The effect of [Phe(1)psi(CH(2)-NH)Gly(2)]-nociceptin(1-13)NH(2) on feeding and c-Fos immunoreactivity in selected brain sites

Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand of the ORL1 receptor. N/OFQ, when administered centrally, stimulates feeding in a fashion similar to other opioids. Intracerebroventricular administration of N/OFQ induces changes in c-Fos immunoreactivity in several feeding-related brain sites. A synthetic pseudopeptide, [Phe(1)iota(CH(2)-NH)Gly(2)]-nociceptin(1-13)-NH(2) (hereafter: [FG]N/OFQ(1-13)NH(2)), has been labeled both as an ORL1 agonist and antagonist. The present study was designed to examine the influence of [FG]N/OFQ(1-13)NH(2) on food intake in rats. We also evaluated c-Fos immunoreactivity in those areas of the brain which have been shown to exhibit altered c-Fos expression upon N/OFQ administration. We found that [FG]N/OFQ(1-13)NH(2) increases food consumption in satiated rats. This effect is short-lasting and can be reversed by the opioid antagonist naloxone. Co-administration of [FG]N/OFQ(1-13)NH(2) does not affect orexigenic response to N/OFQ. Intracerebroventricularly-injected [FG]N/OFQ(1-13)NH(2) induces c-Fos expression in the nucleus of the solitary tract, hypothalamic paraventricular and supraoptic nuclei, central nucleus of amygdala, lateral septal and lateral habenular nuclei-brain areas that have been shown to be activated by N/OFQ. These results support the hypothesis that [FG]N/OFQ(1-13)NH(2) acts as an agonist of ORL1 receptor in vivo.     

Psychometric evaluation of the Taiwan version of the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire.

BACKGROUND AND PURPOSE: To adapt the Taiwan version of the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and evaluate its psychometric properties. METHODS: The DASH questionnaire was adapted through the process of translation, back-translation, and expert review. Eighty two subjects with upper extremity disorders were recruited in a medical center and 46 of these patients could be followed up to assess retest reliability in less than 10 days. Cronbach alpha and intraclass correlation coefficient were used to evaluate the internal consistency and test-retest reliability. Principal axis factor analysis was performed to assess the factor-construct validity, while concurrent validity was tested with the Medical Outcomes Study Short Form-36 (SF-36) Taiwan version questionnaire. RESULTS: The internal consistency of the Taiwan version of the DASH questionnaire was high (Cronbach alpha = 0.96) and the test-retest reliability was satisfactory (intraclass correlation coefficient = 0.9). Principal axis factor analysis confirmed the 1-factor model. The Pearson correlation coefficients of the DASH questionnaire to the SF-36 showed a correlation with physical component summary scores rather than mental component summary scores. Bodily pain, physical function and role-physical scores among the SF-36 subscales were most significantly correlated with DASH disability/symptom scores. CONCLUSION: The Taiwan version of the DASH questionnaire is a valid and reliable measure of health status for patients with upper-extremity disorders.     

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.     

Evolution of AbGRI2-0, the Progenitor of the AbGRI2 Resistance Island in Global Clone 2 of Acinetobacter baumannii

A320, isolated in the Netherlands in 1982 and also known as RUH134, is the earliest available multiply antibiotic-resistant (MAR) Acinetobacter baumannii isolate belonging to global clone 2 (GC2) and is the reference strain for this clone. The draft genome sequence of A320 was used to investigate the original location and configuration of the IS26-bounded AbGRI2 resistance island found in current GC2 isolates. PCR mapping and sequencing were used to order contigs composing the resistance islands. A320 contains two IS26-bounded resistance islands, AbGRI2-0a and AbGRI2-0b, of 7.8 kb and 25.4 kb, respectively. Together they contain bla_TEM, aacC1, aadA1, sul1, catA1, and aphA1b genes, which confer resistance to antibiotics used clinically in the 1970s, as well as an incomplete mercury resistance module. Tracking the continuity of the chromosome and the target site duplications revealed that the two resistance islands were originally together as AbGRI2-0, an island of 32.4 kb, and were subsequently separated via an IS26-mediated intramolecular inversion that reversed the orientation of 1.54 Mb of the chromosome and duplicated an IS26. A320 contains an ancestral form of AbGRI2, and the original insertion site of the AbGRI2 island was identified. Many of the AbGRI2 versions present in the completed GC2 genomes can be derived from it via the variant AbGRI2-1. IS26-mediated inversions have also played a part in forming AbGRI2-0, and, upon reversal, large regions of AbGRI2-0 are identical to parts of AbaR0, the ancestral version of the AbaR islands present in GC1 isolates. This indicates a common source.     

Research priorities to address polypharmacy in older adults with cancer

Polypharmacy poses a significant public health problem that disproportionately affects older adults (≥65 years) since this population represents the largest consumers of medications. Clinicians caring for older adults with cancer must rely on evidence to understand polypharmacy and its implications, not only to communicate with patients and other healthcare providers, but also because of the significant interplay between polypharmacy, cancer, cancer-related treatment, and clinical outcomes. Interest in polypharmacy is rising because of its prevalence, the origins and facilitating factors behind it, and the direct and indirect clinical outcomes associated with it. The growing body of publications focused on polypharmacy in older adults with cancer demonstrates that this is a significant area of research; however, limited evidence exists to guide medication use (e.g., prescribing, administration) in this population. Currently, research priorities aimed at polypharmacy in the field of geriatric oncology lack clarity. We identified current gaps in the literature in order to establish research priorities for polypharmacy in older adults with cancer. The five research priorities—Polypharmacy Methodology and Definitions, Suboptimal Medication Use, Comorbidities and Geriatric Syndromes, Underrepresented Groups, and Polypharmacy Interventions—highlight critical areas for future research to improve outcomes for older adults with cancer.