The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the neuromodulation appropriateness consensus committee.

INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) of the International Neuromodulation Society (INS) evaluated evidence regarding the safety and efficacy of neurostimulation to treat chronic pain, chronic critical limb ischemia, and refractory angina and recommended appropriate clinical applications. METHODS: The NACC used literature reviews, expert opinion, clinical experience, and individual research. Authors consulted the Practice Parameters for the Use of Spinal Cord Stimulation in the Treatment of Neuropathic Pain (2006), systematic reviews (1984 to 2013), and prospective and randomized controlled trials (2005 to 2013) identified through PubMed, EMBASE, and Google Scholar. RESULTS: Neurostimulation is relatively safe because of its minimally invasive and reversible characteristics. Comparison with medical management is difficult, as patients considered for neurostimulation have failed conservative management. Unlike alternative therapies, neurostimulation is not associated with medication-related side effects and has enduring effect. Device-related complications are not uncommon; however, the incidence is becoming less frequent as technology progresses and surgical skills improve. Randomized controlled studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome. Similar studies of neurostimulation for peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, and other causes of nerve injury are needed. International guidelines recommend spinal cord stimulation to treat refractory angina; other indications, such as congestive heart failure, are being investigated. CONCLUSIONS: Appropriate neurostimulation is safe and effective in some chronic pain conditions. Technological refinements and clinical evidence will continue to expand its use. The NACC seeks to facilitate the efficacy and safety of neurostimulation.

Effect of statin therapy in the outcome of bloodstream infections due to Staphylococcus aureus: a prospective cohort study.

INTRODUCTION Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB). METHODS A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy. RESULTS We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01-0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27-1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10-1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27-2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19-1.29; p = 0.15). CONCLUSIONS Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.

Prevalence, treatment and control of dyslipidaemia in Switzerland: still a long way to go.

BACKGROUND: There is little information regarding the prevalence and management of dyslipidaemia in Switzerland. DESIGN: Cross-sectional population-based study of 3238 women and 2846 men aged 35-75. METHODS: Dyslipidaemia prevalence, treatment and control were defined according to PROCAM guidelines adapted to Switzerland. RESULTS: About 29% of the overall sample presented with dyslipidaemia, of which 39% were treated and 58% of those treated were controlled. Among the 710 patients with personal history of cardiovascular disease (CVD) and/or diabetes, 632 (89%) presented with dyslipidaemia, of which 278 (44%) and 134 (21%) patients were treated and adequately controlled, respectively. On multivariate analysis, hypolipidaemic drug treatment was positively related with age and body mass index (P for trend <0.001), and negatively related with smoking status (P for trend <0.002), whereas personal history of CVD and/or diabetes had no effect [odds ratio (OR)=1.12, 95% confidence interval (CI): 0.90-1.38]. Adequate control of lipid levels was negatively related with female sex (OR=0.65, 95% CI: 0.45-0.94) and personal history of CVD and/or diabetes (OR=0.42, 95% CI: 0.30-0.59). When personal history of CVD and/or diabetes was replaced by PROCAM risk categories, patients in the highest risk were also less well controlled. CONCLUSION: In this population-based study, one-third of the participants was dyslipidaemic, but less than half was treated and only one-fifth was adequately controlled. The low treatment and control levels among individuals at high risk for CVD calls for a better application of recommendations regarding personal preventive measures.

The cervico-thoracic outlet compression syndrome. Analysis of surgical treatment.

Surgical treatment of the thoracic outlet compression syndrome is being presently reconsidered. Until these last few years, there was the choice between two interventions only: scalenotomy, a simple operation entailing no complication, but with a 60% recurrence rate--or the resection of the first rib through an axillary approach, an efficacious intervention which caused, however, serious nervous complications in 14% of treated cases. The follow-up of 75 cases operated for a TOCS reveals to the authors that--all techniques taken into account--results are unsatisfactory in 33% of cases. These failures are due either to technical deficiencies, or to a complication arising in the course of the operation, or to an erroneous diagnosis. The authors resort to surgery only to treat serious vascular syndromes (absolute indication) or invalidating neurological compression syndromes, after failure of physical therapy (relative indication). They propose a cervical approach--the only one enabling a safe dissection of the brachial plexus--a partial scalenectomy, resection of all fibrous bands pressing on nervous trunks, or the resection of a cervical rib. Should the costo-clavicular space appear anatomically too narrow, the first rib, already partially freed by the cervical approach, will be resected through the axillary route.

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester.

OBJECTIVE: To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa/fa) and lean (Fa/?) Zucker rats. DESIGN: Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10-100 nM) of PMA. MEASUREMENTS: Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14CO2 and 3H2O from [U-14C]glucose and [5-3H]glucose, respectively. RESULTS: PMA (200 nM) induced maximal translocation of ventricular PKCalpha from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10-100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats. CONCLUSION: Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCalpha activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.

Cancers du sein : comment associer l'hormonothérapie et la radiothérapie en situation adjuvante [How to combine hormonotherapy and radiation treatment in adjuvant breast cancer?]

Combined radiation and hormone therapies have become common clinical practice in recent years for locally-advanced prostate cancers. The use of such concomitant therapy in the treatment of breast disease has been infrequently reported in the literature, but seems justified given the common hormonal dependence of breast cancer and the potential synergistic effect of these two treatment modalities. As adjuvant therapy, two strategies are used in daily clinical practice: upfront aromatase inhibitors or sequentially after a variable delay of tamoxifen. These molecules may, thus, interact with radiotherapy. Retrospectives studies recently published did not show any differences in terms of locoregional recurrences between concurrent or sequential radiohormonotherapy. Lung and skin fibroses due to concurrent treatment are still under debate. Nevertheless, late side effects appeared to be increased by such a treatment, particularly in hypersensitive patients identified at risk by the lymphocyte predictive test. Concurrent radiohormonotherapy should, thus, be delivered cautiously at least for these patients. This article details the potent advantages and risks of concurrent use of adjuvant hormonotherapy and radiotherapy in localized breast cancers.

Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytosolic platelet calcium.

Although platelet cytosolic calcium has been shown to decrease during pharmacological treatment of hypertension, there is no evidence that cytosolic calcium also falls during a nonpharmacological reduction in blood pressure. To provide such evidence, we examined prospectively the relation between platelet cytosolic calcium and ambulatory blood pressure during weight reduction in moderately overweight (body mass index [BMI] greater than 25), mildly hypertensive individuals. The experimental group (responders: BMI reduction greater than 5%) consisted of 19 patients who lost 8.5 +/- 2.9 kg (mean +/- SD, p less than 0.05) during a 10-week hypocaloric diet, whereas the control group (nonresponders: BMI reduction less than 5%) consisted of 12 patients who showed no relevant change in body weight (-2.0 +/- 1.3 kg) during the same period of time. The moderate weight loss of the responders decreased blood pressure by 14/5 mm Hg (p less than 0.05), as measured by ambulatory monitoring, which renders a placebo effect unlikely. This nonpharmacological reduction in blood pressure was accompanied by a proportional 11% decrease (p less than 0.05) in platelet cytosolic calcium and also by significant (p less than 0.05) decreases in plasma catecholamines and serum cholesterol. These findings establish the concept of a nonpharmacological reduction in free cytosolic platelet calcium in humans and add further evidence suggesting a link between intracellular calcium homeostasis and blood pressure regulation.

Effect of a pathological scapular tilt after total shoulder arthroplasty.

Total shoulder arthroplasty (TSA) is an accepted and most successfully used treatment for different shoulder pathologies. Different risk factors for the failure of the prosthesis are known. A pathological scapular orientation, observed in elderly people or in patients suffering from neuromuscular diseases, could be a cause of failure, which has not been investigated yet. To test this hypothesis, a numerical musculoskeletal model of the glenohumeral joint was used to compare two TSA cases: a reference normal case and a case with a pathological anterior tilt of the scapula. An active abduction of 150° was simulated. Joint force, contact pattern, polyethylene and cement stress were evaluated for both cases. The pathological tilt slightly increased the joint force and the contact pressure, but also shifted the contact pattern. This eccentric contact increased the stress level within the polyethylene of the glenoid component and within the surrounding cement layer. This adverse effect occurred mainly during the first 60° of abduction. Therefore, a pathological orientation of the scapula may increase the risk of a failure of the cement layer around the glenoid component. These preliminary numerical results should be confirmed by a clinical study.

Runaway Greenhouse Effect in a Semigray Radiative-Convective Model

The effects of the nongray absorption (i.e., atmospheric opacity varying with wavelength) on the possible upper bound of the outgoing longwave radiation (OLR) emitted by a planetary atmosphere have been examined. This analysis is based on the semigray approach, which appears to be a reasonable compromise between the complexity of nongray models and the simplicity of the gray assumption (i.e., atmospheric absorption independent of wavelength). Atmospheric gases in semigray atmospheres make use of constant absorption coefficients in finite-width spectral bands. Here, such a semigray absorption is introduced in a one-dimensional (1D) radiative– convective model with a stratosphere in radiative equilibrium and a troposphere fully saturated with water vapor, which is the semigray gas. A single atmospheric window in the infrared spectrum has been assumed. In contrast to the single absolute limit of OLR found in gray atmospheres, semigray ones may also show a relative limit. This means that both finite and infinite runaway effects may arise in some semigray cases. Of particular importance is the finding of an entirely new branch of stable steady states that does not appear in gray atmospheres. This new multiple equilibrium is a consequence of the nongray absorption only. It is suspected that this new set of stable solutions has not been previously revealed in analyses of radiative–convective models since it does not appear for an atmosphere with nongray parameters similar to those for the earth’s current state

Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.

BACKGROUND: The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue. METHODS: We performed a multicentre, parallel, randomized controlled, closed-label, observer-blinded trial. We recruited from the practices of 44 primary care physicians in France from March to July 2006. We randomly assigned 198 women aged 18-53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily; n = 102) or placebo (n = 96) for 12 weeks. The primary outcome was fatigue as measured on the Current and Past Psychological Scale. Biological markers were measured at 6 and 12 weeks. RESULTS: The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference -18.9%, 95% CI -34.5 to -3.2; p = 0.02), but there were no significant effects on quality of life (p = 0.2), depression (p = 0.97) or anxiety (p = 0.5). Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL; p = 0.002) and ferritin (11.4 μg/L; p < 0.001) and decreased soluble transferrin receptor (-0.54 mg/L; p < 0.001) at 12 weeks. INTERPRETATION: Iron supplementation should be considered for women with unexplained fatigue who have ferritin levels below 50 μg/L. We suggest assessing the efficiency using blood markers after six weeks of treatment. Trial registration no. EudraCT 2006-000478-56.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia.

Patients with defective ectodysplasin A (EDA) have X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM#305100), a condition comprising hypotrichosis, inability to sweat, abnormal teeth, and frequent pulmonary infections. The XLHED dogs show the same clinical signs as humans with the disorder, including frequent respiratory infections that can be fatal. The respiratory disease in humans and dogs is thought to be due to the absence of tracheal and bronchial glands which are a vital part of the mucociliary clearance mechanism. In our XLHED model, the genetically missing EDA was replaced by postnatal intravenous administration of recombinant EDA resulting in long-term, durable corrective effect on adult, permanent dentition. After treatment with EDA, significant correction of the missing tracheal and bronchial glands was achieved in those dogs that received higher doses of EDA. Moreover, successful treatment resulted in the presence of esophageal glands, improved mucociliary clearance, and the absence of respiratory infection. These results demonstrate that a short-term treatment at a neonatal age with a recombinant protein can reverse a developmental disease and result in vastly improved quality of life.

Finite field treatment of vibrational polarizabilities and hyperpolarizabilities: on the role of the Eckart conditions, their implementation, and their use in characterizing key vibrations

In the finite field (FF) treatment of vibrational polarizabilities and hyperpolarizabilities, the field-free Eckart conditions must be enforced in order to prevent molecular reorientation during geometry optimization. These conditions are implemented for the first time. Our procedure facilities identification of field-induced internal coordinates that make the major contribution to the vibrational properties. Using only two of these coordinates, quantitative accuracy for nuclear relaxation polarizabilities and hyperpolarizabilities is achieved in π-conjugated systems. From these two coordinates a single most efficient natural conjugation coordinate (NCC) can be extracted. The limitations of this one coordinate approach are discussed. It is shown that the Eckart conditions can lead to an isotope effect that is comparable to the isotope effect on zero-point vibrational averaging, but with a different mass-dependence

Die epidurale Rückenmarkstimulation (SCS) zur Therapie peripherer arterieller Durchblutungsstörungen [Spinal cord stimulation (SCS) in the treatment of peripheral arterial occlusive disease]

Spinal cord stimulation (SCS) represents a well established procedure in the treatment of critical ischemia of the extremities. The knowledge and distribution of SCS in Austria are still poor despite satisfactory data. The evaluations and recommendations from the consensus group demonstrate that SCS might represent a suitable additional treatment option for selected patients with peripheral arterial disease (PAD) when performed in experienced centers under clear indications. The complication rate is low and mainly due to device-related problems. There are valid scientific criteria proving that SCS treatment can reduce the risk of amputation, decrease pain and improve wound healing in patients with non-reconstructable, non-unstable PAD in stages IV and V according to Rutherford (stages III and IV according to Fontaine).This effect is more evident when patient selection is based on tcPO(2) measurements. A careful selection of patients is essential for the success of this neuromodulatory treatment, in addition a certain degree of patient compliance in terms of perception and understanding of the therapy is mandatory.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

Objectives:  Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. Methods:  Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. Results:  Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. Conclusions:  These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.