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Summary Objective. To estimate the prevalence of self-reported adverse reactions (AdR) to subcutaneous airborne allergen immunotherapy (SCIT) and to describe factors associated with its occurrence. Methods. Real-life, observational, descriptive study of all patients treated with SCIT at a Portuguese allergy unit between 03/2017 and 06/2019, and who answered ≥1 time to a pre-SCIT evaluation questionnaire assessing the occurrence of local and/or systemic AdR in the previous administration. Results. 939 questionnaires from 231 patients (42% female, 35% with asthma) were included. Most (60%) SCIT preparations had multiple allergens with concentration adjusted to prevent dilution (MA-NoDil), 26% were single allergen with standard concentration (SA-SC), 10% single allergen with higher than standard concentration (SA-HC), and 4% mixtures without concentration adjustment (MA-Dil). SCIT-related AdR were self-reported in 313 (33%) administrations, 97% at the injection site and 11% grade 1 systemic symptoms. In a multivariable model, being a female and having asthma were associated with higher risk of AdR. MA-NoDil SCIT presented a lower risk of AdR compared to SA-SC SCIT. Conclusions. SCIT-related AdR were self-reported in 1/3 of the administrations, most at the injection site. The risk of AdR was higher in females and in patients with asthma. The lower risk of adverse reactions observed in SCIT preparations with multiple allergens with no dilutional effect should be further explored in future, targeted studies.

Aims Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in cardiac remodelling. Available information regarding their prognostic utility in heart failure (HF) and cardiac resynchronization therapy (CRT) is controversial. The aim of this study was to analyse MMP-2 and TIMP-1 levels as predictors of long-term mortality in HF patients treated with CRT. Methods and results We prospectively included 42 consecutive patients with successfully implanted CRT. Matrix metalloproteinase-2 and TIMP-1 assays were performed prior to implant. Patients were evaluated at baseline and at the outpatient clinic at 6-month intervals. Clinical response, left ventricular (LV) remodelling, and mortality were analysed. During a mean follow-up of 60 ± 34 months, long-term mortality from any cause was 36% (15 patients). The cause of death was end stage of HF in 12 patients, sudden death in 2 patients, and 1 unknown. After adjustment using a Cox regression model, the independent predictors of long-term mortality were baseline TIMP-1, hazard ratio (HR) 1.18 (95% confidence interval (95% CI) [1.05–1.33], P = 0.007), baseline glomerular filtration rate (GFR), HR 0.97 (95% CI [0.94–1.00], P = 0.05), and permanent atrial fibrillation (AF), HR 3.14 (95% CI [1.02–9.67], P = 0.04). Area under receiver operating characteristic curve for TIMP-1 was 0.79 (95% CI [0.63–0.94]). Tissue inhibitor of matrix metalloproteinase-1 ≥ 248 ng/mL predicts mortality with 80% sensitivity and 71% specificity. Conclusion Tissue inhibitor of matrix metalloproteinase-1 is a powerful predictor of long-term mortality in HF patients treated with CRT.

Background— Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.; Methods and Results— Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (−0.81 to 4.92) versus 5.02% (3.90 to 10.12), P =0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27–52) mm Hg, wedge capillary pressure 18 (16–22) mm Hg, pulmonary vascular resistance 362 (235–603) dyn s cm -5 . There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH ( r =−0.679; P =0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure ( r =0.553; P =0.014), transpulmonary gradient ( r =0.560; P =0.013), and pulmonary vascular resistance ( r =0.626; P =0.004). Conclusions— In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.

Aims A maximum percentage of ventricular pacing is mandatory to obtain a good response to CRT. Atrioventricular junction (AVJ) ablation has been recommended to attain this objective in patients with AF. The aims of our study were: (i) to determine whether the presence of complete AVJ block (induced or spontaneous) improves survival in patients with permanent AF treated with CRT and (ii) to analyse the predictors of mortality in AF patients treated with CRT. Methods and results From a series of 608 patients treated with CRT in our centre from 2000 to 2011, a cohort of 155 patients with permanent AF was analysed. Patients in AF were divided into two groups, AF + AVJ block [76 (49%)] and AF non-AVJ block [79 (51%)]. Mean follow-up was 30 months (interquartile range 13–51 months). During the follow-up, 62 patients died. Overall and cardiovascular mortality were similar between both groups: hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.51–1.39, P = 0.51 and HR 0.94, 95% CI 0.52–1.68, P = 0.82. Multivariate analysis identified three independent predictors of mortality: basal NYHA functional class IV (HR 2.25, 95% CI 1.12–4.22, P = 0.03), glomerular filtration rate (HR 0.98, 95% CI 0.96–0.99, P = 0.03), and LVEF (HR 0.94, 95% CI 0.89–0.99, P = 0.02). Conclusions AVJ block did not improve survival for patients in AF treated with CRT. Basal NYHA functional class IV, poor renal function, and LVEF were the independent predictors of mortality.

