive electrophysiological research in the monkey equivalent of this region has demonstrated how neuronal populations code for properties such as speed and direction, and that neurometric functions relate to psychometric functions within the individual monkey. In humans, the physiological correlates of inter-individual perceptual differences are still largely unknown. To address this question, we used functional magnetic resonance imaging (fMRI) while participants viewed translational motion in different directions, and we measured thresholds for direction discrimination of moving stimuli in a separate psychophysics experiment. After determining hMT+ in each participant with a functional localizer, we were able to decode the different directions of visual motion from it using pattern classification (PC). We also characterized the variability of fMRI signal in hMT+ during stimulus and rest periods with a generative model. Relating perceptual performance to physiology, individual direction discrimination thresholds were significantly correlated with the variability measure in hMT+, but not with PC accuracies. Individual differences in PC accuracy were driven by non-physiological sources of noise, such as head-movement, which makes this method a poor tool to investigate inter-individual differences. In contrast, variability analysis of the fMRI signal was robust to non-physiological noise, and variability characteristics in hMT+ correlated with psychophysical thresholds in the individual participants. Higher levels of fMRI signal variability compared to rest correlated with lower discrimination thresholds. This result is in line with theories on stochastic resonance in the context of neuronal populations, which suggest that endogenous or exogenous noise can increase the sensitivity of neuronal populations to incoming signals.


An apple MYB transcription factor, MdMYB3, is involved in regulation of anthocyanin biosynthesis and flower development.
Red coloration of fruit is an important trait in apple, and it is mainly attributed to the accumulation of anthocyanins, a class of plant flavonoid metabolites. Anthocyanin biosynthesis is genetically determined by structural and regulatory genes. Plant tissue pigmentation patterns are mainly controlled by expression profiles of regulatory genes. Among these regulatory genes are MYB transcription factors (TFs), wherein the class of two-repeats (R2R3) is deemed the largest, and these are associated with the anthocyanin biosynthesis pathway. Although three MdMYB genes, almost identical in nucleotide sequences, have been identified in apple, it is likely that there are other R2R3 MYB TFs that are present in the apple genome that are also involved in the regulation of coloration of red color pigmentation of the skin of apple fruits. In this study, a novel R2R3 MYB gene has been isolated and characterized in apple. This MYB gene is closely related to the Arabidopsis thaliana AtMYB3, and has been designated as MdMYB3. This TF belongs to the subgroup 4 R2R3 family of plant MYB transcription factors. This apple MdMYB3 gene is mapped onto linkage group 15 of the integrated apple genetic map. Transcripts of MdMYB3 are detected in all analyzed tissues including leaves, flowers, and fruits. However, transcripts of MdMYB3 are higher in excocarp of red-skinned apple cultivars than that in yellowish-green skinned apple cultivars. When this gene is ectopically expressed in Nicotiana tabacum cv. Petite Havana SR1, flowers of transgenic tobacco lines carrying MdMYB3 have exhibited increased pigmentation and accumulate higher levels of anthocyanins and flavonols than wild-type flowers. Overexpression of MdMYB3 has resulted in transcriptional activation of several flavonoid pathway genes, including CHS, CHI, UFGT, and FLS. Moreover, peduncles of flowers and styles of pistils of transgenic plants overexpressing MdMYB3 are longer than those of wild-type plants, thus suggesting that this TF is involved in regulation of flower development. This study has identified a novel MYB transcription factor in the apple genome. This TF, designated as MdMYB3, is involved in transcriptional activation of several flavonoid pathway genes. Moreover, this TF not only regulates the accumulation of anthocyanin in the skin of apple fruits, but it is also involved in the regulation of flower development, particularly that of pistil development.


