Vitamin E, γ-tocopherol, diminishes ex vivo basophil response to dust mite allergen.

Epidemiologic studies suggest that dietary vitamin E is a candidate intervention for atopic disease. We used in vitro and ex vivo exposures to test the hypothesis that the most common dietary isoform of vitamin E, γ-tocopherol (γT), could suppress FcεRI-mediated basophil activation. Rat basophilic leukemia (RBL)-SX38 cells that express human FcεRI were treated with or without γT, followed by stimulation with α-IgE. In the ex vivo study, 20 Der f 1-allergic volunteers consumed a γT-enriched supplement for 7 days. Their basophils were challenged ex vivo with α-IgE and graded doses of Der f 1 before and after the supplementation period. γt treatment of RBL-SX38 cells significantly reduced basophil degranulation and de novo TH2 cytokine production. Daily consumption of a γT-rich supplement by dust mite-allergic volunteers reduced basophil activation after ex vivo dust mite challenge. Vitamin E supplements rich in γT may be useful adjuncts in decreasing atopic disease.

Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014--United States.

Since mid-2006, a licensed human papillomavirus (HPV) vaccine has been available and recommended by the Advisory Committee on Immunization Practices (ACIP) for routine vaccination of adolescent girls at ages 11 or 12 years. Two vaccines that protect against HPV infection are currently available in the United States. Both the quadrivalent (HPV4) and bivalent (HPV2) vaccines protect against HPV types 16 and 18, which cause 70% of cervical cancers; HPV4 also protects against HPV types 6 and 11, which cause 90% of genital warts. In 2011, the ACIP also recommended HPV4 for the routine vaccination of adolescent boys at ages 11 or 12 years. HPV vaccines can be safely co-administered with other routinely recommended vaccines, and ACIP recommends administration of all age-appropriate vaccines during a single visit. To assess progress with HPV vaccination coverage among adolescents aged 13-17 years, characterize adherence with recommendations for HPV vaccination by the 13th birthday, and describe HPV vaccine adverse reports received postlicensure, CDC analyzed data from the 2007-2013 National Immunization Survey-Teen (NIS-Teen) and national postlicensure vaccine safety data among females and males. Vaccination coverage with ≥1 dose of any HPV vaccine increased significantly from 53.8% (2012) to 57.3% (2013) among adolescent girls and from 20.8% (2012) to 34.6% (2013) among adolescent boys. Receipt of ≥1 dose of HPV among girls by age 13 years increased with each birth cohort; however, missed vaccination opportunities were common. Had HPV vaccine been administered to adolescent girls born in 2000 during health care visits when they received another vaccine, vaccination coverage for ≥1 dose by age 13 years for this cohort could have reached 91.3%. Postlicensure monitoring data continue to indicate that HPV4 is safe. Improving practice patterns so that clinicians use every opportunity to recommend HPV vaccines and address questions from parents can help realize reductions in vaccine-preventable infections and cancers caused by HPV.

National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years--United States, 2013.

The Advisory Committee on Immunization Practices (ACIP) recommends that adolescents routinely receive 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, 2 doses of meningococcal conjugate (MenACWY) vaccine, and 3 doses of human papillomavirus (HPV) vaccine.* ACIP also recommends administration of "catch-up"† vaccinations, such as measles, mumps, and rubella (MMR), hepatitis B, and varicella, and, for all persons aged ≥6 months, an annual influenza vaccination. ACIP recommends administration of all age-appropriate vaccines during a single visit. To assess vaccination coverage among adolescents aged 13-17 years, CDC analyzed data from the 2013 National Immunization Survey-Teen (NIS-Teen).§ This report summarizes the results of that analysis, which show that from 2012 to 2013, coverage increased for each of the vaccines routinely recommended for adolescents: from 84.6% to 86.0% for ≥1 Tdap dose; from 74.0% to 77.8% for ≥1 MenACWY dose; from 53.8% to 57.3% for ≥1 HPV dose among females, and from 20.8% to 34.6% for ≥1 HPV dose among males. Coverage varied by state and local jurisdictions and by U.S. Department of Health and Human Services (HHS) region. Healthy People 2020 vaccination targets for adolescents aged 13-15 years were reached in 42 states for ≥1 Tdap dose, 18 for ≥1 MenACWY dose, and 11 for ≥2 varicella doses. No state met the target for ≥3 HPV doses.¶ Use of patient reminder and recall systems, immunization information systems, coverage assessment and feedback to clinicians, clinician reminders, standing orders, and other interventions can help make use of every health care visit to ensure that adolescents are fully protected from vaccine-preventable infections and cancers (5), especially when such interventions are coupled with clinicians' vaccination recommendations.

Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310.

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.

Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity.

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for NaV1.7 over NaV1.5 and highly efficacious in in vivo models of pain and hNaV1.7 target engagement. An analysis of the physicochemical properties of literature NaV1.7 inhibitors suggested that acyl sulfonamides with high fsp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against NaV1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNaV1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the NaV1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious NaV1.7 inhibitors reported to date.

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain.

Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3- a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain.

The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

Zoos and public health: A partnership on the One Health frontier.

Today, accredited zoos are not just places for entertainment, they are actively involved in research for conservation and health. During recent decades in which the challenges for biodiversity conservation and public health have escalated, zoos have made significant changes to address these difficulties. Zoos increasingly have four key areas of focus: education, recreation, conservation, and research. These key areas are important in addressing an interrelated global conservation (i.e. habitat and wildlife loss) and public health crisis. Zoo and public health professionals working together within a One Health framework represent a powerful alliance to address current and future conservation and public health problems around the world. For researchers, practitioners, and students, the collaboration between zoos and public health institutions offers the opportunity to both teach and operationalize this transdisciplinary approach. Using examples from our programs, we give a template for moving forward with collaborative initiatives and sustainable solutions involving partners in both zoos and public health institutions. We provide examples of cooperative programs and suggest a model for consideration in the development of further activities in this area.

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.

Suicide in twins.

Suicide appears to cluster in families, suggesting that genetic factors may play a role in this behavior. We studied 176 twin pairs in which one or both twins had committed suicide. Seven of the 62 monozygotic twin pairs were concordant for suicide compared with two of the 114 dizygotic twin pairs (11.3% vs 1.8%). The presence of psychiatric disorder in the twins and their families was examined in a subsample of 11 twin pairs, two of whom were concordant for suicide. Eleven of these 13 twin suicide victims had been treated for psychiatric disorder, as had eight of their nine surviving cotwins. In addition, twins in 10 pairs had other first- or second-degree relatives who had been treated for psychiatric disorder. Thus, these twin data suggest that genetic factors related to suicide may largely represent a genetic predisposition for the psychiatric disorders associated with suicide. However, they leave open the question of whether there may be an independent genetic component for suicide.

Prolactin mediates estradiol-induced inflammation in the lateral prostate of Wistar rats.

Inflammation was induced in the lateral prostate of castrated Wistar rats by exposure to a sc implant of estradiol-filled Silastic tubing, followed by the addition of a dihydrotestosterone implant to restore prostatic wet weight. The presence of inflammation was correlated with increased serum PRL, elevated pituitary weight, and a greater than 2-fold increase in the lateral prostate DNA concentration. The administration of bromocriptine (4 mg/kg.day) to these animals was effective in suppressing pituitary weight and hyperprolactinemia and mitigated the lateral prostate inflammatory response. Inflammation was restored in the bromocriptine-treated hormone-implanted rats by administering exogenous ovine PRL at a dose of 2 mg/kg twice a day. The results indicate that estradiol-induced inflammation in the rat lateral prostate is mediated at least in part by the release of PRL from the pituitary.

Schizophrenia in the National Academy of Sciences-National Research Council Twin Registry: a 16-year update.

The authors present a 16-year update on schizophrenia in the National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry. As of October 1981, a recorded diagnosis of schizophrenia was equally common in monozygotic and dizygotic twins. However, probandwise concordance for schizophrenia was significantly greater in monozygotic (30.9%) than in dizygotic (6.5%) twins. Biases in zygosity determination, diagnosis, or ascertainment could not plausibly explain these results. Correction for selection effects in construction of the registry produced concordance rates for schizophrenia approaching those found in previous studies. According to registry data, genetic factors appear at least as important in the etiology of schizophrenia as in several common medical conditions, including diabetes and hypertension. Results from the NAS-NRC Twin Registry support the etiologic importance of genetic factors in schizophrenia.

Anatomic, metabolic, neuropsychological, and molecular genetic studies of three pairs of identical twins discordant for dementia of the Alzheimer's type.

Three pairs of twins, each with proved monozygosity, were shown to be discordant for dementia of the Alzheimer's type and to have remained discordant for periods of 8 to 11 years. Dementia of the Alzheimer's type was demonstrated by history; serial clinical examinations; serial measurements of cerebral glucose utilization using positron emission tomography and of cerebral ventricular volumes and of rates of change of volumes using quantitative computed tomography; and by serial neuropsychological tests. The results of each of these measures showed no evidence of clinical abnormality in any unaffected twin. DNA markers from the proximal long arm of chromosome 21 did not distinguish between the affected and the unaffected member of any pair of identical twins. Family pedigrees were negative for Alzheimer's disease. The results suggest that environmental or other nongenetic factors contribute to Alzheimer's disease in discordant monozygotic twins, or that some cases arise by a postzygotic somatic mutation.

Maternal exposure to atrazine during lactation suppresses suckling-induced prolactin release and results in prostatitis in the adult offspring.

The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), TIDA neuronal growth is impaired and elevated PRL levels are present in the prepubertal male. These observations, combined with the finding that alterations in PRL secretion (i.e., hyperprolactinemia) in the adult male rat have been implicated in the development of prostatitis, led us to hypothesize that early lactational exposure to agents that suppress suckling-induced PRL release would lead to a disruption in TIDA development, altered PRL regulation, and subsequent prostatitis in the male offspring. To test this hypothesis, suckling-induced PRL release was measured in Wistar dams treated twice daily with the herbicide atrazine (ATR, by gavage, on PND 1-4 at 0, 6.25, 12.5, 25, and 50 mg/kg body weight), or twice daily with the dopamine receptor agonist bromocriptine (BROM, sc, at 0.052, 0.104, 0.208, and 0.417 mg/kg); BROM is known to suppress PRL release. Similarly, atrazine has also been reported to suppress PRL in adult females. Serum PRL was measured on PND 3 using a serial sampling technique and indwelling cardiac catheters. A significant rise in serum PRL release was noted in all control females within 10 min of the initiation of suckling. Fifty-mg/kg ATR inhibited suckling-induced PRL release in all females, whereas 25 and 12.5 mg/kg ATR inhibited this measure in some dams and had no discernible effect in others. The 6.25 mg/kg dose of ATR was without effect. BROM, used here as a positive control, also inhibited suckling-induced PRL release at doses of 0.104 to 0.417 mg/kg, with no effect at 0.052 mg/kg. To examine the effect of postnatal ATR and BROM on the incidence and severity of inflammation (INF) of the lateral prostate of the offspring, adult males were examined at 90 and 120 days. While no effect was noted at 90 days of age, at 120 days, both the incidence and severity of prostate inflammation was increased in those offspring of ATR-treated dams (25 and 50 mg/kg). The 12.5 mg/kg ATR and the two highest doses of BROM increased the incidence, but not the severity, of prostatitis. Combined treatment of ovine prolactin (oPRL) and 25 or 50 mg/kg ATR on PND 1-4 reduced the incidence of inflammation observed at 120 days, indicating that this increase in INF, seen after ATR alone, resulted from the suppression of PRL in the dam. To determine whether or not there is a critical period for these effects, dams were dosed with 25 and 50 mg/kg on PND 6-9 and PND 11-14. Inflammation was increased in those offspring from dams treated on PND 6-9, but this increase was not significant. Dosing on PND 11-14 was without effect. These data demonstrate that ATR suppresses suckling-induced PRL release and that this suppression results in lateral prostate inflammation in the offspring. The critical period for this effect is PND 1-9.

17beta-estradiol is a hormonal regulator of mirex tumor promotion sensitivity in mice.

Mirex, an organochlorine pesticide, is a potent non-phorbol ester tumor promoter in mouse skin. Previous studies have shown that female mice are 3 times more sensitive to mirex tumor promotion than male mice and that ovariectomized (OVX) female mice are resistant to mirex promotion, suggesting a role for ovarian hormones in mirex promotion. To determine whether the ovarian hormone 17-beta estradiol (E2) is responsible for the sensitivity of female mice to mirex promotion, female mice were initiated with DMBA; 2 weeks later groups of mice were OVX and implants, with or without E2, were surgically implanted subcutaneously. These mice were treated topically twice weekly with mirex for 26 weeks. E2 implanted OVX mice demonstrated high normal physiologic levels of serum E2 throughout the tumor promotion experiment. E2 implants restored by 80% the intact mirex-sensitive phenotype to the OVX mice. Consistent with a role for E2 and ERalpha and ERbeta, treatment of DMBA-initiated female mice with topical ICI 182,780, an estrogen-receptor antagonist, reduced mirex tumor multiplicity by 30%. However, in cells co-transfected with ERalpha or ERbeta and estrogen-responsive promoter reporter, mirex did not stimulate promoter reporter activity, suggesting that the promotion effect of mirex is downstream of ERalpha/beta. Finally, a tumor promotion study was conducted to determine whether E2 implants could increase the sensitivity of male mice to mirex promotion. E2 implants in male mice did increase sensitivity to mirex promotion; however, the implants did not produce the full female sensitivity to mirex tumor promotion. Collectively, these studies indicate that E2 is a major ovarian hormone responsible for mirex tumor promotion sensitivity in female mice.