Aims Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT). Methods and results A cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy responders were defined as patients who survived, were not transplanted, and increased their basal 6 min walking distance test (6MWDT) by ≥10% or improved their NYHA functional class. Overall, 25 patients (60%) were classed as responders. At 12-month follow-up, six patients (14.2%) had died and one (2.4%) patient had been transplanted. Compared with responders, non-responders had higher levels of TIMP-1 (277 ± 59 vs. 216 ± 46 ng/mL, P = 0.001), MMP-2 (325 ± 115 vs. 258 ± 56 ng/mL, P = 0.02), and creatinine (1.76 ± 0.8 vs. 1.25 ± 0.3 mg/dL, P = 0.01). In a multivariate analysis, TIMP-1 was the only independent predictor of non-response to CRT [OR 0.97, 95% (CI 0.96–0.99) P = 0.005]. TIMP-1≥248 ng/mL predicted non-response with 71% sensitivity and 72% specificity. Conclusion TIMP-1 is an independent predictor of non-response in patients treated with CRT.

Background: The traditional Mediterranean diet is claimed to possess antioxidant and immune-regulatory properties in several chronic diseases. Typical Mediterranean foods have recently been associated with improvement of symptoms of asthma and rhinitis in children. However the effect of adherence to Mediterranean diet on adult asthma outcomes is unknown. We aimed to investigate the association between adherence to Mediterranean diet and asthma control. Methods: Cross sectional study of 174 asthmatics, mean (SD) age of 40 (15) years. The patients were defined as controlled, in contrast to noncontrolled, if they showed FEV1 ‡ 80% of predicted, exhaled nitric oxide (NO) £ 35 ppb, and Asthma Control Questionnaire score

Stored electrograms or marker channels are available in most of modern cardiac pacemaker models. We sought to analyse these information to uncover terminal events of pacemaker patients dying suddenly. Method and results We made post-mortem pacemaker (PM) interrogations in 19 patients dying suddenly out of hospital between the years 1997 and 2005 (mean age 59 +/- 13 years, 90% males). The systems had activated arrhythmia monitoring algorithms. Indications of pacing were sick sinus syndrome in seven, AV-block in five, and heart failure due to asynchrony in seven cases. The interrogated pacemakers were CHORUS 7034 (n = 12), CONTAK TR (n = 2), and INSYNC III (n = 5). For interpretation stored marker channels and electrograms were analysed. The mean observation time after PM implantation prior death was 2.11 +/- 1.44 years, the mean left ventricular ejection fraction from the last available echo examination in the year prior death was 27.5 +/- 8%, mean age was 63 +/- 12 years. In 17/19 cases (89%), a tachycardia (most likely ventricular tachycardia) was found correlating to the time of death. The mean cycle length of the terminal arrhythmia was 307 +/- 144 (250-344) ms, corresponding to a heart rate of 195 +/- 95 (174-240) bpm. We found no evidence of specific pacemaker-related problems such as electronic failure, battery depletion, or undersensing.Post-mortem analysis of arrhythmia monitoring of pacemaker patients revealed tachycardias (most likely ventricular tachycardia) to be related to sudden death. These findings give some insight in mechanisms of terminal events in this group.

Background: It has been hypothesized that the response of holo-transcobalamin (holo-TC) to oral vitamin B -12 may be used to assess absorption. To develop a reliable clinical absorption test that uses holo-TC, it is necessary to determine the optimal timeline for vitamin B-12 administration and postdose assessment. Objective: The objective of this study was to assess the magnitude and patterns of change in the postabsorption response of holo-TC to oral vitamin B-12. Design: Adult (18 -49 y) male and female participants (n = 21) with normal vitamin B-12 status were given three 9-μg doses of vitamin B-12 at 6-h intervals beginning early morning (baseline) on day 1. Blood was drawn at 17 timed intervals over the course of 3 d for the analysis of holo-TC and other indicators of vitamin B-12 status. Results: Mean holo-TC increased significantly (P < 0.001) from baseline at 6 h (11%) and 24 h (50%). TC saturation increased significantly (P < 0.001) from baseline at 12.5 h (33%) and 24 h (50%). The mean cobalamin concentration changed significantly (P

The main purpose of this study was to characterize the initial neurotransmission cascade elicited by methamphetamine, analysing simultaneously with in vivo microdialysis monoamine, amino acid and neuropeptide release in substantia nigra and neostriatum of the rat. The main effect of a single systemic dose of methamphetamine (15 mg/kg, subcutaneously) was an increase in dopamine levels, both in substantia nigra ( approximately 10-fold) and neostriatum ( approximately 40-fold), accompanied by a significant, but lesser, increase in dynorphin B ( approximately two-fold, in both regions), and a decrease in monoamine metabolites. A similar effect was also observed after local administration of methamphetamine (100 microm) via the microdialysis probes, but restricted to the treated region. In other experiments, rats were repeatedly treated with methamphetamine or saline, with the last dose administered 12 h before microdialysis. Dopamine K+-stimulated release was decreased following repeated methamphetamine administration compared with that following saline, both in the substantia nigra (by approximately 65%) and neostriatum (by approximately 20%). In contrast, the effect of K+-depolarization on glutamate, aspartate and GABA levels was increased following repeated administration of methamphetamine. In conclusion, apart from an impairment of monoamine neurotransmission, repeated methamphetamine produces changes in amino acid homeostasis, probably leading to NMDA-receptor overstimulation.

Cardiac resynchronization therapy (CRT) is a new method for the correction of inter‐ and/or intraventricular conduction delays of patients with heart failure. The long‐term impact of CRT on central hemodynamics is not fully characterized. We performed complete right heart catheterization studies in 31 patients receiving a CRT device pre and 6 months after implantation. Most of the patients improved in their NYHA stage, their LVEF, and in parallel showed reduced right atrial (RA) pulmonary artery (PA) and pulmonary capillary wedge (PCW) pressures and pulmonary vascular resistance both at rest and at 25 watts. In addition, we found a reduction in heart rate accompanied by an increased mean arterial pressure both at rest and at 25 watts. Accordingly, brain natriuretic peptide levels (BNP) were lowered. It was concluded that, besides other well‐known effects on ventricular coordination, central hemodynamics after 6 months were improved during CRT. Copyright © 2007 Wiley Periodicals, Inc.

Under the clinical impression that patients with chronic obstructive pulmonary disease (COPD) may demonstrate signs compatible with hypogonadism, we investigated whether oral glucocorticoid therapy is associated with testosterone deficiency. Thirty six men with COPD of whom 16 were receiving oral glucocorticoid medication (mean+/-SEM dose 9.4+/-1.1 mg prednisolone) were investigated in a cross-sectional cohort study. Patients with or without oral glucocorticoid therapy were not different in terms of age, smoking history and additional therapy. Vital capacity, forced expiratory volume in one second, airway resistance, intrathoracic gas volume and blood gases at rest were not different between the groups. However, patients receiving glucocorticoids had a shorter 6 min walking distance (mean+/-SEM 205+/-27 versus 288+/-26 m; p=0.02) compared to patients without oral steroid therapy. Serum levels of testosterone (mean+/-SEM 13.7+/-0.9) were below normal (

Recently the existence of a neurotensin striatonigral pathway strongly up-regulated by methamphetamine has been demonstrated. The aim of the present study was to investigate, using immunohistochemistry and radioimmunoassay, the modulation of this pathway by dopamine antagonists. Rats were injected either with methamphetamine alone or together with the dopamine D1 receptor antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzapine hydrochloride), or with the dopamine D2 receptor antagonist, sulpiride. Both techniques showed that this neurotensin striatonigral pathway is regulated by dopamine D1 receptors, since SCH 23390 totally prevented the methamphetamine-induced increase in neurotensin-like immunoreactivity, both in the striatum and in the substantia nigra pars reticulata. Conversely, sulpiride was unable to counteract the effect of methamphetamine in these two areas, suggesting that dopamine D2 receptors are not involved in the regulation of this neurotensin pathway. On the other hand, neurotensin-like immunoreactivity was markedly increased in striatal cell bodies and in the globus pallidus after treatment with sulpiride, indicating that this pathway is mainly regulated by dopamine D2 receptors.

