A Pooled Analysis of Two Randomized,Double‐Blind,Placebo‐Controlled Trials of Milnacipran Monotherapy in the Treatment of Fibromyalgia

Milnacipran has been shown to significantly improve the pain, global well‐being, and physical function of fibromyalgia (FM), and is approved by the U.S. Food and Drug Administration for the management of this disorder. Post hoc analyses of data from two pivotal trials were conducted to further assess the clinical benefits of milnacipran, to determine the impact of baseline pain severity on treatment outcomes, and to confirm the safety and tolerability of this medication in patients with FM. Patients in these trials were randomized to placebo (n = 624), milnacipran 100 mg/day (n = 623), or milnacipran 200 mg/day (n = 837). Two different composite responder analyses were used to evaluate efficacy: a 2‐measure analysis, requiring ≥ 30% improvement from baseline visual analog scale 24‐hour recall pain scores and a Patient Global Impression of Change (PGIC) score of “very much improved” or “much improved”; and a 3‐measure analysis, requiring a ≥ 6‐point improvement from baseline in SF‐36 Physical Component Summary scores in addition to the pain and PGIC criteria. Additionally, a pooled analysis of mean changes from baseline pain scores was conducted in order to evaluate the efficacy of milnacipran over the entire course of treatment. At 3 months, composite responder rates were significantly higher in the milnacipran treatment groups than in the placebo group (2‐ and 3‐measure composite responder analyses: P ≤ 0.001, both doses vs. placebo). These improvements were not dependent on baseline pain severity. Similar composite responder results were observed in patients who continued treatment for up to 6 months. Significant improvements in mean pain scores were seen with both doses of milnacipran vs. placebo as early as 1 week after treatment initiation and were sustained for up to 6 months of milnacipran treatment. The most common adverse events associated with milnacipran were nausea, headache, and constipation.     

The relationship between unmet needs and distress amongst young people with cancer

Purpose  

Most psychosocial research in cancer has been restricted to paediatric or older adult populations. This study aimed to explore psychological distress and unmet needs in adolescents and young adults (AYA) with cancer and identify predictors of distress among demographic and illness characteristics and supportive care needs.     

The Use of a Simultaneous Prompting Procedure To Teach Receptive Manual Sign Identification to Adults with Disabilities

This study examined the effectiveness of a simultaneous prompting procedure to teach receptive manual sign identification to adults with disabilities in a small group format. A multiple probe design across behaviors evaluated the acquisition of targeted signs by adults attending a day habilitation program. In addition, the investigator collected data on observational learning of nontargeted signs presented to group members. All participants learned to verbally label manual signs modeled by the instructor and showed an increase in the ability to label nontargeted signs.     

Urinary incontinence. Impact on working women.

Until recently, the impact of urinary incontinence (UI) on working women, a population generally characterized as healthy, has not been the focus of research. Women employed full time at a large university center participated in a cross sectional survey about UI. Of the 1,113 women surveyed, age 18 and older, 21% (n = 232) reported UI at least monthly. Incontinent women were significantly older and had a higher body mass index than continent women. Using disposable products, limiting fluids, avoiding caffeinated beverages, using voiding schedules, and keeping extra clothes or underwear were strategies used to manage UI at work. Responses to an open ended question related to the impact of UI on working life included: interference with sleep and resulting fatigue at work, embarrassment, alteration of concentration, and emotional distress. Implications for nurses are discussed in relation to assessment, education, and management of UI in the occupational setting.     

Fluorescence polarization assay and SDS-PAGE confirms matrilysin degrades fibronectin and collagen IV whereas gelatinase A degrades collagen IV but not fibronectin.

Matrilysin and gelatinase A are hypothesized to have significant roles in uterine and ovarian function. However, proteolytic activity assays for these enzymes are limited. We describe the development of simple and rapid assays for the proteolysis of fluorescein-labeled full-length substrates, collagen IV (Col-IV) and fibronectin (FN), and demonstrate the selectivity of matrilysin (MMP-7) compared to gelatinase A (MMP-2) for fibronectin. Changes in fluorescence intensity (FIU) and fluorescence polarization (mP) resulting from the protease activity of matrilysin and gelatinase A were measured. These studies show that the fluorescently labeled substrates, Col-IV and FN, are as reliable and amenable to rapid in vitro assay as peptide substrates. In addition, they are easier to use than previously described, non-fluorescent methods. The results demonstrate that assays using full-length, biological matrix proteins are more sensitive indicators of MMP-specific substrate activity than peptide based assays.     

Repeatability and validity of an upper limb and neck discomfort questionnaire: the utility of the standardized Nordic questionnaire

The repeatability and validity of a questionnaire for upper limb and neck complaints were assessed in a population of 105 hospital outpatients with a range of upper limb and neck disorders (including cervical spondylosis, adhesive capsulitis, lateral epicondylitis, carpal tunnel syndrome and Raynaud's phenomenon). Subjects were asked to complete a modified Nordic-style upper limb and neck discomfort questionnaire on two occasions closely spaced in time. The repeatability of their responses was assessed by calculating a kappa coefficient (kappa), and the sensitivity and specificity of component items in the questionnaire were determined for specific diagnostic categories of upper limb and neck disorder. Symptom reports for pain in the upper limb and neck, pain interfering with physical activities, neurological symptoms and blanching were all found to be highly repeatable (kappa = 0.63-0.90). A number of regional pain reports proved to be very sensitive in relation to specific upper limb disorders, but, with the exception of reported finger blanching in patients with Raynaud's phenomenon, none proved to have a good specificity (range = 0.33-0.38). We conclude that a modified Nordic-style questionnaire is repeatable and sensitive, and is likely to have a high utility in screening and surveillance. However a complementary examination schedule of adequate specificity and repeatability is essential to establish a clinical diagnosis.     

Effect of forward and reverse selection for ethanol-induced locomotor response on other measures of ethanol sensitivity

BACKGROUND: Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST-1 and -2) and low (SLOW-1 and -2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse-selected lines, named r-FAST and r-SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection. METHODS: These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling-induced convulsions during chronic ethanol withdrawal, and ethanol-induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined. RESULTS: Handling-induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol-induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r-SLOW mice only. Ethanol clearance rates were similar among all lines and replicates. CONCLUSIONS: These data demonstrate the usefulness of reverse-selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait-relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait-relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.     

Functional glycosylphosphatidylinositol anchor signal sequences in the Pneumocystis carinii PRT1 protease family.

Pneumocystis carinii is fungus which is a frequent cause of severe pneumonia in immunocompromised individuals. The P. carinii genome contains the PRT1 subtelomeric multigene family that encodes a kexin-like serine protease which is expressed on the surface of P. carinii. Analysis of the sequence of the carboxy-terminal sequence of many copies of PRT1 showed that they contained motifs characteristic of a glycosylphosphatidylinositol (GPI) anchor signal sequence. The ability of the C-terminal sequences of PRT1 to direct the addition of a GPI anchor was tested. CD14, a GPI-anchored monocyte glycoprotein antigen, was used as the basis of a heterologous system. CD14 was truncated to remove the carboxy-terminal sequences responsible for GPI-anchor addition. Addition of carboxy-terminal sequences from PRT1 restored high-level surface expression to the truncated CD14. Further, the majority of CD14-PRT1 recombinant protein was removed from the cell membrane by treatment with GPI-specific phospholipase C. These results suggest that the carboxy-terminal residues of most of the members of the PRT1 family of proteases have the potential to form a functional GPI-attachment signal.