Future prospects of anticytokine therapy in chronic heart failure

Several lines of evidence suggest that chronic heart failure is a state of chronic inflammation. Indeed, various pro-inflammatory markers, including the cytokines TNF-alpha, and interleukin 6 and 1, are activated in the course of the disease. In chronic heart failure, these substances are frequently induced even before the classical neurohormones angiotensin II and noradrenaline. Although the recently published anti-TNF-alpha trials with etanercept and infliximab have called the beneficial effects of targeting single cytokines into question, the overactive immune system remains a promising target for therapeutic interventions, which aim at slowing down disease progression. Broader approaches are required. These comprise targeting bacterial lipopolysaccharide (endotoxin) that enters the circulation through the oedematous gut wall, immune modulation therapy with patient-derived whole blood exposed to oxidative stress, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (the so-called statins) and a number of other substances including pentoxifylline and thalidomide.     

Discovery and development of biomarkers of neurological disease

The identification of clinically relevant biomarkers for neurological diseases poses unique challenges. These include an historical lack of availability of relevant tissues from the site of pathology, relatively poorly matured techniques for disease diagnosis, the complexity and cellular heterogeneity of the brain, and a clear deficiency of models for functional validation of candidate biomarkers. Here, the unique challenges that neurological disorders introduce to biomarker discovery are described and how modern technological advances in genomics, proteomics and metabolomics are overcoming these obstacles and are driving the discovery of novel biomarkers to improve early diagnosis and therapeutic treatment is discussed.     

Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.     

Differential dopaminergic modulation of executive control in healthy subjects

Rationale Executive control (EC) has different subcomponents, e.g., response inhibition (measured, for example, by the Stroop task) and working memory (WM—measured, for example, by delayed response tasks, DRT). EC has been associated with networks involving the prefrontal cortex (PFC). Moreover, there is evidence that dopamine agonists, especially those with a D1 profile, may modulate EC, since in the PFC D1 subtype receptors are more abundant.Objective This study aimed to selectively distinguish whether D1 versus D2 dopamine agonism differentially influences EC related to the inhibition of irrelevant information and WM. Because of its D1 component, we predicted that the administration of pergolide (mixed D1/D2 agonist), in comparison with bromocriptine (D2 selective agonist) and placebo, would enhance performance in both EC tasks. Using a lateralized Stroop task, we predicted a decrease in the interference effect, as well as error rates, while no increase in facilitation effects. For the DRT task, we predicted fewer error scores in the delay condition.Methods Forty male healthy subjects participated in this randomized, double-blind, placebo-controlled, crossover study.Results For the Stroop task no superiority of pergolide was found; however, with bromocriptine, decreased interference was found. No modulation of lateralization effects was shown in interference measures. Moreover, subjects on pergolide showed an absence of facilitation effects. No effects of either agonist were found for the DRT.Conclusion Our findings suggest that dopamine agonists modulate two EC tasks differently. Furthermore, there seems to be a selective modulation of different aspects of the Stroop task.     

Inhibition of erythrocyte “apoptosis” by catecholamines

Osmotic shock, oxidative stress and Cl⁻ removal activate a non-selective Ca²⁺-permeable cation conductance in human erythrocytes. The entry of Ca²⁺ leads to activation of a scramblase with subsequent exposure of phosphatidylserine at the cell surface. Phosphatidylserine mediates binding to phosphatidylserine receptors on macrophages which engulf and degrade phosphatidylserine exposing cells. Moreover, phosphatidylserine exposure may lead to adherence of erythrocytes to the vascular wall. In the present study, we explored whether activation of the non-selective cation conductance and subsequent phosphatidylserine exposure might be influenced by catecholamines. Phosphatidylserine exposure has been determined by FITC-annexin V binding while cell volume was estimated from forward scatter in FACS analysis. Removal of Cl⁻ enhanced annexin binding and decreased forward scatter, an effect significantly blunted by the β agonist isoproterenol (IC₅₀ approx. 1 μM). Fluo-3 fluorescence measurements revealed an increase of cytosolic Ca²⁺ activity following Cl⁻ removal, an effect again significantly blunted by isoproterenol exposure (10 μM). Whole-cell patch-clamp experiments performed in Cl⁻ free bath solution indeed disclosed a time-dependent inactivation of a non-selective cation conductance following isoproterenol exposure (10 μM). Phenylephrine (IC₅₀<10 μM), dobutamine (IC₅₀ approx. 1 μM) and dopamine (IC₅₀ approx. 3 μM) similarly inhibited the effect of Cl⁻ removal on annexin binding and forward scatter. In conclusion, several catecholamines inhibit the Cl⁻ removal-activated Ca²⁺ entry into erythrocytes, thus preventing increase of cytosolic Ca²⁺ activity, subsequent cell shrinkage and activation of erythrocyte scramblase. The catecholamines thus counteract erythrocyte phosphatidylserine exposure and subsequent clearance of erythrocytes from circulating blood.     

