Fiber type-related changes in rat skeletal muscle calcium homeostasis during aging and restoration by growth hormone

The mechanisms by which aging induces muscle impairment are not well understood yet. We studied the impact of aging on Ca2+ homeostasis in the slow-twitch soleus and the fast-twitch extensor digitorum longus (EDL) muscles of aged rats by using the fura-2 fluorescent probe. In both muscles aging increases the resting cytosolic calcium concentration ([Ca2+]i). This effect was independent on calcium influx since a reduced resting permeability of sarcolemma to divalent cations was observed in aged muscles likely due to a reduced activity of leak channels. Importantly the effects of aging on resting [Ca2+]i, fiber diameter, mechanical threshold and sarcolemmal resting conductances were less pronounced in the soleus muscle, suggesting that muscle impairment may be less dependent on [Ca2+]i in the slow-twitch muscle. The treatment of aged rats with growth hormone restored the resting [Ca2+]i toward adult values in both muscles. Thus, an increase of resting [Ca2+]i may contribute to muscle weakness associated with aging and may be considered for developing new therapeutic strategies in the elderly.     

Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy

OBJECTIVE: Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy. METHODS: The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle. RESULTS: We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness. INTERPRETATION: Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.     

Predictors of antipsychotic medication adherence in patients recovering from a first psychotic episode

BACKGROUND: Many patients recovering from a first psychotic episode will discontinue medication against medical advice, even before a 1-year treatment course is completed. Factors associated with treatment adherence in patients with chronic schizophrenia include beliefs about severity of illness and need for treatment, treatment with typical versus atypical antipsychotic and medication side effects. METHOD: In this 2-year prospective study of 254 patients recovering from a first episode of schizophrenia, schizophreniform, or schizoaffective disorder we examined the relationship between antipsychotic medication non-adherence and patient beliefs about: need for treatment, antipsychotic medication benefits, and negative aspects of antipsychotic medication treatment. We also examined the relationship between medication non-adherence and treatment with either haloperidol or olanzapine, and objective measures of symptom response and side effects. RESULTS: The likelihood of becoming medication non-adherent for 1 week or longer was greater in subjects whose belief in need for treatment was less (HR=1.75, 95% CI 1.16, 2.65, p=0.0077) or who believed medications were of low benefit (HR=2.88, 95 CI 1.79-4.65, p<0.0001). Subjects randomized to haloperidol were more likely to become medication non-adherent for >or=1 week than subjects randomized to olanzapine (HR-1.51, 95% CI 1.01, 2.27, p=0.045). CONCLUSION: Beliefs about need for treatment and the benefits of antipsychotic medication may be intervention targets to improve likelihood of long-term medication adherence in patients recovering from a first episode of schizophrenia, schizoaffective, or schizophreniform disorder.     

Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats

Increased oxidative stress is implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). However, the efficacy of antioxidant therapy on DPN complicating type 2 diabetes remains unexplored. We therefore determined the ability of the antioxidant taurine to reverse deficits of hind limb sciatic motor and digital sensory nerve conduction velocity (NCV), nerve blood flow (NBF), and sensory thresholds in hyperglycemic Zucker diabetic fatty (ZDF) rats. Experimental groups comprised lean nondiabetic (ND), ND treated with taurine (ND + T), untreated ZDF diabetic (D), and D rats treated with taurine (D + T). Compared to ND rats, 23%, 15% and 56% deficits of motor NCV, sensory NCV and NBF, respectively as well as thermal and mechanical hyperalgesia were reversed by taurine. An 84% deficit of dorsal root ganglion neuron calcitonin gene-related peptide in D rats was prevented by taurine. In summary, the antioxidant taurine reverses neurological and neurovascular deficits in experimental type 2 diabetes.     

Improving on National Quality Indicators of Breast Cancer Care in a Large Public Hospital as a Means to Decrease Disparities for African American Women

Background

In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for stage I, II, and III breast cancer. The purpose of this study was to document compliance with the 3 NQF breast quality indicators during 2 time intervals in a metropolitan public hospital.

Materials and Methods

Tumor registry and medical records were used to identify patient demographics and treatments before (2005–2006) and after (2008) implementations in 2007 as a result of the NQF audit. Program changes included: hiring a dedicated medical oncology nurse practitioner, requiring the radiation oncology case manager to attend weekly multidisciplinary conferences, educating Patient Navigators of the importance of multimodal care, and providing support groups for patients addressing importance of completion of all treatment options.