Incidence of Airway Interventions in the Setting of Serious Facial Trauma.
Airway obstruction is the second leading cause of preventable death on the battlefield. Most airway obstruction occurs secondary to traumatic disruptions of the airway anatomical structures. Facial trauma is frequently cited as rationale for maintaining cricothyrotomy in the medics' skill set over the supraglottic airways more commonly used in the civilian setting. We used a series of emergency department procedure codes to identify patients within the Department of Defense Trauma Registry (DoDTR) from January 2007 to August 2016. This is a sub-group analysis of casualties with documented serious facial trauma based on an abbreviated injury scale of 3 or greater for the facial body region. Our predefined search codes captured 28,222 DoDTR casualties, of which we identified 136 (0.5%) casualties with serious facial trauma, of which 19 of the 136 had documentation of an airway intervention (13.9%). No casualties with serious facial trauma underwent nasopharyngeal airway (NPA) placement, 0.04% underwent cricothyrotomy (n = 10), 0.03% underwent intubation (n = 9), and a single subject underwent supraglottic airway (SGA) placement (<0.01%). We only identified four casualties (0.01% of total dataset) with an isolated injury to the face. Serious injury to the face rarely occurred among trauma casualties within the DoDTR. In this subgroup analysis of casualties with serious facial trauma, the incidence of airway interventions to include cricothyrotomy was exceedingly low. However, within this small subset the mortality rate is high and thus better methods for airway management need to be developed.


Plasma fibrinopeptide A and beta-thromboglobulin in pre-eclampsia and pregnancy hypertension.
Increased plasma levels of beta-thromboglobulin (beta TG) and fibrinopeptide A (FPA), markers of platelet release and thrombin generation respectively, were measured in normal women, women taking oral contraceptives, normal pregnancy and pregnant women with hypertension or pre-eclampsia. No significant increases in beta TG or FPA were found in women taking oral contraceptives. Significantly increased concentrations of beta TG, but not FPA, were found in normal pregnant women in the second and third trimester of pregnancy when compared with non-pregnant age-matched controls. In eleven women with pregnancy hypertension and thirteen women with pre-eclampsia significantly elevated levels of both beta TG and FPA were found when compared with age, parity and gestation-matched pregnant controls. Although the mean value for both beta TG and FPA in the group with pre-eclampsia was higher than the group with pregnancy hypertension, the difference was not statistically significant. These findings provide additional evidence that pre-eclampsia and pregnancy hypertension are associated with activation of the coagulation system and the platelet release reaction.


"Etazene, safer than heroin and fentanyl": Non-fentanyl novel synthetic opioid listings on one darknet market.
Novel synthetic opioids are fueling the overdose deaths epidemic in North America.Recently, non-fentanyl novel synthetic opioids have emerged in forensic toxicological results. Cryptomarkets have become important platforms of distribution for illicit substances. This article presents the data concerning the availability trends of novel non-fentanyl synthetic opioids listed on one cryptomarket. Listings from the EmpireMarket cryptomarket "Opiates" section were collected between June 2020 and August 2020. Collected data were processed using eDarkTrends Named Entity Recognition algorithm to identify novel synthetic opioids, and to analyze their availability trends in terms of frequency of listings, available average weights, average prices, quantity sold, and geographic indicators of shipment origin and destination information. 35,196 opioid-related listings were collected through 12 crawling sessions. 17 nonfentanyl novel synthetic opioids were identified in 2.9 % of the collected listings for an average of 9.2 kg of substance available at each data point. 587 items advertised as non-fentanyl novel synthetic opioids were sold on EmpireMarket for a total weight of between 858 g and 2.7 kg during the study period. 45.5 % of these listings were advertised as shipped from China. Fourteen of the 17 non-fentanyl novel synthetic opioids were identified for the first time on one large cryptomarket suggesting a shift in terms of novel non-fentanyl synthetic opioids availability. This increased heterogeneity of available novel synthetic opioids could reduce the efficiency of existing overdose prevention strategies. Identification of new opioids underpins the value of cryptomarket data for early warning systems of emerging substance use trends.


Nonadherence to dialysis among saudi patients - Its prevalence, causes, and consequences.
Dialysis nonadherence among Saudi hemodialysis (HD) patients has not been studied previously. We study its prevalence, causes, and consequences. All chronic HD patients at our center were enrolled. Their demographics as well as levels of hemoglobin (Hb), Kt/v, potassium, and phosphate; dialysis type; dialysis vintage; duration; and shift were recorded. Nonadherence, defined as missed dialysis session or patient-derived shortening of the dialysis session by >10 min at least once over a month's period, was recorded. We analyzed the relationship of nonadherence to emergency room visits, hospitalizations, interdialytic weight gain (IDWG), intradialytic symptoms, home-to-hospital distance, and smoking habits. Two hundred and sixty-five patients were included; their mean age was 61.8 ± 18.2 years, 47.3% were male, dialysis vintage was 3.8 ± 3.3 years, 5.9% were on HD, and 34.1% were on hemodiafiltration. During the study period, the nonadherence rate was 25% for missed dialysis sessions and 72% for shortened dialysis on at least one occasion. Nonadherence was more likely to occur in males than females (75% and 66%, respectively, P = 0.05), in smokers (57.1% vs. 21.7%, P = 0.0003), and in night shifts rather than day shifts (33.6% vs. 20.6%, P = 0.042). Nonadherent patients had lower Kt/V than adherent patients (1.22 ± 0.2 and 1.31 ± 0.2, respectively P = 0.01), had higher mean IDWG (2.7 ± 1.0 and 2.4 ± 1.0 kg, respectively, P = 0.02), and are more likely to be hospitalized (50% vs. 32%, P = 0.01). On the other hand, no differences were observed in serum phosphate, potassium, or Hb levels; intradialytic symptoms; education; employment; the distance between the dialysis unit and home; type of dialysis; Charlson Comorbidity Index; or the dialysis vintage. The prevalence of nonadherence in our group was comparable to that of other reports and is more likely to occur in male patients, smokers, and those in night shifts. It is associated with lower dialysis adequacy, higher mean IDWG, and higher hospitalization rate.


Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice.
Severe combined immunodeficient (SCID) mice transplanted with human bone marrow were treated with human mast cell growth factor, a fusion of interleukin-3 and granulocyte-macrophage colony-stimulating factor (PIXY321), or both, starting immediately or 1 month later. Immature human cells repopulated the mouse bone marrow with differentiated human cells of multiple myeloid and lymphoid lineages; inclusion of erythropoietin resulted in human red cells in the peripheral blood. The bone marrow of growth factor-treated mice contained both multipotential and committed myeloid and erythroid progenitors, whereas mice not given growth factors had few human cells and only granulocyte-macrophage progenitors. Thus, this system allows the detection of immature human cells, identification of the growth factors that regulate them, and the establishment of animal models of human hematopoietic diseases.


Enhanced rhamnolipid production in Burkholderia thailandensis transposon knockout strains deficient in polyhydroxyalkanoate (PHA) synthesis.
Microbially produced rhamnolipids have significant commercial potential; however, the main bacterial producer, Pseudomonas aeruginosa, is an opportunistic human pathogen, which limits biotechnological exploitation. The non-pathogenic species Burkholderia thailandensis produces rhamnolipids; however, yield is relatively low. The aim of this study was to determine whether rhamnolipid production could be increased in Burkholderia thailandensis through mutation of genes responsible for the synthesis of the storage material polyhydroxyalkanoate (PHA), thereby increasing cellular resources for the production of rhamnolipids. Potential PHA target genes were identified in B. thailandensis through comparison with known function genes in Pseudomonas aeruginosa. Multiple knockout strains for the phbA, phbB and phbC genes were obtained and their growth characteristics and rhamnolipid and PHA production determined. The wild-type strain and an rhamnolipid (RL)-deficient strain were used as controls. Three knockout strains (ΔphbA1, ΔphbB1 and ΔphbC1) with the best enhancement of rhamnolipid production were selected for detailed study. ΔphbB1 produced the highest level of purified RL (3.78 g l-1) compared to the wild-type strain (1.28 g l-1). In ΔphbB1, the proportion of mono-rhamnolipid was also increased compared to the wild-type strain. The production of PHA was reduced by at least 80% in all three phb mutant strains, although never completely eliminated. These results suggest that, in contrast to Pseudomonas aeruginosa, knockout of the PHA synthesis pathway in Burkholderia thailandensis could be used to increase rhamnolipid production. The evidence of residual PHA production in the phb mutant strains suggests B. thailandensis possesses a secondary unelucidated PHA synthesis pathway.


Rickettsia and Bartonella species in fleas from Reunion Island.
Rickettsia felis, Rickettsia typhi, and Bartonella DNA was detected by molecular tools in 12% of Rattus rattus fleas (Xenopsylla species) collected from Reunion Island. One-third of the infested commensal rodents captured during 1 year carried at least one infected flea. As clinical signs of these zoonoses are non-specific, they are often misdiagnosed.


Dampness in buildings and health. Nordic interdisciplinary review of the scientific evidence on associations between exposure to "dampness" in buildings and health effects (NORDDAMP).
Several epidemiological investigations concerning indoor environments have indicated that "dampness" in buildings is associated to health effects such as respiratory symptoms, asthma and allergy. The aim of the present interdisciplinary review is to evaluate this association as shown in the epidemiological literature. A literature search identified 590 peer-reviewed articles of which 61 have been the foundation for this review. The review shows that "dampness" in buildings appears to increase the risk for health effects in the airways, such as cough, wheeze and asthma. Relative risks are in the range of OR 1.4-2.2. There also seems to be an association between "dampness" and other symptoms such as tiredness, headache and airways infections. It is concluded that the evidence for a causal association between "dampness" and health effects is strong. However, the mechanisms are unknown. Several definitions of dampness have been used in the studies, but all seems to be associated with health problems. Sensitisation to mites may be one but obviously not the only mechanism. Even if the mechanisms are unknown, there is sufficient evidence to take preventive measures against dampness in buildings.


Ministernotomy for repair of congenital cardiac disease.
We report our experience with repair of a variety of congenital heart defects utilizing a ministernotomy incision. A ministernotomy was used in 79 patients with a variety of congenital heart diseases from November 2004 to August 2007. Patients included 36 males and 43 females with ages ranging from 1 month to 122 months (median age, 22 months). The weight ranged from 3.5 kg to 40 kg (median weight, 10.9 kg). There were no deaths, and one conversion to full median sternotomy (1/79, 1.3%). The median cardiopulmonary bypass time was 59 min, and median aortic cross-clamp time was 38 min. One patient underwent atrial septal defect (ASD) repair with fibrillatory arrest time of 35 min. The operating time ranged from 103 min to 312 min (median operating time, 168 min). The intensive care unit (ICU) stay ranged from 1 to 21 days (median ICU stay, 1 day) and the hospital stay ranged from 2 to 56 days (median hospital stay, 4 days). There were no reinterventions for residual cardiac defects. We demonstrate the safety and efficacy of ministernotomy for the correction of a range of congenital heart defects with improved cosmetic results.


Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells.
Metastasis is the leading cause of cancer mortality. Extravasation of cancer cells is a critical step of metastasis. We report a novel proof-of-concept study that investigated whether non-toxic blood-soluble chemical agents capable of rheological modification of the near-vessel-wall blood flow can reduce extravasation of tumor cells and subsequent development of metastasis. Using an experimental metastasis model, we demonstrated that systemic administration of nanomolar concentrations of so-called drag-reducing polymer dramatically impeded extravasation and development of pulmonary metastasis of breast cancer cells in mice. This is the first proof-of-principle study to directly demonstrate physical/rheological, as opposed to chemical, way to prevent cancer cells from extravasation and developing metastasis and, thus, it opens the possibility of a new direction of adjuvant interventional approach in cancer.


Echoes of the brain within the posterior cingulate cortex.
There is considerable uncertainty about the function of the posterior cingulate cortex (PCC). The PCC is a major node within the default mode network (DMN) and has high metabolic activity and dense structural connectivity to widespread brain regions, which suggests it has a role as a cortical hub. The region appears to be involved in internally directed thought, for example, memory recollection. However, recent nonhuman primate work provides evidence for a more active role in the control of cognition, through signaling an environmental change and the need to alter behavior. For an organism to flexibly react to a changing environment, information processed in functionally distinct brain networks needs to be integrated by such a cortical hub. If the PCC is involved in this process, its brain activity should show a complex and dynamic pattern that partially reflects activity in other brain networks. Using fMRI in humans and a multivariate analysis, we demonstrate that the PCC shows this type of complex functional architecture, where echoes of multiple other brain networks are seen in separable yet overlapping subregions. For example, a predominantly ventral region shows strong functional connectivity to the rest of the DMN, whereas two subregions within the dorsal PCC show high connectivity to frontoparietal networks involved in cognitive control. PCC subregions showed distinct patterns of activity modulation during the performance of an attentionally demanding task, suggesting that parts of the dorsal PCC interact with frontoparietal networks to regulate the balance between internally and externally directed cognition.


