Memantine treatment does not affect compulsive behavior or frontostriatal connectivity in an adolescent rat model for quinpirole-induced compulsive checking behavior

RATIONALE: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. OBJECTIVE: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity. METHODS: Juvenile Sprague-Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). RESULTS: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. CONCLUSIONS: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI

Risk of breast cancer in women after a salivary gland carcinoma or pleomorphic adenoma in the Netherlands

Salivary and mammary gland tumors show morphological similarities and share various characteristics, including frequent overexpression of hormone receptors and female preponderance. Although this may suggest a common etiology, it remains unclear whether patients with a salivary gland tumor carry an increased risk of breast cancer (BC). Our purpose was to determine the risk of BC in women diagnosed with salivary gland carcinoma (SGC) or pleomorphic adenoma (SGPA). BC incidence (invasive and in situ) was assessed in two nationwide cohorts: one comprising 1567 women diagnosed with SGC and one with 2083 women with SGPA. BC incidence was compared with general population rates using standardized incidence ratio (SIR). BC risk was assessed according to age at SGC/SGPA diagnosis, follow-up time and (for SGC patients) histological subtype. The mean follow-up was 7.0 years after SGC and 9.9 after SGPA diagnosis. During follow-up, 52 patients with SGC and 74 patients with SGPA developed BC. The median time to BC was 6 years after SGC and 7 after SGPA. The cumulative risk at 10 years of follow-up was 3.1% after SGC and 3.5% after SGPA (95% Confidence Interval (95%CI) 2.1%-4.7% and 2.6%-4.6%, respectively). BC incidence was 1.59 times (95%CI 1.19-2.09) higher in the SGC-cohort than expected based on incidence rates in the general population. SGPA-patients showed a 1.48 times (95%CI 1.16-1.86) higher incidence. Women with SGC or SGPA have a slightly increased risk of BC. The magnitude of risk justifies raising awareness, but is no reason for BC screening

What predicts change in pulmonary function and quality of life in asthma or COPD ?

Information about predictors of decline in pulmonary function (forced expiratory volume in 1 second [FE

Physical therapy plus general practitioners’ care versus general practitioners’ care alone for sciatica: a randomised clinical trial with a 12-month follow-up

A randomised clinical trial in primary care with a 12-months follow-up period. About 135 patients with acute sciatica (recruited from May 2003 to November 2004) were randomised in two groups: (1) the intervention group received physical therapy (PT) added to the general practitioners’ care, and (2) the control group with general practitioners’ care only. To assess the effectiveness of PT additional to general practitioners’ care compared to general practitioners’ care alone, in patients with acute sciatica. There is a lack of knowledge concerning the effectiveness of PT in patients with sciatica. The primary outcome was patients’ global perceived effect (GPE). Secondary outcomes were severity of leg and back pain, severity of disability, general health and absence from work. The outcomes were measured at 3, 6, 12 and 52 weeks after randomisation. At 3 months follow-up, 70% of the intervention group and 62% of the control group reported improvement (RR 1.1; 95% CI 0.9–1.5). At 12 months follow-up, 79% of the intervention group and 56% of the control group reported improvement (RR 1.4; 95% CI 1.1; 1.8). No significant differences regarding leg pain, functional status, fear of movement and health status were found at short-term or long-term follow-up. At 12 months follow-up, evidence was found that PT added to general practitioners’ care is only more effective regarding GPE, and not more cost-effective in the treatment of patients with acute sciatica than general practitioners’ care alone. There are indications that PT is especially effective regarding GPE in patients reporting severe disability at presentation

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Prolonged conservative treatment or 'early' surgery in sciatica caused by a lumbar disc herniation: rationale and design of a randomized trial [ISRCT 26872154]

BACKGROUND: The design of a randomized multicenter trial is presented on the effectiveness of a prolonged conservative treatment strategy compared with surgery in patients with persisting intense sciatica (lumbosacral radicular syndrome). METHODS/DESIGN: Patients presenting themselves to their general practitioner with disabling sciatica lasting less than twelve weeks are referred to the neurology outpatient department of one of the participating hospitals. After confirmation of the diagnosis and surgical indication MRI scanning is performed. If a distinct disc herniation is discerned which in addition covers the clinically expected site the patient is eligible for randomization. Depending on the outcome of the randomization scheme the patient will either be submitted to prolonged conservative care or surgery. Surgery will be carried out according to the guidelines and between six and twelve weeks after onset of complaints. The experimental therapy consists of a prolonged conservative treatment under supervision of the general practitioner, which may be followed by surgical intervention in case of persisting or progressive disability. The main primary outcome measure is the disease specific disability of daily functioning. Other primary outcome measures are perceived recovery and intensity of legpain. Secondary outcome measures encompass severity of complaints, quality of life, medical consumption, absenteeism, costs and preference. The main research question will be answered at 12 months after randomization. The total follow-up period covers two years. DISCUSSION: Evidence is lacking concerning the optimal treatment of lumbar disc induced sciatica. This pragmatic randomized trial, focusses on the 'timing' of intervention, and will contribute to the decision of the general practictioner and neurologist, regarding referral of patients for surgery