A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence

PURPOSE: We primarily compared the effectiveness of combined pelvic floor muscle training (PFMT) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence (SUI). In addition, we compared the effectiveness of combined treatment with single treatments, single treatments with each other and single treatments with no treatment. MATERIALS AND METHODS: This blinded, doubly controlled, randomized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherlands, United Kingdom and United States. Women averaged 2 or more incontinence episodes daily and were randomized to 1 of 4 combinations of 80 mg duloxetine daily, placebo, PFMT and imitation PFMT, including combined treatment (in 52), no active treatment (in 47), PFMT only (in 50) and duloxetine only (in 52). The primary efficacy measure was incontinence episode frequency. Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life questionnaire score. RESULTS: The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone. However, pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment. A completer population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone. CONCLUSIONS: The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI. We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment.     

Intrajoint comparisons of gene expression patterns in human osteoarthritis suggest a change in chondrocyte phenotype.

Osteoarthritis (OA) is a degenerative cartilage disease with varying degrees of severity within a given joint. The purpose of this study was to define a sampling procedure for comparing human minimal and advanced OA cartilage in the same patient and to determine basic patterns of gene expression in these regions. A specific hypothesis under study was that the expression level of Bcl-2 would correlate with Sox9 and aggrecan mRNA expression in vivo as has been demonstrated in vitro. Femoral condylar advanced OA cartilage was located within 1cm of overt lesions, and minimal cartilage was taken from areas with no obvious surface defects. Histological sections were scored for disease severity and chondroitin sulfate and hydroxyproline content was determined. The expression level of nine specific genes (aggrecan, collagen type II, Bcl-2, Sox9, Link protein, osteopontin, and MMP-13, -3, and -9) was determined by quantitative real time PCR. The scores for fibrillation, chondrocyte cloning, and proteoglycan depletion were significantly different between advanced and minimal OA cartilage. The advanced OA cartilage had significantly less chondroitin sulfate than the minimal OA cartilage. Osteopontin mRNA expression showed a 3.6-fold increase in advanced compared to minimal OA cartilage. In contrast, the level of mRNA coding for aggrecan, link protein, Bcl-2, Sox9 and MMP-3, -9, -13 were all decreased in advanced compared to minimal cartilage in the majority of the patients studied. Collagen type II mRNA expression displayed a wide-range of variation. A statistically significant correlation was observed both between Bcl-2 and Sox9 mRNA level, and between Bcl-2 and aggrecan mRNA expression. The patient matched comparison of minimal and advanced OA cartilage revealed differences in cellular and tissue characteristics, and changes in gene expression that may be involved in OA progression. In addition, Bcl-2 may also play a role in regulating the expression of aggrecan through Sox9 in vivo as well as in vitro.     

Punishment Learning in U.S. Veterans With Posttraumatic Stress Disorder

Learning processes have been implicated in the development and course of posttraumatic stress disorder (PTSD); however, little is currently known about punishment‐based learning in PTSD. The current study investigated impairments in punishment‐based learning in U.S. veterans. We expected that veterans with PTSD would demonstrate greater punishment‐based learning compared to a non‐PTSD control group. We compared a PTSD group with and without co‐occurring depression (n = 27) to a control group (with and without trauma exposure) without PTSD or depression (n = 29). Participants completed a computerized probabilistic punishment‐based learning task. Compared to the non‐PTSD control group, veterans with PTSD showed significantly greater punishment‐based learning. Specifically, there was a significant Block × Group interaction, F(1, 54) = 4.12, p = .047, η² = .07. Veterans with PTSD demonstrated greater change in response bias for responding toward a less frequently punished stimulus across blocks. The observed hypersensitivity to punishment in individuals with PTSD may contribute to avoidant responses that are not specific to trauma cues.     

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

Objective:

Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features.

Methods:

A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined.

Results:

Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy–Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC).

Conclusion:

The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making.

Advances in knowledge:

The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.     

The role of enteral nutrition in the reversal of parenteral nutrition-associated liver dysfunction in infants

Background

Liver dysfunction in children dependent on parenteral nutrition (PN) is well established, and the extent of hyperbilirubinemia has been shown to correlate with morbidity and mortality. The aim of this study was to assess whether increasing provisions of enteral nutrition can improve PN-associated hyperbilirubinemia over time.

Methods

A retrospective review was conducted on infants in our institution's Short Bowel Syndrome Clinic from 1999 to 2004. Inclusion criteria included PN duration more than 1 month, serum direct bilirubin more than 3 mg/dL while on PN, and tolerance of full enteral nutrition with eventual discontinuation of PN. Paired t tests were used for statistical analyses.

Results

Twelve infants were identified with a PN duration of 5 ± 1 months. Five patients underwent liver biopsy while on PN, and histological evidence of cholestasis was found on all specimens. Peak total and direct bilirubin levels were 10.5 ± 1.9 and 7.0 ± 1.6 mg/dL, respectively, and occurred at time of PN discontinuation. Only 2 patients had improvement in serum bilirubin levels before initiation of full enteral nutrition. After initiation of full enteral nutrition and discontinuation of PN, all patients achieved permanent normalization of bilirubin levels by 4 months (P < .05) after a 1-month plateau phase. Alkaline phosphatase levels approached reference range within this time but were not significant.