Concomitant increases in galectin-1 and its glycoconjugate ligands (carcinoembryonic antigen, lamp-1, and lamp-2) in cultured human colon carcinoma cells by sodium butyrate.
Galactoside-binding lectins (galectins) with molecular masses of about 14.5 kilodaltons (galectin-1) and 31 kilodaltons (galectin-3) have been found in a variety of normal and malignant cells and have been implicated in the regulation of cell growth, cell adhesion, and metastasis. The KM12 human colon carcinoma cell line was found to express only galectin-3. Because the levels of both galectins are developmentally regulated and can be modulated during the differentiation of several cultured tumor cell lines, we studied the ability of 11 differentiation-inducing agents to induce galectin-1 expression in the KM12 cells. Treatment of these cells with sodium butyrate, an established differentiation-inducing agent for colon carcinoma cells, resulted in the induction of galectin-1, which was detected by immunoblotting as well as by affinity chromatography. This effect was not seen with any of the 10 other differentiating agents: hexamethylene bisacetamide, dimethyl sulfoxide, dimethyl formamide, herbimycin A, mycophenolic acid, retinoic acid, difluoromethyl ornithine, dibutyryl cAMP, 8-chloro cAMP, and transforming growth factor beta 1. Galectin-1 induction by butyrate was observed in seven other human colon carcinoma cell lines. Further studies with the KM12 cells revealed that butyrate caused cell flattening, suppressed cell proliferation and colony formation in agarose, and increased the level of carcinoembryonic antigen, a marker of human colon carcinoma cell differentiation, within 48 h of treatment. The increase in galectin-1 level was dependent linearly on butyrate concentration (range, 1-4 mM). Galectin-1 mRNA expression was detected by Northern blotting as early as 6 h, and the protein was detected after 24 h of treatment initiation. The level of the constitutively expressed galectin-3 was also increased by butyrate but to a lesser extent than the level of galectin-1. Butyrate-induced galectin-1 was detected on the cell surface by immunoprecipitation from radioiodinated cell surface proteins as well as by indirect immunofluorescence labeling. Affinity-purified human galectin-1 was found to bind to purified polylactosamine-containing glycoproteins and to detergent-solubilized cellular proteins electroblotted onto nitrocellulose membranes. Affinity chromatography of [3H]glucosamine-labeled KM12 cell extracts on immobilized galectin-1 followed by immunoprecipitation from the lactose-eluted material demonstrated that lysosome-associated membrane glycoprotein-1, carcinoembryonic antigen, and nonspecific cross-reacting antigen are the major galectin-1-binding proteins in these cells. These results indicate that galectin-1 expression may be associated with the differentiation of KM12 cells and that several glycoproteins shown to be important in colon carcinoma adhesion and metastasis are capable of functioning as its endogenous ligands.


Prevalence of same-sex behavior and orientation in England: results from a national survey.
There are few data sources on the prevalence of same-sex sexual orientation in England.We aimed to measure the prevalence of same-sex orientation and behavior in the English general population and assess the impact of enquiry format on reporting. The Adult Psychiatric Morbidity Survey 2007 used a multi-stage, stratified probability-sampling design (n=7,403). Two questions addressed sexual orientation and sexual partnership and each had two versions. Version A of the sexual orientation question used "homosexual." Version B used "gay or lesbian." Version A of the sexual partnership question required participants who had male and female partners to say which was predominant, while Version B had a midpoint response option: "about equally with men and women." Participants were randomized between versions. Overall, 5.3% of men and 5.6%of women reported they were not entirely heterosexual. The question using "gay or lesbian" elicited higher (though not statistically significant) reporting of non-heterosexual orientation than the question using "homosexual." A significantly larger proportion of men and women (96.0 and 96.1%) reported entirely heterosexual partnerships in response to Version A of the partnership question than in response to Version B (94.0 and 92.9%) where Version B asked specifically about "kissing, touching, intercourse, or any other form of sex." These figures constitute the first national prevalence data on combined sexual orientation and sexual behavior in England, based on a random probability sample of the general population. They demonstrate that people are willing to report their sexual orientation in survey research, but reporting is sensitive to question wording.