Results

A total of 213 female patients were diagnosed with and treated for stage I, II, or III breast cancer in 2005–2006 and 2008. Of these, 189 (89%) were African American (AA) women. Also, 70 patients of 86 (81.3%) received radiation therapy, 60 of 77 (77.9%) received or were considered for adjuvant chemotherapy, and 124 of 144 (86.1%) for hormonal therapy according to NQF indicators. After 2007, patients receiving radiation therapy increased from 75.8 to 95.8%. Patients receiving or considered for adjuvant chemotherapy or hormonal therapy increased from 73.7 to 93.7% and from 84.1 to 90.0%, respectively.

Conclusions

NQF breast cancer indicators provided a mechanism to improve compliance of multimodal treatment in our center. Raising awareness of these indicators in the multidisciplinary conference, hiring dedicated personnel, and educating patients has led to major improvements in breast cancer care.     

Intracapsular hip pressures in a porcine model: does position and volume matter?

This study outlines a relationship between joint volume, positioning, and intracapsular pressure in a healthy hip. After measuring the native intracapsular pressure in 12 porcine specimens, each joint was injected with radio-opaque-colored saline as pressures were measured. At 20 mmHg, the hip was placed in its position of ease and then in differing positions while pressures were recorded. Position significantly altered pressures, with the lowest values in neutral and the highest in hyperextension (P<0.001). Extreme hip positions may be detrimental because of high pressures created within the joint, possibly explaining complications associated with some hip diagnostic and treatment methods.     

Supportive Versus Immunosuppressive Therapy of Progressive IgA nephropathy (STOP) IgAN trial: rationale and study protocol

Introduction: The best treatment of IgA nephropathy (IgAN) is currently not well defined. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial aims to answer if, in IgAN patients, an immunosuppressive treatment is more effective than a supportive treatment. Methods: In a randomized prospective multicenter study (www.clinicaltrials.gov, NCT00554502), we will treat 148 patients at risk for progressive IgA nephropathy following a 6-month run-in phase, in 2 groups: (group a) supportive treatment: patients with a persistent proteinuria >0.75 g/day will receive a maximized therapy to reduce blood pressure and urinary protein loss using angiotensin-converting enzyme inhibitors and AT1 blockers, statins, dietary counseling for a low-sodium and low-protein diet and education/intervention programs to stop smoking. (group b) immunosuppressive treatment: in addition to the identical treatment of group a, patients will receive treatment with steroids (glomerular filtration rate [GFR] > or =60 ml/min) or steroids plus cyclophosphamide/azathioprine (GFR <60 ml/min). Study end points are the complete remission of the disease and the individual degree of renal functional loss. If the immunosuppressive therapy shows a superior efficacy with respect to prevention of renal failure, the potentially higher therapy cost and risk might be justified. Finally, our trial can serve as a model for various other types of glomerulonephritis, for which such trials are very difficult to perform, given their infrequency.     

Type I interferons in the treatment of pancreatic cancer: mechanisms of action and role of related receptors

OBJECTIVE: We evaluated the role of type I interferons (IFNs) and IFN receptors in the regulation of cell growth in 3 human pancreatic adenocarcinoma cell lines (BxPC-3, MiaPaCa-2, and Panc-1). BACKGROUND: Chemotherapy and radiotherapy have a marginal role in the management of pancreatic adenocarcinoma. The addition of IFN-alpha showed promising results in early clinical trials. METHODS: Cell proliferation and apoptosis were evaluated by DNA measurement and DNA fragmentation, respectively. Type I IFN receptor (IFNAR-1 and IFNAR-2 subunits) was determined by quantitative RT-PCR and immunocytochemistry. Cell cycle distribution was evaluated by propidium iodide staining and flow-cytometric analysis. RESULTS: The incubation with IFN-beta for 6 days showed a potent inhibitory effect on the proliferation of BxPC-3 (IC(50), 14 IU/mL) and MiaPaCa-2 (IC(50), 64 IU/mL). The inhibitory effect of IFN-beta was stronger than IFN-alpha in all 3 cell lines and mainly modulated by the stimulation of apoptosis, although cell cycle arrest was induced as well. The expression of the type I IFN receptors was significantly higher in BxPC-3 (the most sensitive cell line to IFN) and mainly localized on the membrane, whereas in Panc-1 (the most resistant cell line) about 60% to 70% of cells were negative for IFNAR-2c with a mainly cytoplasmic staining for IFNAR-2c. CONCLUSION: The antitumor activity of IFN-beta is more potent than IFN-alpha in pancreatic cancer cell lines through the induction of apoptosis. Further studies should investigate in vivo whether the intensity and distribution of IFNAR-1 and IFNAR-2c may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer.