Localization of the cannabinoid CB1 receptor and the 2-AG synthesizing (DAGLα) and degrading (MAGL, FAAH) enzymes in cells expressing the Ca(2+)-binding proteins calbindin, calretinin, and parvalbumin in the adult rat hippocampus.

The retrograde suppression of the synaptic transmission by the endocannabinoid sn-2-arachidonoylglycerol (2-AG) is mediated by the cannabinoid CB1 receptors and requires the elevation of intracellular Ca(2+) and the activation of specific 2-AG synthesizing (i.e., DAGLα) enzymes. However, the anatomical organization of the neuronal substrates that express 2-AG/CB1 signaling system-related molecules associated with selective Ca(2+)-binding proteins (CaBPs) is still unknown. For this purpose, we used double-label immunofluorescence and confocal laser scanning microscopy for the characterization of the expression of the 2-AG/CB1 signaling system (CB1 receptor, DAGLα, MAGL, and FAAH) and the CaBPs calbindin D28k, calretinin, and parvalbumin in the rat hippocampus. CB1, DAGLα, and MAGL labeling was mainly localized in fibers and neuropil, which were differentially organized depending on the hippocampal CaBPs-expressing cells. CB(+) 1 fiber terminals localized in all hippocampal principal cell layers were tightly attached to calbindin(+) cells (granular and pyramidal neurons), and calretinin(+) and parvalbumin(+) interneurons. DAGLα neuropil labeling was selectively found surrounding calbindin(+) principal cells in the dentate gyrus and CA1, and in the calretinin(+) and parvalbumin(+) interneurons in the pyramidal cell layers of the CA1/3 fields. MAGL(+) terminals were only observed around CA1 calbindin(+) pyramidal cells, CA1/3 calretinin(+) interneurons and CA3 parvalbumin(+) interneurons localized in the pyramidal cell layers. Interestingly, calbindin(+) pyramidal cells expressed FAAH specifically in the CA1 field. The identification of anatomically related-neuronal substrates that expressed 2-AG/CB1 signaling system and selective CaBPs should be considered when analyzing the cannabinoid signaling associated with hippocampal functions.

Tapia's syndrome: pathogenetic mechanisms, diagnostic management, and proper treatment: a case series.

BACKGROUND Tapia's syndrome is an uncommon disease described in 1904 by Antonio Garcia Tapia, a Spanish otolaryngologist. It is characterized by concomitant paralysis of the hypoglossal (XIIth) and pneumogastric (Xth) nerves. Only 69 cases have been described in the literature. Typically, the reported patients presented with a history of orotracheal intubation. Common symptoms are dysphonia, tongue deviation toward the affected side, lingual motility disturbance, and swallowing difficulty. CASE PRESENTATION In the report, we describe three cases of Tapia's syndrome in three Caucasian patients who underwent surgery with general anesthesia. Two of these patients underwent neck abscess drainage, and the third had an open reduction of a shoulder fracture. The clinical symptoms of Tapia's syndrome appeared after extubation. All three of our patients recovered their lost function at 3 months after diagnosis. CONCLUSIONS We underline the importance of performing airway endoscopy and a specific program of swallowing rehabilitation for the proper management of Tapia's syndrome.

Ulcerative colitis impairs the acylethanolamide-based anti-inflammatory system reversal by 5-aminosalicylic acid and glucocorticoids

Studies in animal models and humans suggest anti-inflammatory roles on the N acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.

Randomised controlled study in the primary healthcare sector to investigate the effectiveness and safety of auriculotherapy for the treatment of uncomplicated chronic rachialgia: a study protocol.

BACKGROUND Uncomplicated chronic rachialgia is a highly prevalent complaint, and one for which therapeutic results are contradictory. The aim of the present study is to evaluate the effectiveness and safety of treatment with auriculopressure, in the primary healthcare sector, carried out by trained healthcare professionals via a 30-hour course. METHODS/DESIGN The design consists of a multi-centre randomized controlled trial, with placebo, with two parallel groups, and including an economic evaluation. Patients with chronic uncomplicated rachialgia, whose GP is considering referral for auriculopressure sensory stimulation, are eligible for inclusion. Sampling will be by consecutive selection, and randomised allocation to one of the two study arms will be determined using a centralised method, following a 1:1 plan (true auriculopressure; placebo auriculopressure). The implants (true and placebo) will be replaced once weekly, and the treatment will have a duration of 8 weeks. The primary outcome measure will be the change in pain intensity, measured on a visual analogue scale (VAS) of 100 mm, at 9 weeks after beginning the treatment. A follow up study will be performed at 6 months after beginning treatment. An assessment will also be made of the changes measured in the Spanish version of the McGill Pain Questionnaire, of the changes in the Lattinen test, and of the changes in quality of life (SF-12). Also planned is an analysis of cost-effectiveness and also, if necessary, a cost-benefit analysis. DISCUSSION This study will contribute to developing evidence on the use of auriculotherapy using Semen vaccariae [wang bu liu xing] for the treatment of uncomplicated chronic rachialgia. TRIAL REGISTRATION Current Controlled Trials ISRCTN01897462.

Efficacy and safety of acupuncture for the treatment of non-specific acute low back pain: a randomised controlled multicentre trial protocol [ISRCTN65814467]

BACKGROUND Low back pain and its associated incapacitating effects constitute an important healthcare and socioeconomic problem, as well as being one of the main causes of disability among adults of working age. The prevalence of non-specific low back pain is very high among the general population, and 60-70% of adults are believed to have suffered this problem at some time. Nevertheless, few randomised clinical trials have been made of the efficacy and efficiency of acupuncture with respect to acute low back pain. The present study is intended to assess the efficacy of acupuncture for acute low back pain in terms of the improvement reported on the Roland Morris Questionnaire (RMQ) on low back pain incapacity, to estimate the specific and non-specific effects produced by the technique, and to carry out a cost-effectiveness analysis. METHODS/DESIGN Randomised four-branch controlled multicentre prospective study made to compare semi-standardised real acupuncture, sham acupuncture (acupuncture at non-specific points), placebo acupuncture and conventional treatment. The patients are blinded to the real, sham and placebo acupuncture treatments. Patients in the sample present symptoms of non specific acute low back pain, with a case history of 2 weeks or less, and will be selected from working-age patients, whether in paid employment or not, referred by General Practitioners from Primary Healthcare Clinics to the four clinics participating in this study. In order to assess the primary and secondary result measures, the patients will be requested to fill in a questionnaire before the randomisation and again at 3, 12 and 48 weeks after starting the treatment. The primary result measure will be the clinical relevant improvement (CRI) at 3 weeks after randomisation. We define CRI as a reduction of 35% or more in the RMQ results. DISCUSSION This study is intended to obtain further evidence on the effectiveness of acupuncture on acute low back pain and to isolate the specific and non-specific effects of the treatment.

Acquisition and cross-transmission of Staphylococcus aureus in European intensive care units

Objective. To study the acquisition and cross-transmission of Staphylococcus aureus in different intensive care units (ICUs). Methods. We performed a multicenter cohort study. Six ICUs in 6 countries participated. During a 3-month period at each ICU, all patients had nasal and perineal swab specimens obtained at ICU admission and during their stay. All S. aureus isolates that were collected were genotyped by spa typing and multilocus variable-number tandem-repeat analysis typing for cross-transmission analysis. A total of 629 patients were admitted to ICUs, and 224 of these patients were found to be colonized with S. aureus at least once during ICU stay (22% were found to be colonized with methicillin-resistant S. aureus [MRSA]). A total of 316 patients who had test results negative for S. aureus at ICU admission and had at least 1 follow-up swab sample obtained for culture were eligible for acquisition analysis. Results. A total of 45 patients acquired S. aureus during ICU stay (31 acquired methicillin-susceptible S. aureus [MSSA], and 14 acquired MRSA). Several factors that were believed to affect the rate of acquisition of S. aureus were analyzed in univariate and multivariate analyses, including the amount of hand disinfectant used, colonization pressure, number of beds per nurse, antibiotic use, length of stay, and ICU setting (private room versus open ICU treatment). Greater colonization pressure and a greater number of beds per nurse correlated with a higher rate of acquisition for both MSSA and MRSA. The type of ICU setting was related to MRSA acquisition only, and the amount of hand disinfectant used was related to MSSA acquisition only. In 18 (40%) of the cases of S. aureus acquisition, cross-transmission from another patient was possible. Conclusions. Colonization pressure, the number of beds per nurse, and the treatment of all patients in private rooms correlated with the number of S. aureus acquisitions on an ICU. The amount of hand disinfectant used was correlated with the number of cases of MSSA acquisition but not with the number of cases of MRSA acquisition. The number of cases of patient-to-patient cross-transmission was comparable for MSSA and MRSA.

Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus SEMICYUC-SENPE: Acute renal failure

Nutritional support in acute renal failure must take into account the patient's catabolism and the treatment of the renal failure. Hypermetabolic failure is common in these patients, requiring continuous renal replacement therapy or daily hemodialysis. In patients with normal catabolism (urea nitrogen below 10 g/day) and preserved diuresis, conservative treatment can be attempted. In these patients, relatively hypoproteic nutritional support is essential, using proteins with high biological value and limiting fluid and electrolyte intake according to the patient's individual requirements. Micronutrient intake should be adjusted, the only buffering agent used being bicarbonate. Limitations on fluid, electrolyte and nitrogen intake no longer apply when extrarenal clearance techniques are used but intake of these substances should be modified according to the type of clearance. Depending on their hemofiltration flow, continuous renal replacement systems require high daily nitrogen intake, which can sometimes reach 2.5 g protein/kg. The amount of volume replacement can induce energy overload and therefore the use of glucose-free replacement fluids and glucose-free dialysis or a glucose concentration of 1 g/L, with bicarbonate as a buffer, is recommended. Monitoring of electrolyte levels (especially those of phosphorus, potassium and magnesium) and of micronutrients is essential and administration of these substances should be individually-tailored.

Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations

Summary Points Brucellosis remains the commonest anthropozoonosis worldwide, and its treatment remains complex, requiring protracted administration of more than one antibiotic. In November 2006, a consensus meeting aimed at reaching a common specialist statement on the treatment of brucellosis was held in Ioannina, Greece under the auspices of the International Society of Chemotherapy and the Institute of Continuing Medical Education of Ioannina. The author panel suggests that the optimal treatment of uncomplicated brucellosis should be based on a six-week regimen of doxycycline combined either with streptomycin for 2–3 weeks, or rifampicin for six weeks. Gentamicin may be considered an acceptable alternative to streptomycin, while all other regimens/combinations should be considered second-line. The development of a common global therapeutic language for human brucellosis, and future, properly conducted clinical trials would definitely solve controversies regarding the disease.

Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer.

BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

Use of palliative radiotherapy in brain and bone metastases (VARA II study).

INTRODUCTION Metastases are detected in 20% of patients with solid tumours at diagnosis and a further 30% after diagnosis. Radiation therapy (RT) has proven effective in bone (BM) and brain (BrM) metastases. The objective of this study was to analyze the variability of RT utilization rates in clinical practice and the accessibility to medical technology in our region. PATIENTS AND METHODS We reviewed the clinical records and RT treatment sheets of all patients undergoing RT for BM and/or BrM during 2007 in the 12 public hospitals in an autonomous region of Spain. Data were gathered on hospital type, patient type and RT treatment characteristics. Calculation of the rate of RT use was based on the cancer incidence and the number of RT treatments for BM, BrM and all cancer sites. RESULTS Out of the 9319 patients undergoing RT during 2007 for cancer at any site, 1242 (13.3%; inter-hospital range, 26.3%) received RT for BM (n = 744) or BrM (n = 498). These 1242 patients represented 79% of all RT treatments with palliative intent, and the most frequent primary tumours were in lung, breast, prostate or digestive system. No significant difference between BM and BrM groups were observed in: mean age (62 vs. 59 yrs, respectively); gender (approximately 64% male and 36% female in both); performance status (ECOG 0-1 in 70 vs. 71%); or mean distance from hospital (36 vs. 28.6 km) or time from consultation to RT treatment (13 vs. 14.3 days). RT regimens differed among hospitals and between patient groups: 10 × 300 cGy, 5 × 400 cGy and 1x800cGy were applied in 32, 27 and 25%, respectively, of BM patients, whereas 10 × 300cGy was used in 49% of BrM patients. CONCLUSIONS Palliative RT use in BM and BrM is high and close to the expected rate, unlike the global rate of RT application for all cancers in our setting. Differences in RT schedules among hospitals may reflect variability in clinical practice among the medical teams.

Gouty tophi in the penis: a case report and review of the literature.

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate crystals in different anatomical locations. We report the case of a 61-year-old man who received consultation for gouty tophi in the penis, which is an unusual location for this type of pathology, that was resolved with the surgical removal of the tophi. We provide a review on gout and its treatment as well as other locations where atypical gouty tophi have been described.

Primary renal lymphoma: report of three new cases and literature review.

OBJECTIVES We report the cases of three patients with primary renal lymphoma. Diagnosis and subsequent treatment are discussed. METHODS The literature on the origin, epidemiology, clinical presentation, diagnosis, treatment and prognosis of primary renal lymphoma was reviewed. RESULTS The first patient was diagnosed after radical nephrectomy and subsequently was given six cycles of CVP (cyclophosphamide, vincristine, prednisone). The diagnosis of the second patient was established by renal biopsy, and the patient received six cycles of CHOP (cyclophosphamide, adriamycin, vincristine and predisone). The last patient had a lymphoma, secondary to immunosuppression, in a transplanted kidney. In this case transplant nephrectomy sufficed to cure the patient's lymphoma. All patients had B-cell non-Hodgkin lymphoma (an extrarenal origin was ruled out by bone marrow biopsy), and were disease-free 15 months, 7 months, and 6.5 years after diagnosis, respectively. CONCLUSIONS Primary renal lymphoma is rare. Diagnosis is established by renal biopsy, although it often presents as a mass simulating renal cell cancer and diagnosis is obtained after radical nephrectomy. Treatment consists of chemotherapy (CHOP). associated with rituximab.

Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

OBJECTIVES: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe. DESIGN: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis. SETTING AND PARTICIPANTS: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998. OUTCOME MEASURES: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models. RESULTS: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours. CONCLUSIONS: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat.

β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.