The effect of acute subcutaneous administration of methamphetamine on the expression of neurotensin mRNA was investigated in the adult rat striatum. At different time points (2, 6 and 24 h) following drug administration rats were killed, and mRNA levels were quantified both on films and emulsion-dipped tissue sections from two striatal levels. Two hours after methamphetamine injection, a dramatic increase in neurotensin mRNA levels was detected in different areas of the striatum at both rostral and caudal levels. Numerous positive cells were observed in the dorsomedial, dorsolateral and ventrolateral parts of the striatum. This up-regulation reflected an increase both in the number of cells expressing neurotensin mRNA and in the mean mRNA levels. This increase was still present after 6 h and was similar to the 2 h treated group at the rostral level of the striatum, but lower at the caudal one. Twenty-four hours after methamphetamine injection, neurotensin mRNA levels were back to control values, or in some areas even below. A strong increase in neurotensin mRNA-expressing cells was also seen in the olfactory tubercle, and the time-course was similar to the one observed in the striatum. In a second set of experiments, the effect of methamphetamine was evaluated on adjacent striatal sections hybridized with probes directed against neurotensin and substance P mRNAs, respectively. Two hours after drug administration, a significant increase in the levels of both peptide mRNAs was observed (+190% for neurotensin, +80% for substance P). These results demonstrate that methamphetamine is able to induce a dramatic, rapid and transient increase in striatal neurotensin mRNA levels, which may partly account for the elevation in neurotensin peptide levels observed in the striatonigral pathway after methamphetamine. The different anatomical localization of neurotensin mRNA-expressing cells observed after haloperidol and methamphetamine treatments, as well as the fact that the D1 receptor antagonist SCH-23390 is able to counteract the effect of methamphetamine but not that of haloperidol on neurotensin mRNA expression, suggests that there are at least two different subpopulations of neurotensin cells in the striatum. One population is regulated via D1 receptors and projects to the substantia nigra pars reticulata. The second is sensitive to D2 receptor stimulation and may project to the globus pallidus and/or may represent interneurons.

As recently described, adherence to the Mediterranean diet is associated with improved asthma control. However, evidence of how specific nutrients such as fatty acids and antioxidants may affect this relationship remains largely unknown. We aimed to examine the association between dietary intake of fatty acids and antioxidants and asthma control. A cross-sectional study was developed in 174 asthmatics, mean age of 40 (sd 15) years. Dietary intake was obtained by a FFQ, and nutritional content was calculated using Food Processor Plus™ software (ESHA Research, Inc., Salem, OR, USA). Good asthma control was defined by the combination of forced expiratory volume during the first second, exhaled NO (eNO) and Asthma Control Questionnaire (ACQ) score (control: forced expiratory volume in the first second ≥ 80 %; eNO ≤ 35 ppb; ACQ n-6:n-3 PUFA ratio predicted high eNO, whereas high intakes of n-3 PUFA, α-linolenic acid (ALA) and SFA were associated with low eNO. Odds for controlled asthma improved along with an increased intake of n-3 PUFA (OR 0·14, 95 % CI 0·04, 0·45; P for trend = 0·001), SFA (OR 0·36, 95 % CI 0·13, 0·97; P for trend = 0·047) and ALA (OR 0·18, 95 % CI 0·06, 0·58; P for trend = 0·005). A high n-6:n-3 PUFA ratio increased the odds for uncontrolled asthma (OR 3·69, 95 % CI 1·37, 9·94; P for trend = 0·009), after adjusting for energy intake, sex, age, education and use of inhaled corticosteroids. Higher intakes of n-3 PUFA, ALA and SFA were associated with good asthma control, while the risk for uncontrolled asthma increased with a higher n-6:n-3 PUFA ratio. The present results introduce a protective effect of ALA in asthma control, independent of marine n-3 fatty acids, and provide a rationale to dietary intervention studies in asthma.

Axonal transport of the vesicular monoamine transporter was assayed in the rat brain by in vivo binding of the specific ligand [3H]reserpine. Because of the marked localization of reserpine binding sites in dopaminergic cell bodies and nerve terminals, the dopaminergic nigrostriatal pathway was chosen for the study of the axonal transport of the monoamine carrier present in the membrane of synaptic vesicles. When labelled reserpine was injected into the substantia nigra, a delayed accumulation of radioactivity in the ipsilateral striatum was observed approximately 4 h after the injection. Similarly, injection into the right striatum was followed by a substantial accumulation of radioactivity in the ipsilateral substantia nigra, which was prevented by peripheral injection of unlabelled reserpine or tetrabenazine. This process was rapid and dependent on microtubules. In senescent rats, the amount of retrogradely transported [3H]reserpine was significantly reduced. These results demonstrate that labelled reserpine may be used to monitor in vivo fast axonal transport in central neurons.

Background Analysis of myocardial strain using two-dimensional (2D) echocardiography to assess left ventricular (LV) mechanical dyssynchrony by measuring time differences in peak systolic strains from opposing LV walls has been proposed. However, peak systolic strain may be difficult to identify. Objective The purpose of this study was to evaluate (1) LV dyssynchrony by assessing the overlap among strain traces of the LV walls throughout the cardiac cycle and (2) its usefulness in identifying responders to cardiac resynchronization therapy (CRT). Methods Fifty patients with heart failure and LV systolic dysfunction undergoing CRT were studied with 2D echocardiography at baseline and 6-month follow-up. Myocardial radial strain and circumferential strain were analyzed using commercially available software. The resulting strain traces were postprocessed with a mathematical script. Results Quantification of LV dyssynchrony was expressed as an index of temporal overlap from the analyzed traces. Responders to CRT were defined by ≥15% reduction of LV end-systolic volume at 6-month follow-up. Responders to CRT had higher LV dyssynchrony in both radial strain and circumferential strain analysis. A cutoff time overlap ≥7% for radial strain (area under the curve 0.79) and ≥8.5% for circumferential strain (area under the curve 0.66) identified responders to CRT. Conclusion Quantifying the temporal superposition of LV wall deformations with a computed algorithm allows measurement of LV intraventricular dyssynchrony throughout the cardiac cycle. The derived index is useful in stratifying the probability of response to CRT.