Relationship of cell type and lymph node metastasis to survival after resection of bronchial carcinoma.

In the completed adjuvant chemotherapy lung trials conducted by the Veterans Administration Surgical Group, the cell type was recorded in 2,341 of 2,349 curative resections; extent of lymph node involvement was known in all cases. Nodes were normal in 1,231 patients. Five- and ten-year survival computed by the life-table method was 33.7% and 20.4%, respectively. These rates were significantly greater than the 16.2% and 8.8% recorded in 1,118 patients whose nodes showed metastases. Among patients whose cell type was known, five-year survival in 484 with hilar node involvement was 17.4% and was not significantly different from 20.1% in 364 patients in whom only lobar nodes were involved. The survival was 8.9% in 268 patients with cancer in the mediastinal nodes; this was significantly worse than either of the aforementioned groups. A five-year survival of 26.8% in 1,482 patients with squamous cell carcinoma was greater than the 24.3% in 359 with adenocarcinoma and 22.4% in 500 with undifferentiated cell types, but the differences were not significant. Variations between these groups remained nonsignificant when nodes were normal and were of only borderline significance, at the 5% level, when they showed metastasis. When a curative resection has been accomplished, cell-type as classified in this study has little bearing on long-term survival, whereas the presence of node metastasis as well as its location is of the utmost importance.

Perinatal exposure to estrogenic compounds and the subsequent effects on the prostate of the adult rat: evaluation of inflammation in the ventral and lateral lobes.

Although the effects of estrogenic compounds administered during the perinatal period on the size and morphology of the prostate have been well documented, the effects of such exposures on inflammatory changes in the prostate have not been well characterized. Since neonatal estradiol exposure has been shown to cause periods of hyperprolactinemia later in life and a relationship exists between high prolactin levels and rat lateral prostate inflammation, we hypothesized that an exposure to environmental compounds with estrogenic activity could result in an increase in lateral prostate inflammation in adulthood. To investigate this possibility and compare differences between estrogen agonists and antagonists, we examined the effect of a perinatal exposure to 17beta-estradiol, the insecticide methoxychlor, the partial estrogen agonist tamoxifen, and the pure antiestrogen ICI 182,780. Dams were dosed from gestation day (GD)18 to parturition and then the pups were dosed from postnatal day (PND) 1 to 5 with 0.1 mL of a solution of 0.355 mM and .0178 mM by sc injection, respectively, of all compounds in sesame oil, except for methoxychlor, which was administered only to the dam by gavage from GD 18 through PND 5 at a dose of 50 mg/kg in sesame oil. At 90 d of age, the weight of the lateral and ventral prostate in the estradiol group was significantly decreased. Tamoxifen caused a decrease in the weight of the lateral prostate, whereas the ventral lobe was not affected. ICI 182,780 did not alter prostate weight. The methoxychlor exposure increased the lateral lobe weight, but the ventral lobe weight was not affected. In the estradiol and tamoxifen groups, an inflammatory infiltrate was observed in the ventral prostates in 45.0 and 27.8% of the animals, respectively. There was a significant increase in the percent and severity of inflammation in the lateral prostate (as determined by a myeloperoxidase or neutrophil quantification assay) in the estradiol, tamoxifen, and methoxychlor groups as compared to controls. The ICI group was comparable to the controls in both ventral and lateral lobes. This study demonstrates that perinatal exposure to estrogenic compounds can result in alterations in the size of the adult prostate and increase the incidence of prostatitis.

Toxicology of selected pesticides, drugs, and chemicals. Zinc.

Zinc poisoning in small animals has been described in dogs, cats, birds, and ferrets, but the dog appears to be the species most often affected. Ingestion of zinc-containing metallic objects, including pennies, and zinc oxide ointments has been associated with the majority of the toxicoses. Clinical signs include anorexia, vomiting, diarrhea, hemolytic anemia, kidney dysfunction, and possible liver and pancreatic abnormalities. Treatments that have proven efficacious include fluid diuresis, blood transfusions as needed, general supportive care, and removal of the source of zinc. Further evaluation of the benefit of chelation therapy is urgently needed.

Involvement of Arkansas hospitals in promotion of car restraint device use among young children.

Child restraint devices are a proven means of reducing automobile-related deaths and injuries among infants and toddlers. To determine the role that Arkansas hospitals play in promoting use of these devices, a survey similar to one conducted previously in Tennessee was performed of hospitals providing newborn and/or pediatric services. Hospital policies relating to discharge of patients in car restraints were more likely to pertain to newborns than to older children. Nearly all the facilities having such policies claimed that these were strictly enforced. Hospitals are encouraged to establish discharge policies and to expand educational efforts and loaner programs.