Polymorphism screening in the cardiac K+ channel gene KCNA5

BACKGROUND: Common deoxyribonucleic acid polymorphisms that modulate normal cardiac electrophysiologic characteristics have previously been identified in long QT syndrome disease genes. In this study we screened an additional gene encoding the cardiac potassium channel KCNA5 (underlying I(Kur)) in 3 ethnic groups and evaluated the functional consequences of the variants identified. METHODS: The coding region was screened by single-stranded conformational polymorphism analysis and direct sequencing, and nonsynonymous variants were studied by patch-clamping transfected Chinese hamster ovary cells. Results Five synonymous and 6 nonsynonymous polymorphisms were found in KCNA5. None of these polymorphisms was present in greater than 7% of alleles screened or in all 3 ethnic groups. Expression of the nonsynonymous KCNA5 variants revealed normal gating. However, 2 variants (P532L and R578K, both in the C-terminus) were resistant to block by the prototypical inhibitor quinidine; the concentration required to block I(Kur) by 50% (IC(50)) was 8.4 micromol/L for wild type versus 54 micromol/L for R578K and 133 micromol/L for P532L (both P < .0001, versus wild type). CONCLUSION: KCNA5 displays little variability in its coding region. C-terminal KCNA5 variants displayed near-normal gating but striking resistance to drug block; thus these pharmacogenomic studies have identified a heretofore-unappreciated role of this region as a modulator of channel sensitivity to drugs. Resistance to I(Kur) blockers may be genetically determined.     

The Autonomous-collaborative Care Model: meeting the future head on

As care needs continue to increase in complexity in inpatient settings, and nurses' scope of practice evolves to keep pace with these changing demands, it is imperative that nurse leaders ensure nursing care delivery models are well aligned to current realities. Older, traditional models of nursing service may no longer foster safe, effective and efficient care or contribute to job satisfaction and high-quality work life for nurses. This paper describes the Autonomous-Collaborative Care Model and its application in a continuing care setting. This innovative and flexible model fosters autonomy and accountability in nursing practice, reduces duplication in the execution of nursing tasks, enhances effective communication and outlines mechanisms for collaboration among various members of the nursing and interprofessional teams. The model has positioned the authors' organization to meet impending shortages of nursing personnel by ensuring that the right category of nurse is assigned to the appropriate patient, by reducing non-nursing work and by supporting nurses' autonomy to practise to their full scope.     

Creation and testing of the Geriatric Self-Efficacy Index for Urinary Incontinence

OBJECTIVES: To report on the content development, construct validity, and reliability testing of the Geriatric Self-Efficacy Index for Urinary Incontinence (GSE-UI).
DESIGN: Prospective cohort study.
SETTING: Six UI outpatient clinics in Quebec, Canada.
PARTICIPANTS: Community-dwelling incontinent men and women aged 65 and older.
MEASUREMENTS: Thirty-eight items were generated using a literature search and interdisciplinary panel of experts. Item reduction was achieved through field-testing with 75 older men and women with UI attending an information session. The final 20-item draft, measuring older adults' level of confidence in preventing urine loss, was administered to a new group of consecutive patients 1 week before and at the time of their first visit to the UI clinic to enable evaluation of test–retest reliability. A 3-day voiding diary, quantifying the frequency of UI, and the Incontinence Quality of Life questionnaire were used to test construct validity.
RESULTS: One hundred sixteen of 300 eligible patients (39%) participated (mean age±standard deviation 74±6, range 65–87). The GSE-UI items showed normal distributions and no ceiling effects. Self-efficacy scores ranged from 16 to 193 (mean 104±41, possible range 0–200) and correlated positively with quality of life scores ( r =0.7, P <.001) and negatively with UI severity ( r =−0.4, P <.001). Internal consistency for the GSE-UI was 0.94 (Cronbach alpha). Initial test–retest reliability of the 20 items using intraclass correlations ranged from 0.50 to 0.86.
CONCLUSION: The GSE-UI will enable measurement of whether a person's confidence in their ability to prevent urine loss is an important mechanism contributing to improvements in UI.     

Pelvic Floor Muscle Morphometry and Function in Women With Primary and Secondary Provoked Vestibulodynia

Introduction

Provoked vestibulodynia (PVD) can be categorized as primary PVD affecting women from their first sexual intercourse or secondary PVD, which appears after a period of pain-free intercourse. There is growing evidence that these subgroups may be distinct entities presenting different pathophysiological mechanisms. Although there are documented pelvic floor muscle alterations in provoked vestibulodynia, no study has yet evaluated whether the pelvic floor muscle morphometry or function differed between women with primary and secondary provoked vestibulodynia.

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret,Chicago and California Consortia

Objective

Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.

Methods

We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.

Results

34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.

Conclusion

Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.     

Anti-B4-blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma

This phase II trial was undertaken to determine the toxicities, response rate, pharmacokinetics and frequency of human anti-mouse antibody (HAMA) and anti-ricin antibody (HARA) when the B-cell restricted immunotoxin anti-B4-bR was administered to patients with previously treated multiple myeloma (MM).
Five patients with MM were scheduled to receive a 7 d continuous infusion of anti-B4-bR. The initial four patients received therapy at 40 μg/kg lean body weight (LBW)/d. Two patients received a 7 d infusion, one patient received 6 d, and another patient 5 d of therapy. The fifth patient was treated for 7 d at a lower dose of 30 μg/kg LBW/d because of the side-effects observed in the initial patients.
Pharmacokinetic studies demonstrated a peak serum level >2.6 n M in three of the patients. Side-effects of therapy included hepatic transaminase elevations, myalgias, thrombocytopenia, nausea, vomiting, decrease in performance status, and capillary leak syndrome. One patient developed HAMA and two patients HARA. One patient developed neurologic toxicity with akinetic mutism, and died following therapy. No patient demonstrated a significant decline in M-component during therapy.
We concluded that anti-B4-bR can be administered by continuous infusion to patients with multiple myeloma, although immunotoxin levels >3 n M were associated with increased incidence of toxicity and required dose adjustment. Future trials using anti-B4-bR in MM will be needed to determine the optimal dose and administration schedule in this patient population, and to determine whether there is evidence of biologic activity.     

Altered decamer and nonamer from an HLA-A0201-restricted epitope of Survivin differentially stimulate T-cell responses in different individuals

Survivin is a universal tumor antigen that is being currently targeted in vaccine approaches against cancer. Our study here examined the immunogenicity of a novel variant of an HLA-A0201-binding decamer peptide from region 95 to 104 of Survivin (ELMLGEFLKL) with a T → M modification at position 3 in the peptide. We found that this new modified 10-mer peptide had enhanced HLA-A0201 binding and induced a stronger T-cell response over its wild type counterpart peptide (ELTLGEFLKL) in select HLA-A0201⁺ normal donors. In addition, when compared to the previously characterized altered 96-104 peptide (LMLGEFLKL) from the same region of Survivin currently used in vaccine trials, we found that both peptides had similar immunogenicity, but donor T cells preferentially reacted strongly to either one or the other, but not strongly to both. These results suggest that these two closely related Survivin peptides yield distinct T-cell responses and that most individuals dominantly respond to one or the other altered peptide. We also found a novel association between positive reactivity to the new altered decamer Survivin peptide in some individuals and their expression of the HLA-C0701 allele along with HLA-A0201. Thus, vaccinating with both the 10-mer and 9-mer peptides would be required to immunize a maximum number of individuals in the HLA-A0201⁺ population and could lead to more consistent T-cell responses against this region of Survivin.