The effects of a 3-month physical training programme on airway inflammation and clinical outcomes were studied in school-aged children with asthma. Subjects with persistent allergic asthma (aged 12.7+/-3.4 yrs; n = 34) were randomly allocated into training and control groups. Exercise consisted of twice-weekly 50-min sessions for 12 weeks. Inflammation was assessed by levels of exhaled nitric oxide, blood eosinophils, eosinophil cationic protein, C-reactive protein, and total and mite-specific immunoglobulin (Ig)E. Lung volumes and bronchial responsiveness to methacholine were determined. The Paediatric Asthma Quality of Life Questionnaire and Paediatric Asthma Caregiver's Quality of Life Questionnaire were used to evaluate activity restrictions, symptoms and emotional stress. The efficacy of the training was assessed by accelerometry. Following the programme, the exercise group spent twice as much time as the controls undertaking moderate-to-vigorous activities. No differences in changes were seen between groups for asthma outcomes. However, total IgE decreased more in the exercise group, as did mite-specific IgE. Training did not increase inflammation in children with persistent asthma, and may have decreased both total and allergen-specific immunoglobulin E levels. It is concluded that there is no reason to discourage asthmatic children with controlled disease to exercise.

γ-Butyrolactone is a drag known to inhibit the flow of electrical impulses in dopaminergic neurones and to prevent dopamine release in the striatum. In this study, we investigated the effects of this compound on the retrograde transport of neurotensin in the nigrostriatal dopanunergic pathway. The amount of radioactivity measured in the substantia nigra after injection of iodinated neurotensin into the striatum and the time course of its accumulation were not found to be modified in γ-butyrolactone-treated rats. We therefore conclude that the retrograde axonal transport of neurotensin in the nigrostriatal pathu-γ is not affected by reduced dopaminergic firing or by inhibition of the striatal release of dopamine.

Acute studies in cardiac resynchronization therapy (CRT) showed that hemodynamic effects may depend on the coronary sinus (CS) lead position. However, there are no data on the longterm effect of CS lead position. In 45 heart failure patients with left bundle branch block and QRS >150 ms (age 59±10 years, 17 dilative cardiomyopathy, 23 ischemic, 5 valvular), biventricular pacemakers were implanted. CS leads were positioned in posterior (P, n=15), lateral (L, n=19) or, if no other option available, anterior (A, n=11) side branches. Before and 6 months after implantation, clinical state, echocardiography, brain natriuretic peptide (BNP) and right heart catheterization were evaluated. Baseline parameters were similar between groups. After 6 months, there were 32/34 responders in groups P and L compared to 7/11 responders in group A (94 vs roups P and L: Arterial pressure +8 and +9% vs +2%; PCWP –23 and –15% vs –4%, pulmonary pressure –18 and –12% vs –3% (p

Cardiac resynchronization therapy (CRT) using coronary sinus (CS) leads is a new method for the therapy of congestive heart failure (CHF). Because the intervention is more complex than regular pacemaker implantations, information on the feasibility and side effects of this method are of interest. From 1999 to June 2005, CRT implantations were attempted in 244 patients (pts; mean age 64±12 years, range 14–90 years), 82% were male, 44% had coronary artery disease, 29% were in atrial fibrillation, 71 had preexisting pacemakers. In 97% of the pts the intervention was successful (27% of the systems with defibrillation capabilities). In 285 interventions, 255 CS leads were positioned according to CS vein anatomy in 130 posterolateral, 97 anterolateral and 28 anterior side branches (16 patients received 2 CS leads). Over-the-wire leads were used in 88%, 71% were additionally preshaped. We observed no mortality but 37 complications (12.5%): CS dissection in 9, CS perforation in 1, ventricular fibrillation in 4, asystole in 5, pulmonary edema in 1, pneumothorax in 2, need for early CS lead revision in 19 (dislodgement n=7, phrenic nerve stimulation n=12) and infection with explantation in 2 cases. An improvement in NYHA functional class was found in 88% of pts (only 55% if anterior lead position). Perioperative complications during CS lead implantation occur in 10–15% of cases. Most patients responded well to CRT. Patients should be informed about the possible need for a reoperation. During implantation, immediate defibrillation and stimulation capabilities must be available. Anterior lead positions should be avoided.