Conclusion

These data demonstrate for the first time that although PN-dependent infants can achieve normalization of marked hyperbilirubinemia with enteral nutrition, the improvement in liver function usually begins only after full enteral nutrition is tolerated and PN is withdrawn. These findings support the aggressive weaning of PN to enteral nutrition in infants with short bowel syndrome.     

Vitamin D, parathyroid hormone levels and bone mineral density in community-dwelling older women: The Rancho Bernardo Study

Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss, and prevalence of hip fractures in 615 community-dwelling postmenopausal aged 50–97 years. Mean level of 25(OH)D and PTH were 102.0 nmol/l±35.0 nmol/l and 49.4 ng/l±23.2 nmol/l, respectively; 49% of women were current hormone therapy users. The overall prevalence of vitamin D insufficiency (25(OH)D<50 nmol/l) was 2%, and prevalence of high PTH levels (>65 ng/l) was 17.4%. In multiple linear regression analyses hip BMD was negatively and independently associated with PTH levels ( p =0.04), and positively and independently associated with 25(OH)D levels ( p =0.03). There were only 23 women (3.7%) who experienced a hip fracture. In age-adjusted analyses there were no significant differences of 25(OH)D and PTH levels by hip fracture status. Across the entire range of values, the overall correlation between 25(OH)D and PTH was moderate ( r =–0.20). However, after the threshold vitamin D level of 120 nmol/l, all PTH values were below 65 ng/l. Further studies are necessary to identify the optimal vitamin D levels necessary to prevent secondary hyperparathyroidism.     

Initiation and Maintenance of Weight Loss after Laparoscopic Adjustable Gastric Banding. The role of Outcome Expectation and Satisfaction with the Psychosocial Outcome

Background  A premise of this study was that different psychological processes would predict the initiation and maintenance of weight loss after surgery for morbid obesity. Our aim was to examine whether more favorable preoperative expectations of psychosocial outcomes predict weight loss in the first year after laparoscopic adjustable gastric banding (LAGB) and whether postoperative satisfaction with these outcomes predicts weight maintenance in the second year after the operation. Methods  Six months before and 1 year after surgery, the “Obesity Psychosocial State Questionnaire” was filled out by 91 patients (77 female, 14 male, mean age 45 ± 9 years, mean preoperative body mass index 47 ± 6 kg/m²). We evaluated the preoperative outcome expectations and the postoperative satisfaction for the seven domains of psychosocial and physical functioning of this questionnaire, as well as the correlations between these scores and both weight loss and weight maintenance. Results  Patients showed high satisfaction with psychosocial outcomes after LAGB in all seven domains (p < 0.001), even though the improvement was less than expected in five of the domains (p ≤ 0.01). While weight loss 1 year after the operation was related to satisfaction with psychosocial outcomes (p ≤ 0.05), preoperative expectations were not related to weight loss in the first year after surgery, and satisfaction with the outcomes was not related to weight maintenance in the second year after surgery. Conclusion  Our study suggests that surgically induced effects of weight loss and weight maintenance are achieved independently of the patient’s preoperative expectations of and postoperative satisfaction with the psychosocial outcomes.     

Increased RANK ligand in bone marrow of orchiectomized rats and prevention of their bone loss by the RANK ligand inhibitor osteoprotegerin

Orchiectomized (ORX) rats were used to examine the extent to which their increased bone resorption and decreased bone density might relate to increases in RANKL, an essential cytokine for bone resorption.Serum testosterone declined by > 95% in ORX rats 1 and 2 weeks after surgery (p < 0.05 versus sham controls), with no observed changes in serum RANKL. In contrast, RANKL in bone marrow plasma and bone marrow cell extracts was significantly increased (by  100%) 1 and 2 weeks after ORX. Regression analyses of ORX and sham controls revealed a significant inverse correlation between testosterone and RANKL levels measured in marrow cell extracts (R = − 0.58), while marrow plasma RANKL correlated positively with marrow plasma TRACP-5b, an osteoclast marker (R = 0.63). The effects of RANKL inhibition were then studied by treating ORX rats for 6 weeks with OPG-Fc (10 mg/kg, twice/week SC) or with PBS, beginning immediately after surgery. Sham controls were treated with PBS. Vehicle-treated ORX rats showed significant deficits in BMD of the femur/tibia and lower trabecular bone volume in the distal femur (p < 0.05 versus sham). OPG-Fc treatment of ORX rats increased femur/tibia BMD and trabecular bone volume to levels that significantly exceeded values for ORX or sham controls. OPG-Fc reduced trabecular osteoclast surfaces in ORX rats by 99%, and OPG-Fc also prevented ORX-related increases in endocortical eroded surface and ORX-related reductions in periosteal bone formation rate. Micro-CT of lumbar vertebrae from OPG-Fc-treated ORX rats demonstrated significantly greater cortical and trabecular bone volume and density versus ORX-vehicle controls. In summary, ORX rats exhibited increased RANKL protein in bone marrow plasma and in bone marrow cells, with no changes in serum RANKL. Data from regression analyses were consistent with a potential role for testosterone in suppressing RANKL production in bone marrow, and also suggested that soluble RANKL in bone marrow might promote bone resorption. RANKL inhibition prevented ORX-related deficits in trabecular BMD, trabecular architecture, and periosteal bone formation while increasing cortical and trabecular bone volume and density. These results support the investigation of RANKL inhibition as a strategy for preventing bone loss associated with androgen ablation or deficiency.