Context: Two reports suggested that vitamin D2 is less effective than vitamin D3 in maintaining vitamin D status.
Objective: Our objective was to determine whether vitamin D2 was less effective than ...vitamin D3 in maintaining serum 25-hydroxyvitamin D levels or increased the catabolism of 25-hydroxyvitamin D3.
Subjects and Design: This was a randomized, placebo-controlled, double-blinded study of healthy adults ages 18–84 yr who received placebo, 1000 IU vitamin D3, 1000 IU vitamin D2, or 500 IU vitamin D2 plus 500 IU vitamin D3 daily for 11 wk at the end of the winter.
Results: Sixty percent of the healthy adults were vitamin D deficient at the start of the study. The circulating levels of 25-hydroxyvitamin D (mean ± sd) increased to the same extent in the groups that received 1000 IU daily as vitamin D2 (baseline 16.9 ± 10.5 ng/ml; 11 wk 26.8 ± 9.6 ng/ml), vitamin D3 (baseline 19.6 ± 11.1 ng/ml; 11 wk 28.9 ± 11.0 ng/ml), or a combination of 500 IU vitamin D2 and 500 IU vitamin D3 (baseline 20.2 ± 10.4 ng/ml; 11 wk 28.4 ± 7.7 ng/ml). The 25-hydroxyvitamin D3 levels did not change in the group that received 1000 IU vitamin D2 daily. The 1000 IU dose of vitamin D2 or vitamin D3 did not raise 25-hydroxyvitamin D levels in vitamin D-deficient subjects above 30 ng/ml.
Conclusion: A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels. Therefore, vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.
Objectives/Hypothesis
Parotid gland calcifications can be incidental findings on computed tomography (CT) and have been reported to be associated with chronic inflammatory conditions. Associations ...between parotid gland calcification and other common medical conditions have not been reported.
Methods
Following institutional review board approval, 1,571 patients who underwent noncontrast head CT with 1.25‐mm slice thickness on a 64‐detector row CT between January 2011 and July 2011 were retrospectively reviewed for parotid gland calcifications. Medical records were reviewed for chronic kidney disease, alcoholism, autoimmune conditions, endocrine disorders, elevated alkaline phosphatase, and HIV (human immunodeficiency virus) status. Statistical analyses were performed using Fisher's exact test and multiple logistic regression.
Results
Sixty‐three of 1,571 (4%) patients had parotid gland calcifications. Significant associations were observed between parotid gland calcifications and HIV infection (P = 0.002), chronic kidney disease (P < 0.0001), alcoholism (P < 0.0001), elevated alkaline phosphatase (P = 0.003), and autoimmune disease (P = 0.02).
Conclusion
Parotid gland calcifications were associated with HIV, alcoholism, chronic kidney disease, autoimmune disease, and elevated alkaline phosphatase.
Level of Evidence
4. Laryngoscope, 125:1360–1365, 2015
A novel class of synthetic compounds, termed GH-secretagogues (GHSs),
have been shown to be potent stimulators of GH release, although their
mechanism of action and functional significance remains ...obscure. The
recent cloning of the rat GHS receptor (GHS-R) permitted the
identification of numerous sites of expression of GHS-R in brain, but
nothing is yet known about the cell types that express this receptor.
We performed dual chromogenic and autoradiographic in
situ hybridization to test the hypothesis that GHRH neurons in
the hypothalamus coexpress GHS-R mRNA. GHS-R-hybridizing cells showed
extensive overlap with GHRH-expressing neurons in both the arcuate
(Arc) and ventromedial (VMN) hypothalamic nuclei. Quantification of the
double-labeled cells revealed that approximately 27% of
GHRH-hybridizing neurons in the Arc, and 22% of those in the VMN,
expressed the GHS-R gene. These studies are the first to colocalize the
GHS-R to any neurochemical cell type in rat brain. The results provide
evidence that the GHSs may directly modulate GHRH release, and thereby
stimulate GH secretion, through interaction with the GHS-R on
hypothalamic GHRH mRNA-containing neurons.
Many tissues express thyroid hormone metabolizing deiodinases that both activate and inactivate thyroid hormones through conversion processes. Many believe that the primary role of thyroid hormone ...deiodinases is the activation of the prohormone thyroxine (T(4)) to the active hormone triiodothyronine because athyreotic humans can be treated with T(4) alone. In our hands a nonspecific deiodinase inhibitor (iopanoic acid IOP) decreased cutaneous cell proliferation in vitro, so we hypothesized that topical IOP would inhibit epidermal proliferation in vivo.
IOP was applied topically to mice. Treatments were applied daily for 1 week. Skin biopsies were either stained for 5-bromo-2-deoxyuridine or flash-frozen to assay for deiodinase activity.
Topical IOP resulted in a dose-dependent increase in epidermal proliferation. Assay revealed significant inactivating type 3 deiodinase (Dio3) activity in the epidermis but little or no activating (Dio1 or Dio2) activity. Dio3 activity was decreased 44%±21% in epidermis from mice treated with low-dose IOP and 80%±4% in epidermis from mice treated with high-dose IOP (p<0.001).
We hypothesize that keratinocytes express Dio3 in vivo to maintain cutaneous health and prevent the skin from becoming hyperproliferative. Our data support the developing recognition that the primary role of thyroid hormone deiodinases in some tissues may be the degradation of thyroid hormone to protect the tissue against thyrotoxicosis.
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant ...fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
The Community Health Practice Guidelines (CHPG) project was initiated to develop a systematic approach to the critical evaluation of evidence on the effectiveness and efficiency of community health ...interventions and to the formulation of evidence-based practice recommendations. Three community health interventions—immunization delivery methods, partner notification for sexually transmitted diseases and the combination of restaurant inspection and education of food handlers—were used as prototypes to develop a standardized approach. The CHPG process consists of three components: a review of scientific evidence, a practice survey and formulation of practice guidelines. Imperatives for further development of the CHPG and define research priorities process include creating a coalition of public health organizations to sponsor the process and refining the consensus process so that the practice guidelines accurately reflect both the scientific basis of public health practice and the values of those affected. Le projet des Lignes directrices en matière de pratiques de santé communautaire (LDPSC) a été lancé en vue d'élaborer une démarche systématique pour l'évaluation critique des faits relevés relativement à l'efficacité et à l'efficience des interventions en santé communautaire et pour la formulation de recommandations pratiques fondées sur les faits. Trois interventions en santé communautaire — les modes d'administration des vaccins, la déclaration aux partenaires dans les cas de maladies transmises sexuellement, et la double question de l'inspection des restaurants et de la formation des personnes préposées à la manutention des aliments — ont servi de prototypes pour la mise au point d'une démarche standardisée. Le processus adopté par le projet LDPSC se déroule en trois parties : l'examen des preuves scientifiques, une enquête sur les pratiques, et la formulation de lignes directrices relatives aux pratiques. Les éléments essentiels à l'expansion du projet LDPSC et à la définition du processus d'établissement des priorités de recherche comprennent la création d'une coalition des organismes de santé publique, afin de parrainer le processus, et le perfectionnement de la méthode utilisée pour en arriver à des consensus, afin que les lignes directrices reflètent exactement aussi bien les fondements scientifiques des pratiques de santé publique que les valeurs des personnes touchées par ces pratiques.
IntroductionFucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human ...immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. MethodsCA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. ResultsPatients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 90%). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval CI) was higher with BMS-986012 plus nivolumab (38% 20.7%-57.7%) than with monotherapy (4% 0.8%-11.0%). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively. ConclusionsBMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).
Implicit Puritanism in American moral cognition Uhlmann, Eric Luis; Poehlman, T. Andrew; Tannenbaum, David ...
Journal of experimental social psychology,
March 2011, 2011-03-00, 20110301, 2011-03, Letnik:
47, Številka:
2
Journal Article
Recenzirano
Three studies provide evidence that the judgments and behaviors of contemporary Americans are implicitly influenced by traditional Puritan-Protestant values regarding work and sex. American ...participants were less likely to display traditional values regarding sexuality when implicitly primed to deliberate, as opposed to intuition and neutral primes. British participants made judgments reflecting comparatively liberal sexual values regardless of prime condition (Study 1). Implicitly priming words related to divine salvation led Americans, but not Canadians, to work harder on an assigned task (Study 2). Moreover, work and sex values appear linked in an overarching American ethos. Asian-Americans responded to an implicit work prime by rejecting revealing clothing and sexually charged dancing, but only when their American cultural identity was first made salient (Study 3). These effects were observed not only among devout American Protestants, but also non-Protestant and less religious Americans.
Cryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and ...neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients.
Seven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L).
All patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment.
Canakinumab, 2 mg/kg or 150 mg s.c., induced rapid and sustained clinical and biochemical responses in pediatric patients with CAPS.
ClinicalTrials.gov: NCT00487708.
Display omitted
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological ...tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
PDF