Background: A common genetic polymorphism [transcobalamin (TC) 776C→G] may affect the function of transcobalamin, the protein required for vitamin B-12 cellular uptake and metabolism. Remethylation of homocysteine is dependent on the production of 5-methyltetrahydrofolate and adequate vitamin B-12 for the methionine synthase reaction. Objectives: The objectives were to assess the influence of the TC 776C→G polymorphism on concentrations of the transcobalamin-vitamin B-12 complex (holo-TC) and to determine the combined effects of the TC 776C→G and methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphisms and vitamin B-12 status on homocysteine concentrations. Design: Healthy, nonpregnant women (n = 359; aged 20-30 y) were screened to determine plasma vitamin B-12, serum holo-TC, and plasma homocysteine concentrations and TC 776C→G and MTHFR 677C→T genotypes. Results: The serum holo-TC concentration for women with the variant TC 776 GG genotype was significantly different (P = 0.0213) from that for subjects with the CC genotype (74 ± 37 and 87 ± 33 pmol/L, respectively). An inverse relation was observed between plasma homocysteine concentrations and both serum holo-TC (P ≤ 0.0001) and plasma vitamin B-12 (P ≤ 0.0001) concentrations, regardless of genotype. Conclusions: These data suggest that the TC 776C→G polymorphism negatively affects the serum holo-TC concentration and provide additional evidence that vitamin B-12 status modulates the homocysteine concentration in this population.

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are important for homocysteine remethylation. This study was designed to determine the influence of genetic variants (MTHFR 677C--T, MTHFR 1298A--C, and MTRR 66A--G), folate, and vitamin B-12 status on plasma homocysteine in women (20-30 y; n = 362). Plasma homocysteine was inversely (P0.0001) associated with serum folate and plasma vitamin B-12 regardless of genotype. Plasma homocysteine was higher (P0.05) for women with the MTHFR 677 TT/1298 AA genotype combination compared with the CC/AA, CC/AC, and CT/AA genotypes. Women with the MTHFR 677 TT/MTRR 66 AG genotype had higher (P0.05) plasma homocysteine than all other genotype combinations except the TT/AA and TT/GG genotypes. There were 5.4-, 4.3-, and 3.8-fold increases (P0.001) in risk for plasma homocysteine in the top 5, 10, and 20%, respectively, of the homocysteine distribution for subjects with the MTHFR 677 TT compared with the CC and CT genotypes. Predicted plasma homocysteine was inversely associated with serum folate (P = 0.003) and plasma vitamin B-12 (P = 0.002), with the degree of correlation dependent on MTHFR 677C--T genotype. These data suggest that coexistence of the MTHFR 677 TT genotype with the MTRR 66A--G polymorphism may exacerbate the effect of the MTHFR variant alone. The potential negative effect of combined polymorphisms of the MTHFR and MTRR genes on plasma homocysteine in at-risk population groups with low folate and/or vitamin B-12 status, such as women of reproductive potential, deserves further investigation.

Inthelastdecadesseveralinvestigatorshavesuggestedtheassociationofandrogenswithhypertension. Recently, some studies have shown that the incidence of cardiovascular diseases is increased in men with low testosterone levels, suggesting a protective role of androgens. Hypertension is one of the mostcommonproblemsinpregnancythatcomplicates5-10 %ofpregnancies.Anincreaseofmorbidity wasobservedinbabiesfrompregnantwomenwithhypertension.However,thepathogenesisremains unclearandthislimitstheabilitytopreventandtreatthispathology.Thebeneficialeffectsofandrogens for vascular system are associated with their ability to cause vasorelaxation. Inhuman vessels, this non genomiceffectofandrogensappeartobeduetoactivationoflargeconductancecalcium-activatedpotassiumchannels(BKCa)andvoltagegatedpotassiumchannels(KV)whichisinducedbycGMPincrease andaconsequentactivationofcGMP-dependentproteinkinase(PKG).Ontheotherhand,thegenomic effects of androgens concerning ionic channels are almost unknown. Our previous studies suggested that androgens increase the expression of BKCa channels and decrease expression of L-type calcium channels (LTCC). The aim of this work was to analyze the genomic effects of androgens on theexpressionofotherproteinsinvolvedintheregulationofvascularcontractility,suchassolubleguanylate cyclase (sGC), the natriuretic peptide receptor-A (NPRA) and PKG. This study also aimed to compare the expression levels of these proteins in human umbilical artery (HUA) from normotensive andhypertensivepregnantwomen.ToachievethesegoalsrealtimePCRwasperformedusingsmooth

It has been reported that methamphetamine (METH) upregulates striatal neurotensin (NT) mRNA levels. The present in situ hybridization study demonstrates, using the dopamine D1 antagonist SCH23390 that this effect is mediated through D1 receptors. Sulpiride, a selective D2 antagonist, induces an upregulation of NT expression, which in some striatal areas is additive to the METH effect. This suggests the existence of at least two NT striatal neuronal populations. One, sensitive to D1 receptors, corresponds to the recently described striatonigral NT pathway. The second one, modulated by D2 receptors, may project to the globus pallidus and/or represent interneurones.

It is now well established that the expression of peptides in rat primary sensory neurons is dramatically changed in response to peripheral nerve injury. Thus, as first shown by Jessell et al. 15 peripheral axotomy causes a decrease in substance P levels in the dorsal horn of the corresponding spinal cord segments, and this is due to down-regulation of peptide synthesis in dorsal root ganglion neurons. 22 In contrast, other peptides such as vasoactive intestinal polypeptide and peptide histidine isoleucine, 27 galanin 12 and neuropeptide Y 32 are all markedly upregulated in the rat L4 and L5 dorsal root ganglia after sciatic nerve sectioning. The levels of another peptide, cholecystokinin and its messenger RNA are normally very low or undectable in rat primary sensory neurons, 5,20,24,25,26 but after peripheral axotomy approximately 30% of the ganglion neurons express cholecystokinin messenger RNA. 30 During the last few years a number of peptide receptors have been cloned, and they all belong to the family of G-protein coupled receptors with seven membrane spanning segments, 21 among them the two cholecystokinin receptors cholecystokinin A and cholecystokinin B . 17,23,34 Ghilardi et al . 11 have recently described presence of cholecystokinin B binding sites in rat dorsal root ganglia neurons. In the present study we report that the messenger RNA for the cholecystokinin B receptor is present at very low levels in normal dorsal root ganglia of the rat, but axotomy causes a very marked increase in the number of sensory neurons of all sizes expressing cholecystokinin B receptor messenger RNA, suggesting an increased sensitivity to cholecystokinin for many primary sensory neurons of different modalities after lesion.

The distribution and origin of neurotensin-like immunoreactivity in the substantia nigra pars reticulata of the rat have been analysed using immunohistochemistry combined with different drug treatments and lesioning techniques. In normal rats, a distinct but weakly fluorescent network of neurotensin-immunoreactive fibers was found in the central part of the substantia nigra pars reticulata. When the animals were treated with reserpine, which suppresses dopamine transmission, a similar pattern of immunoreactivity was found, though the intensity of staining was slightly enhanced. However, when rats were treated with methamphetamine, a potent dopamine releaser, the intensity of immunoreactivity was dramatically increased. In particular, densely packed neurotensin-immunoreactive fibers were found at the dorsal border and at the ventral periphery of the substantia nigra pars reticulata. This pattern of immunoreactivity was found to be similar to that displayed by dynorphin. In the nucleus caudatus, several neurotensin-immunoreactive cell bodies were seen after reserpine treatment. Morphologically similar perikarya were observed in methamphetamine-treated rats, but they were less numerous, whereas no cell bodies were detectable in untreated animals. When a unilateral mechanical transection or an ibotenic acid injection was performed in the striatum, the patterns of neurotensin as well as dynorphin and substance P immunoreactivities in the substantia nigra pars reticulata were strongly affected. Both types of lesion caused a marked, parallel depletion of all three immunoreactive substances on the side ipsilateral to the lesion, where a restricted area was virtually devoid of immunoreactive elements. Thus the present study provides evidence for the existence of a unilateral neurotensin striatonigral pathway, terminating in the pars reticulata. The origin of the neurotensin fibers in the pars compacta has not been established but does not appear to be the caudate nucleus. These results together with evidence from the literature suggest that methamphetamine induced a massive release of dopamine from nigral dendrites acting on presynaptic D1 dopamine receptors located on neurotensinergic terminals leading to a marked increase in neurotensin-like immunoreactivity in the pars reticulata.

In previous studies we have shown that labelled neurotensin injected into the rat striatum was found to be transported retrogradely in dopaminergic neurons through a process which was receptor and microtubule dependent. Now, we show, by in situ hybridization, the consequences of the striatal injection of neurotensin on the gene expression of tyrosine hydroxylase in the substantia nigra. Rats were injected with neurotensin or its fragments in the striatum of one side and with saline or the inactive fragment on the other. The number of nigral cells expressing tyrosine hydroxylase mRNA was found to increase by 40% after injection of neurotensin or its active fragment (neurotensin 8–13). In the same experimental conditions, the inactive fragment (neurotensin 1–8) was without effect. Time-course experiments revealed that the tyrosine hydroxylase mRNA was increased 4 h after neurotensin injection but not at 1 or 16 h. The fact that the increase of mRNA parallels the appearance of labelled neurotensin in the substantia nigra indicates that the changes in the gene expression of tyrosine hydroxylase might be the consequence of the retrograde axonal transport of neurotensin. These results represent the first evidence for the existence of a long-distance retrograde signalling process in which the neuropeptide and presumably its receptor may serve as information molecule between synapses and the cell body.

Two hours after the injection of (3-[125I]iodotyrosyl3) neurotensin into the striatum, a labeling was observed in the ipsilateral substantia nigra. In the present study, we demonstrated by HPLC that this radioactivity corresponded to intact neurotensin and to degradation products of this peptide. This finding provides the first clearcut evidence that a neuropeptide can be internalized and retrogradely transported in brain neurons. Therefore, the fact that intact neurotensin can be seen to exist over a long period of time in the cell body suggests that the retrograde transport process could perhaps be involved in the long-term effects of neuropeptides.

Castel, M NLechardeur, DBlanchard, J CLaduron, P MengIreland1991/03/11Neurosci Lett. 1991 Mar 11;124(1):111-4.; It is now clearly established that fast anterograde axonal transport can be altered during ageing, both in the central and the peripheral nervous systems, but no information is yet available concerning the modifications of fast retrograde axonal transport during senescence. In the present paper, we report the changes occurring in the retrograde axonal transport of neurotensin in dopaminergic neurons of old rats. When iodinated neurotensin was injected into the striatum, a diminution of approximately 50% in the amount of the labelling measured in the ipsilateral substantia nigra was observed in senescent rats by comparison with young adult rats. Nevertheless, the rate of neurotensin transport was not modified. Our results clearly indicate that less neurotensin is transported from the nerve terminals towards the cell bodies in senescent rats which may have possible consequences for dopaminergic neurons.

Introduction Cardiac Resynchronization therapy (CRT) using coronary sinus (CS) leads is a new method for the therapy of congestive heart failure (CHF) in the case of inter- and intraventricular conduction delays. Because the intervention is more complex than regular pacemaker implantations more informations on the feasibility of this intervention are of interest. Methods From 1999-2004 n=255 transvenous coronary sinus leads were implanted in 234 CHF patients (mean age 61±17 years, 14-90 years age spectrum). 88% were over the wire leads, 71% preshaped and over the wire. Perioperative data were analyzed retrospectively. Results 84% of pts. were male, 44% of pts. had coronary artery disease, 30% of pts. were in atrial fibrillation, 78 pts. had preexisting pacemakers (upgrade procedure). 43 (16%) were implanted from the right subclavian vein, the others from the left side. Coronary sinus leads were positioned according to variable vein anatomies: 130x posterolateral, 97x anterolateral and 28x anterior (A). The mean operation time was 110 min +−, mean fluo time was 15,8 +− 11min. Severe complications were: CS dissection 5 cases (contrast media paravasation), ventricular fibrillation: 4 cases (defibrillation needed), asystole: 5 (pacing needed), pulmonary edema: 1 case, pneumothorax: 2 cases, acute CS lead dislodgement 5 cases, infection 1 case. In total we observed 23 severe complications. 12 patients had phrenic nerve stimulation, 5 of them needed reoperation. There were no death during the perioperative phase. 88% of pts. showed an improvement in their NYHA class and could be classified as responders unregardless of the underlying disease, the preexistence of atrial fibrillation or a conventional pacemaker. In regard to anterior lead position the rate of responders was lower (55%). Conclusion Coronary sinus lead implantation is a complex procedure with some hazards. The complication rate is in the range of 10%, but in our series these could be managed without mortality or persistent morbidity. Most patients responded very well to the procedure. Therefore CRT should be offered to otherwise untreatable CHF patients. Anterior CS lead positions should be avoided.

The electroencephalographic (EEG) effects of the ICV administration of neurotensin (NT 1-13), NT 1-8 (an inactive neurotensin fragment) and D TYR-11 NT (a long-lasting analog of neurotensin) were studied in rats. In awake rats, NT 1-13 (30 micrograms) and D TYR-11 NT (10 micrograms) induced an increase of the power spectrum in the theta range activity (4-7 Hz). In rats recorded during the sleep-wakefulness cycles, NT 1-13 (10 and 30 micrograms) and D TYR-11 NT (10 micrograms) had an awakening effect and also induced an increase of latency to the first episode of the different sleep stages (intermediate stage and slow wave sleep). NT 1-8 (30 and 90 micrograms in awake rats, 10 and 90 micrograms for sleep-wakefulness cycles) was inactive in all these experiments. Thus, it seems that all these effects can be linked to neurotensin receptors; indeed only fragments which recognize receptors possess an EEG activity.