Repair of dihydrouracil supported by base excision repair in mNTH1 knock-out cell extracts.
In mammalian cells, thymine glycols and other oxidized pyrimidines such as 5,6-dihydrouracil are removed from DNA by the NTH1 protein, a bifunctional DNA-N-glycosylase. However, mNTH1 knock-out mice in common with other DNA glycosylase-deficient mice do not show any severe abnormalities associated with accumulation of DNA damage and mutations. In the present study we used an in vitro repair system to investigate the mechanism for the removal of 5,6-dihydrouracil from DNA by mNTH1-deficient cell-free extracts derived from testes of mNTH1 knock-out mice. We found that these extracts are able to support the removal of 5,6-dihydrouracil from DNA at about 20% of the efficiency of normal extracts. Furthermore, we also found that single-nucleotide patch base excision repair is the major pathway for removal of 5,6-dihydrouracil in mNTH1-deficient cell extracts, suggesting the involvement of other DNA glycosylase(s) in the removal of oxidized pyrimidines.


Quantification of acylglycines in human urine by HPLC electrospray ionization-tandem mass spectrometry and the establishment of pediatric reference interval in local Chinese.
Urinary organic acids, plasma amino acids and acylcarnitine profile analyses are the main tools used to diagnose inborn errors of metabolisms (IEMs). However, without metabolic decompensation, these parameters are often not helpful. On the other hand, in cases of IEM, acylglycines are consistently raised even when patients appear to be in remission. This study aims to set-up a simple liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the determination of urine acylglycines, complementary to organic acid and acylcarnitine profiles, for the diagnosis of IEM. In addition, local reference intervals for various acylglycines are established by using this method. Acylglycines were isolated by solid-phase extraction, derivatized with n-butanol, separated by HPLC, and detected by ESI-MS/MS. Acylglycines were quantified with deuterated internal standards. Mean recoveries of acylglycines ranged from 90.2 to 109.3%. Within- and between-run imprecisions for all acylglycines have CVs less than 10%. Linear regression coefficients were greater than 0.99. Reference intervals were established according to CLSI guidelines by analyzing 204 samples from apparently healthy individuals less than 18 years of age. The distributions of AG in the "normal" urine were skewed towards the right. After log transformation, all the results were normally distributed. Partitioning into age group reference intervals was not indicated, according to the Harris and Boyd approach. In this context, a single reference interval for each acylglycine could be used. This method of urine acylglycines analysis is a powerful diagnostic tool, complementary to urine organic acids and plasma acylcarnitine profiling, for detecting certain inborn errors of metabolism.


Antigen-specific suppression of anti-influenza antibody production in man. Possible role of a membrane-antigen complex.
E rosette-forming (E+) cells from human secondary lymphoid tissue were incubated with high dose influenza A virus (Mem-Bel) in an attempt to generate suppressor T cells. Suppression was assayed by transferring the antigen-pulsed E+ cells into effector cultures consisting of E+ and E- cells stimulated with immunogenic amounts of either the inducing virus Mem-Bel) or the non-cross-reacting influenza B virus (B/HK). The transfer resulted in marked inhibition of IgG, IgA and IgM antibody production to Mem-Bel but not to the control antigen, B/HK virus. The suppressive effect was specific at the level of induction as well as expression since E+ cells exposed to high dose Mem-Bel could provide help to an effector culture containing E- cells and optimal dose of B/HK virus. However, metabolically active cells did not appear to be required for suppression. Thus, it could be elicited (a) after only 15 min incubation of E+ cells with high-dose virus and (b) by E+ cells exposed to irradiation, incubated in the presence of metabolic inhibitors, or disrupted by repeated freeze thawing. In contrast, treatment of E+ cells with pronase reversed the suppressive effect. Interestingly, virus heated to 70 degree C failed to induced suppression, while retailing the ability to elicit a normal helper response. Suppression induced by exposure to standard amounts of high-dose antigen was mediated by T cells of both helper/inducer (Leu-3a+) and suppressor/cytotoxic subsets (Leu-2a+), but not by B cells. Two groups of observations pointed to the B cell as the target of suppression. First, suppression could still be transferred to effector cultures in which helper T cells had been replaced by T cell-replacing factor or suppressor T cells removed by irradiation. Second, significant inhibition of antibody production was obtained when the transfer of antigen-pulsed E+ cells was delayed for up to 120 h after initiation of the effector culture. Taken together the results suggest that suppression in this system is due to the formation of an antigen bridge between specific receptor sites on the T cell membrane and the target. Although not dependent on triggering of metabolically active suppressor T cells the phenomenon highlights the need for care in interpreting the mechanism of suppression by high-dose antigen and could, in addition, represent a biologically important control mechanism capable of rapid inhibition of effector T cells and B cells in sites of high antigen concentration.


What can we learn about human immunodeficiency virus infection from a study of lymphocytic choriomeningitis virus?
The role of cytotoxic T lymphocytes (CTL) in human immunodeficiency virus (HIV) infection remains elusive. Since the discovery 10 years ago of high levels of specific CTL in this disease, some have argued that they play an important role in virus control, others that they drive disease progression through destruction of T helper cells, and others still that they play no obvious role at all. By contrast, the central role of CTL in murine lymphocytic choriomeningitis virus (LCMV) infection has been very clearly worked out through the use of in vivo depletion and adoptive transfer experiments, as well as knockout and transgenic mice. To interpret the possible roles for CTL in HIV, we have therefore made a comparison between what is known about CTL and their interaction with virus-infected cells in these two infections. This illustrates a potential critical role for these cells in both control of HIV replication and immune-mediated pathology, but one that is highly dependent on virus dose, distribution and dynamics.


Comparison of biosynthetic human insulin and pork insulin in the Gerritzen test.
Biosynthetic human insulin (BHI) produced by recombinant DNA technology has been proven to be identical to pancreatic human insulin. It differs from pork insulin in one carboxy-terminal amino acid of the B-chain, where alanine substitutes for threonine. This leads to a higher hydrophilicity and usually lowers the tendency of insulin molecules to aggregate. To study its biologic effect in man, the Gerritzen test was applied. BHI regular (10 IU) or purified pork insulin (PPI) (10 IU) was injected subcutaneously to evaluate the insulin action profile. The time course of plasma glucose levels under both BHI and PPI did not significantly. BHI seems to lower the blood glucose somewhat faster during the first 30 min and, during the late phase, somewhat less than pork insulin. In general, for both BHI and PPI, the onset of action occurs within 15 and 30 min; after 60 min, plasma glucose levels drop by 44.3% for BHI and by 40% for PPI. The plasma glucose minimum was reached about 2 h after injection; therefore, the slope of the plasma glucose fall after 60 min was only marginal. The minimum levels were steady over about 1.75 h. At 2.5 h postinjection plasma glucose rose gradually and reached starting levels after about 7 h. BHI was as well tolerated in the intradermal skin testing as were pork insulin and a placebo solution.


Scaling laws of marine predator search behaviour.
Many free-ranging predators have to make foraging decisions with little, if any, knowledge of present resource distribution and availability. The optimal search strategy they should use to maximize encounter rates with prey in heterogeneous natural environments remains a largely unresolved issue in ecology. Lévy walks are specialized random walks giving rise to fractal movement trajectories that may represent an optimal solution for searching complex landscapes. However, the adaptive significance of this putative strategy in response to natural prey distributions remains untested. Here we analyse over a million movement displacements recorded from animal-attached electronic tags to show that diverse marine predators-sharks, bony fishes, sea turtles and penguins-exhibit Lévy-walk-like behaviour close to a theoretical optimum. Prey density distributions also display Lévy-like fractal patterns, suggesting response movements by predators to prey distributions. Simulations show that predators have higher encounter rates when adopting Lévy-type foraging in natural-like prey fields compared with purely random landscapes. This is consistent with the hypothesis that observed search patterns are adapted to observed statistical patterns of the landscape. This may explain why Lévy-like behaviour seems to be widespread among diverse organisms, from microbes to humans, as a 'rule' that evolved in response to patchy resource distributions.


Development of disease and virus recovery in transgenic mice containing HIV proviral DNA.
Transgenic mice containing intact copies of the human immunodeficiency virus (HIV) proviral DNA were constructed. Founder animals were not viremic for HIV and remained healthy during a 9-month observation period. After being mated with nontransgenic animals, one founder mouse (No. 13) gave rise to F1 progeny that developed a disease syndrome characterized by marked epidermal hyperplasia, lymphadenopathy, splenomegaly, pulmonary lymphoid infiltrates, growth retardation, and death by day 25 of life. Infectious HIV, indistinguishable from parental virus by immunoblot analysis, was recovered from the spleen, lymph nodes, and skin of five of five affected animals.


Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity.
Clinical management of malignant mesothelioma (MM) is very challenging due to marked resistance of this tumor to chemotherapy. Various mechanisms lead to a less than ideal drug concentration inside of MM cells, diminishing cytotoxicity. Consequently, single cytotoxic drugs achieve very modest response rates in MM patients, and combination regimens using standard and novel therapies have achieved only limited improvement in overall survival. Here, we demonstrate that MYC has either proliferative or pro-survival effects in MM cells during normal or stressed conditions, respectively. A MYC inhibitor 10058-F4 reduced MM cell proliferation via down regulation of cyclin D. Under serum starvation conditions, MM cells became quiescent, and the addition of MYC inhibitors triggered apoptosis in the resting MM cells. We also found that high concentrations of the PAK inhibitor PF3758309 killed MM cells, but the drug had only cytostatic effects at lower concentrations. These quiescent cells underwent apoptosis upon pharmacological inhibition of MYC. A novel MYC inhibitor KJ-Pyr-9 and a newer PAK inhibitor, FRAX597, also demonstrated marked cytotoxic cooperativity. Collectively, these findings demonstrate that targeting of MYC can sensitize MM cells and provide rationale for inhibition of MYC and PAK as a novel combinatory regimen for the treatment of this otherwise therapy-resistant, clinically incurable malignancy.


The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.
We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia. The alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.


Fluoride content of infant foods.
Excessive fluoride consumption during the first 2 years of life is associated with an increased risk of dental fluorosis. Estimates of fluoride intake from various sources may aid in determining a child's risk for developing fluorosis. This study sought to assess the fluoride content of commercially available foods for infants, and to guide dentists who are advising parents of young children about fluoride intake. Three samples each of 20 different foods (including fruits and vegetables, as well as chicken, turkey, beef/ham, and vegetarian dinners) from 3 manufacturers were analyzed (in duplicate) for their fluoride content. Among the 360 samples tested, fluoride concentration ranged from 0.007-4.13 μg fluoride/g food. All foods tested had detectable amounts of fluoride. Chicken products had the highest mean levels of fluoride, followed by turkey products. Consuming >1 serving per day of the high fluoride concentration products in this study would place children over the recommended daily fluoride intake. Fluoride from infant foods should be taken into account when determining total daily fluoride intake.


Impact of bedside bronchoscopy in critically ill lung transplant recipients.
Over 32,000 lung transplants have been performed worldwide for a variety of end-stage lung diseases (http://www.ishlt.org/). Flexible bronchoscopy (FB) is frequently used as a bedside-tool for diagnosis and management of respiratory failure among critically ill lung transplant recipients (LTRs). We study the indications, results, therapeutic impact, and complications of FB in LTRs admitted to medical intensive care unit (MICU). Retrospective chart review was performed for all critically ill LTRs undergoing FB while admitted to MICU at the Cleveland Clinic Foundation between 2009 and 2011. ICD-9 codes for bronchoscopy were used to identify patients. The procedures were categorized as: (i) airway examination and interventions, (ii) microbiological, and (iii) histopathologic diagnosis. SAS version 9.2 was used for analysis. A cohort of 76 LTRs accounted for 93 hospital admissions, 101 MICU admissions, and 129 bronchoscopies. FB was helpful in evaluation and management of airway complications [secretion clearance (18% bronchoscopy procedures), stenosis/dehiscence (8% patients)] and optimizing management of lower respiratory tract infections. Isolation of resistant gram-negative organisms, community-acquired respiratory viruses, and fungi commonly led to modification in antimicrobial therapy (35% microbiological samples). Nonspecific finding of acute lung injury was the most commonly seen histopathology (70%) on transbronchial biopsy. Twenty percent (4/20) of transbronchial biopsies showed acute cellular rejection, with 1 episode contributing to respiratory failure. Occasional hypoxia and hypotension, but no deaths, were noted due to FB during the ICU admission. Use of FB modified clinical management in one third of airway evaluation and microbiological sampling procedures for critically ill LTRs. No fatalities were attributed to bronchoscopy in this critically ill population.


Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye.
Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG. Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion. The data suggest that individuals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli. This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene.