PhRMA survey on the conduct of first-in-human clinical trials under exploratory investigational new drug applications.

The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs.

Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment.

Objective: To evaluate posaconazole pharmacokinetics in subjects with different degrees of hepatic impairment compared with matched healthy subjects.

Research Design And Methods: A total of 37 subjects were enrolled in this open-label, single-dose, parallel-group study; 19 with hepatic impairment and 18 healthy subjects with matching demographics. Each subject received a single 400-mg oral dose of posaconazole after a high-fat meal.

Structural models of FeSe(x).

Two different structural models for non-stoichiometric FeSe(x) are examined and compared with soft x-ray spectroscopy findings for FeSe(x) (x = 0.85, 0.50).

BOUNCE: an exploratory healthy lifestyle summer intervention for girls.

Objectives: To assess the efficacy of the BOUNCE parent-daughter intervention in promoting selected physical fitness measures and activity.

Methods: Thirty-seven Latino and African American parent-daughter pairs participated. The intervention entailed physical activities, nutrition classes, and self-esteem activities.

Tourniquet use in combat trauma: U.K. military experience.

Aim: To determine the prevalence of tourniquet use in combat trauma, the contribution to lives saved and the complications of their use in this environment.

Population: All casualties treated at U.K.

Identifying valence structure in LiFeAs and NaFeAs with core-level spectroscopy.

Resonant x-ray emission spectroscopy (XES) measurements at Fe L(2,3) edges and electronic structure calculations for LiFeAs and NaFeAs are presented. Experiment and theory show that in the vicinity of the Fermi energy, the density of states is dominated by contributions from Fe 3d states. The comparison of Fe L(2,3) XES with spectra of related FeAs compounds reveals similar trends in energy and the ratio of intensities of the L(2) and L(3) peaks (I(L(2))/I(L(3)) ratio).

Individual personality and the spatial distribution of groups of grazing animals: an example with sheep.

Impacts of individual personality on group distribution were investigated using sheep (Ovis aries) as a model. In an indoor exploration test, individuals who visited <4 (out of 6) objects in a novel environment were classified as 'shy' (n=10), and those who visited 5 or 6 objects were classified as 'bold' (n=10). Nine weeks later, using a series of groups (n=40) of either 5 shy or 5 bold sheep, we measured distribution at pasture and responses to disturbance and the approach of a human handler.

Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteers.

Background: Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated.

Methods: A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers.

Predicting the need for early amputation in ballistic mangled extremity injuries.

Background: Despite modern advances, amputation is still a commonly performed operation in war. It is often difficult to decide whether to amputate after high-energy trauma to the lower extremity. To help guide this assessment, scoring systems have been developed with amputation threshold values.

Nociceptin-induced modulation of human T cell function.

There is an accumulating evidence for the immunoregulatory role of the neuropeptide, nociceptin/orphanin FQ (N/OFQ) however its role on T cell function requires elucidation. This study has demonstrated an inhibitory role for N/OFQ on SEB-activated T cell function. N/OFQ decreases T cell proliferation, which is abrogated when the costimulatory receptors CD80 and CD86 are blocked.

Gamma-secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior.

gamma-Secretase cleaves amyloid precursor protein (APP) to generate amyloid-beta (Abeta) peptides, which aggregate in the brain in Alzheimer's disease (AD). gamma-Secretase also cleaves molecules that regulate osteoblast activity, such as Notch and ephrinB2. However, the role of APP in bone is unknown.

Plaque retention by self-ligating vs elastomeric orthodontic brackets: quantitative comparison of oral bacteria and detection with adenosine triphosphate-driven bioluminescence.

Introduction: Enamel decalcification is a common problem in orthodontics. The objectives of this randomized clinical study were to enumerate and compare plaque bacteria surrounding 2 bracket types, self-ligating (SL) vs elastomeric ligating (E), and to determine whether adenosine triphosphate (ATP)-driven bioluminescence could be used for rapid assessment of bacterial load in plaque.

Methods: Patients (ages, 11-17 years) were bonded with SL and E brackets in 14 maxillary and 12 mandibular arches by using a split-mouth design.

Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.

Background: Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam).

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9).

Effects of oral posaconazole on the pharmacokinetics of sirolimus.

Objectives: Azole antifungal agents are often coadministered with immunosuppressants to recipients of solid organ and hematopoietic stem cell transplants. Posaconazole, an extended-spectrum triazole, is an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP3A4, and sirolimus, an immunosuppressant, is a substrate of the enzyme. We evaluated the effects of posaconazole on sirolimus pharmacokinetics in an open-label, multiperiod, drug-interaction study.

RTKN2 Induces NF-KappaB Dependent Resistance to Intrinsic Apoptosis in HEK Cells and Regulates BCL-2 Genes in Human CD4(+) Lymphocytes.

The gene for Rhotekin 2 (RTKN2) was originally identified in a promyelocytic cell line resistant to oxysterol-induced apoptosis. It is differentially expressed in freshly isolated CD4(+) T-cells compared with other hematopoietic cells and is down-regulated following activation of the T-cell receptor. However, very little is known about the function of RTKN2 other than its homology to Rho-GTPase effector, rhotekin, and the possibility that they may have similar roles.

Screening for dyslexia, dyspraxia and Meares-Irlen syndrome in higher education.

This study reports a comparison of screening tests for dyslexia, dyspraxia and Meares-Irlen (M-I) syndrome in a Higher Education setting, the University of Worcester. Using a sample of 74 volunteer students, we compared the current tutor-delivered battery of 15 subtests with a computerized test, the Lucid Adult Dyslexia Screening test (LADS), and both of these with data on assessment outcomes. The sensitivity of this tutor battery was higher than LADS in predicting dyslexia, dyspraxia or M-I syndrome (91% compared with 66%) and its specificity was lower (79% compared with 90%).

Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers.

A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost).

WISECARE+: Results of a European study of a nursing intervention for the management of chemotherapy-related symptoms.

While the use of chemotherapy has significantly improved survival rates, the symptoms associated with chemotherapy remain a major burden for patients. Preventing or appropriately managing side effects significantly improves patients' functional status and quality of life, ultimately leading to greater patient acceptance of chemotherapy. However, symptom assessment and management are fraught with difficulties such as poor patient recall, retrospective assessment conducted by clinicians and lack of appropriate, clinically relevant and patient friendly symptom assessment and management tools.

Rapid GIS-based profiling of West Nile virus transmission: defining environmental factors associated with an urban-suburban outbreak in Northeast Ohio, USA.

Human West Nile virus (WNV) infection was first detected in Cuyahoga county, Ohio, USA, in 2002. During that year's extensive epidemic/epizootic among non-immune human and bird populations, the county experienced 155 cases of severe human West Nile neurological disease (WNND, incidence = 11.1 cases/100,000), with 11 fatalities.

Tourniquet use in combat trauma: UK military experience.

Aim: To determine the prevalence of tourniquet use in combat trauma, the contribution to lives saved and the complications of their use in this environment.

Population: All casualties treated at UK field hospital facilities in Iraq and Afghanistan and meeting criteria for entry into UK Joint Theatre Trauma Registry (JTTR) from 04 Feb 03 to 30 Sep 07.

Methods: Cases were identified from UK JTTR.

Combat "Category A" calls: evaluating the prehospital timelines in a military trauma system.

Aim: To establish the pre-hospital timelines for seriously injured UK military casualties on OP HERRICK.

Population: All consecutive MERT and MERT-E mobilizations from Camp Bastion, Helmand Province, between 04 May 06 and 18 Jun 07.

Methods: Interrogation of MS Access database compiled from paper patient report forms for each casualty transported.