A monitoring system for work-related accidents in Piracicaba, São Paulo, Brazil

The authors report on the development of a work accident monitoring system in Piracicaba, S?o Paulo State, Brazil, with the following characteristics: information feeding the system is obtained in real time directly from accident treatment centers; the system has universal monitoring, covering all work-related accidents in Piracicaba, regardless of the nature of the worker's employment conditions, place of work, or place of residence; health surveillance and promotion of health initiatives are triggered by identification of sentinel events; spatial distribution analysis of work-related accidents is a basic tool in designing accident awareness strategies and accident prevention policies. The system was implemented in November 2003 and by October 2004 had identified 5,320 work-related accidents, or a 3.8% annual proportional incidence of work-related accidents in the municipal area. We illustrate spatial analysis of registered work-related accidents and present a detailed investigation of one example of a serious accident.     

Ultrasound-guided infraclavicular versus supraclavicular block

In this prospective study we compared ultrasound-guided (USG) infraclavicular and supraclavicular blocks for performance time and quality of block. We hypothesized that the infraclavicular approach would result in shorter performance times with a quality of block similar to that of the supraclavicular approach. Eighty patients were randomized into two equal groups: Group I (infraclavicular) and Group S (supraclavicular). All blocks were performed using ultrasound visualization with a 7.5-MHz linear probe and neurostimulation. The anesthetic mixture consisted of 0.5 mL/kg of bupivacaine 0.5% and lidocaine hydrocarbonate 2% (1:3 vol.) with epinephrine 1:200,000. Sensory block, motor block, and supplementation rates were evaluated for the musculocutaneous, median, radial, and ulnar nerves. Surgical anesthesia without supplementation was achieved in 80% of patients in group I compared with 87% in Group S (P = 0.39). Supplementation rates were significantly different only for the radial territory: 18% in Group I versus 0% in group S (P = 0.006). Block performance times were not different between groups (4.0 min in Group I versus 4.65 min in Group S; P = 0.43). Technique-related pain scores were not different between groups (I: 2.0; S: 2.0; P = 1.00). We conclude that USG infraclavicular block is at least as rapidly executed as USG supraclavicular block and produces a similar degree of surgical anesthesia without supplementation.     

The influence of displacement on shoulder function in patients with minimally displaced fractures of the greater tuberosity

INTRODUCTION: There is little outcome data on functional results after non-operative treatment of greater tuberosity fractures, and no clear evidence in minimally displaced (1-5 mm) fractures of the greater tuberosity showing that the results of non-operative treatments are good enough. This study assesses the relationship between degree of displacement in non-operatively treated patients and shoulder function. MATERIALS AND METHODS: We evaluated the radiographs and function in 135 patients after non-operative treatment of minimally displaced (1-5 mm) fractures of the greater tuberosity at a mean time of 3.7 years (2-20 years) after injury. Shoulder function was assessed using the Vienna Shoulder Score (VSS), the Constant Score (CS) and the UCLA-Score. RESULTS: 97% of the evaluated patients had good or excellent results. Patients with a displacement of more than 3 mm had slightly worse results compared to those with less displacement, but this was not statistically significant. Female patients had significantly better results than male patients, and patients in the eighth and ninth decade had significantly worse results compared to younger patients. CONCLUSION: We recommend non-operative treatment in all patients with minimally displaced fractures of the greater tuberosity, as most obtain very good results. The best results followed treatment with Gilchrist bandages or Mitella slings for 3 weeks, followed by intensive rehabilitation.     

Arcuate ligament vascular compression syndrome in infants and children

Background

Arcuate ligament vascular compression syndrome has not been described previously in the pediatric or pediatric surgical literature. However, it is mentioned in the literature of vascular and general surgery and in journals of radiology and orthopedics. In this review, the intraoperative pathological anatomy and the principles of treatment for 8 children will be presented.

Methods

The chart records and the anatomical sketches that were documented by the surgeon immediately after each procedure were analyzed retrospectively. In addition, preoperative courses and long-term follow-up (range, 3-18 years) were evaluated by a defined program.

Results

The diagnosis of celiac artery compression by an arcuate ligament was suspected in children presenting with a history of several years of recurrent acute abdominal pain associated with a typical arterial bruit in the midline of the epigastric region.

Conclusions

Other diseases with recurrent abdominal pain and an arterial bruit must be excluded before making the decision for an operative intervention. Duplex ultrasound and angiography are possibly helpful tools to establish the respective diagnosis, but in the patients of the present series, these techniques neither confirmed compression of the celiac axis nor demonstrated decreased perfusion of the superior mesenteric artery. However, as the clinical symptoms clearly announce the disease, these diagnostic measures are not mandatory.     

The combination of Hirschsprung's disease and achalasia

The unusual combination of Hirschsprung's disease and Achalasia in one case treated by standard procedures led to the discussion about RET germ-line mutations and consequently to the speculation about higher risk for multiple endocrine neoplasia syndrome type 2-related tumors. Although a mutation could be excluded by sequence analysis in this case, the correlation of these specific diseases affords additive investigations to make sure that no further prophylactic procedures were necessary.