Factors associated with HIV status awareness and Linkage to Care following home based testing in rural Malawi.

OBJECTIVE: HIV diagnosis and linkage to care are the main barriers in Africa to achieving the UNAIDS 90-90-90 targets. We assessed HIV-positive status awareness and linkage to care among survey participants in Chiradzulu District, Malawi. METHOD: Nested cohort study within a population-based survey of persons aged 15-59 years between February and May 2013. Participants were interviewed and tested for HIV (and CD4 if found HIV-positive) in their homes. Multivariable regression was used to determine factors associated with HIV-positive status awareness prior to the survey and subsequent linkage to care. RESULTS: Of 8277 individuals eligible for the survey, 7270 (87.8%) participated and were tested for HIV. The overall HIV prevalence was 17.0%. Among HIV-positive participants, 77.0% knew their status and 72.8% were in care. Women (adjusted odds ratio [aOR] 6.5, 95% CI 3.2-13.1) and older participants (40-59 vs. 15-29 years, aOR 10.1, 95% CI 4.0-25.9) were more likely to be aware of their positive status. Of those newly diagnosed, 47.5% were linked to care within 3 months. Linkage to care was higher among older participants (40-59 vs. 15-29, adjusted hazard ratio [aHR] 3.39, 95% CI 1.83-6.26), women (aHR 1.73, 95% CI 1.12-2.67) and those eligible for ART (aHR 1.61, 95% CI 1.03-2.52). CONCLUSIONS: In settings with high levels of HIV awareness, home-based testing remains an efficient strategy to diagnose and link to care. Men were less likely to be diagnosed, and when diagnosed to link to care, underscoring the need for a gender focus in order to achieve the 90-90-90 targets.

The fibroblast growth factor-23 and Vitamin D emerge as nontraditional risk factors and may affect cardiovascular risk.

OBJECTIVES: Fibroblast growth factor-23 (FGF-23) and vitamin D are hormones involved in phosphate homoeostasis. They also directly influence cardiomyocyte hypertrophy. We examined whether the relationships between levels of vitamin D or FGF-23, cardiac phenotype and outcome were independent of established cardiac biomarkers in a large cohort of community-dwelling elderly subjects. DESIGN AND SETTING: Plasma levels of FGF-23 and vitamin D were measured in 1851 men and women (65-84 years) resident in the Lazio region of Italy. Participants were referred to eight cardiology centres for clinical examination, electrocardiography, comprehensive Doppler echocardiography and blood sampling. All-cause mortality or hospitalizations were available after a median follow-up of 47 months with record linkage of administrative data. RESULTS: Vitamin D deficiency (<20 ng mL(-1) ) was found in 72.3% of subjects, but FGF-23 levels were normal [74 (58-97) RU per mL]. After adjustment for cardiovascular risk factors and morbidities, low concentrations of vitamin D and high levels of FGF-23 were associated with a higher left ventricular (LV) mass index. Levels of FGF-23 [hazard ratio (HR) (95% confidence interval (CI)) 1.71 (1.28-2.28), P < 0.0001] but not vitamin D [0.76 (0.57-1.01), P = 0.08] were independently associated with mortality after adjustment for clinical risk factors and two cardiac markers together (N-terminal pro-brain natriuretic peptide and high-sensitivity cardiac troponin T), but did not predict hospital admission. People with above median values of FGF-23 and below median values of vitamin D had greater LV hypertrophy and higher mortality. CONCLUSIONS: In community-dwelling elderly individuals with highly prevalent vitamin D deficiency, FGF-23 levels were associated with LV hypertrophy and predicted mortality independently of two robust cardiac biomarkers. A causal relationship was not demonstrated, but the hormones involved in mineral metabolism emerged as nontraditional risk factors and may affect cardiovascular risk.

Facilitation of blood donation amongst haemochromatosis patients.

BACKGROUND/OBJECTIVE: The standard medical therapy for haemochromatosis is iron removal by regular phlebotomy. Current guidelines suggest that this blood should be made available through national blood services. Here, we describe a pilot facilitating the process of blood donation amongst uncomplicated haemochromatosis patients. METHODS/MATERIALS: At a dedicated clinic, patients with uncomplicated haemochromatosis interested in becoming blood donors were offered an information leaflet and self-referral application. Upon receipt, members of the local Blood Service contacted them to confirm eligibility to donate. Data on demographics and clinical characteristics, including HFE (high Fe) genotype, co-morbidities, alcohol consumption and body mass index, were collected. RESULTS: Since establishing the clinic, 140 patients have attended (93 male) with median age 57. Most (n = 125; 89%) had uncomplicated haemochromatosis. Of these, 55 were potentially eligible blood donors. Amongst those eligible, there are now 29 regular blood donors, including 23 new. CONCLUSION: There is an interest and willingness to donate blood through the Blood Service amongst uncomplicated haemochromatosis patients undergoing therapeutic phlebotomy. Since the introduction of this facilitation process, we have significantly increased the number of regular donors amongst this cohort. If this process was to be replicated more widely across the UK, this could have a significant impact on the blood donor pool.

The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure.

OBJECTIVES: Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF. DESIGN: Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch. RESULTS: (i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts. CONCLUSION: There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.

High-sensitivity cardiac troponin T for detection of subtle abnormalities of cardiac phenotype in a general population of elderly individuals.

OBJECTIVE: To investigate the association between circulating cardiac biomarkers and minor abnormalities in cardiac phenotype [left ventricular (LV) mass and midwall fractional shortening (MFS)] in elderly individuals in a general population sample. DESIGN AND SETTING: We examined the relationship between plasma concentrations of high-sensitivity cardiac troponin T (hs-cTnT) or N-terminal probrain natriuretic peptide (NT-proBNP) and elevated LV mass (LV mass/body surface area >95 g m(-2) for women and 115 g m(-2) for men), reduced MFS (<15%) or isolated LV diastolic dysfunction in 1973 elderly subjects (mean age 73 ± 5 years, range 65-84) resident in the Lazio region of Italy and enrolled in the PREDICTOR study. RESULTS: Overall, 24.8% of subjects had elevated LV mass, and 30.4% had reduced MFS. Median [quartile 1-3] plasma concentrations of hs-cTnT and NT-proBNP were higher in individuals with elevated than those with normal LV mass: 6.6 [3.5-11.6] and 147 [64-296] ng L(-1) vs. 4.6 [3.0-8.1] and 79 [41-151] ng L(-1) respectively (P < 0.001). There was a graded increase in median hs-cTnT concentrations across clinical categories of LV hypertrophy: 4.6 [3.0-8.1], 5.8 [3.1-10.2], 7.6 [3.8-13.7] and 8.4 [3.8-17.6] ng L(-1) for subjects with normal LV mass and mild, moderate or severe LV hypertrophy respectively (P < 0.0001); hs-cTnT also increased with increasing quartiles of MFS or grades of isolated LV diastolic dysfunction. CONCLUSIONS: Within an extremely low range of concentrations, increased hs-cTnT amongst community-dwelling elderly subjects is associated with subtle alterations in cardiac phenotype, suggesting that minor injury to cardiac myocytes and subsequent release of troponin reflect subclinical pathophysiological LV deterioration in this population.

PROPENSIX: pressure garment therapy using compressive dynamic Lycra® sleeve to improve bi-manual performance in unilateral cerebral palsy: a multicenter randomized controlled trial protocol.

BACKGROUND: Upper limb impairment affects activity and participation in children with unilateral cerebral palsy (UCP). Pressure garment therapy (PGT) using compressive dynamic Lycra® garments is an innovative intervention proposed for the management of cerebral palsy consequences. The PROPENSIX study aims to evaluate the efficacy of a therapy using a Lycra® sleeve as compared to a placebo sleeve to improve bi-manual performance measured by the Assisting Hand Assessment (AHA) in children with unilateral cerebral palsy. METHODS: The PROPENSIX trial is a multicenter, prospective, placebo-controlled, double-blinded, randomized study. One hundred children with UCP, aged from 5 to 10, are randomly assigned as soon as they are recruited in a 1:1 ratio to perform usual daily activities, especially activities involving bimanual performances, with Lycra® sleeve or placebo sleeve during 6 months. The primary endpoint is the change in bimanual performance from inclusion to 6 months, evaluated by AHA. The secondary endpoints evaluate changes from inclusion to 6 months in other dimensions of the International Classification of Functioning (ICF), upper limb movement capacity assessed by Quality of Upper Extremity Skill Test (QUEST), and health-related quality of life evaluated by Pediatric Quality of Life Inventory 3.0 Cerebral Palsy Module (PedsQLTM 3.0 CP Module) and in body structures and functions domain assessed by neuro-orthopedic examination and somatosensory evoked potentials (SEP). DISCUSSION: The PROPENSIX study is the largest randomized controlled trial (RCT) aiming to evaluate the efficacy of a PGT using compressive dynamic Lycra® sleeve in UCP. Enhancement of children's bimanual performance at the end of the 6 months wear of the Lycra® sleeve should improve evidence regarding this type of treatment and expand discussion about their recommendation in clinical practice. Data from secondary outcomes assessments should bring interesting arguments to discuss the Lycra® sleeve action on mobility, tonus, and sensory impairments in children with unilateral cerebral palsy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02086214 . Retrospectively registered on March 13, 2014 TRIAL STATUS: Study start data: December 2012. Recruitment status: completed. Primary completion date: April 2021. Estimated study completion date: December 2022. Protocol version 10 (date: February 2018).

A novel method for quantitative monitoring of transplanted islets of langerhans by positive contrast magnetic resonance imaging.

The Automatic Quantitative Ultrashort Echo Time imaging (AQUTE) protocol for serial MRI allows quantitative in vivo monitoring of iron labeled pancreatic islets of Langerhans transplanted into the liver, quantifying graft implantation and persistence in a rodent model. Rats (n = 14), transplanted with iron oxide loaded cells (0-4000 islet equivalents, IEQ), were imaged using a 3D radial ultrashort echo time difference technique (dUTE) on a Siemens MAGNETOM 3T clinical scanner up to 5 months postsurgery. In vivo 3D dUTE images gave positive contrast from labeled cells, suppressing liver signal and small vessels, allowing automatic quantification. Position of labeled islet clusters was consistent over time and quantification of hyperintense pixels correlated with the number of injected IEQs (R² = 0.898, p < 0.0001), and showed persistence over time (5 months posttransplantation). Automatic quantification was superior to standard imaging and manual counting methods, due to the uniform suppressed background and high contrast, resulting in significant timesavings, reproducibility and ease of quantification. Three-dimensional coverage of the whole liver in the absence of cardiac/respiratory artifact provided further improvement over conventional imaging. This imaging protocol reliably quantifies transplanted islet mass and has high translational potential to clinical studies of transplanted pancreatic islets.

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

OBJECTIVE: we evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF). BACKGROUND: predicting long-term maintenance of sinus rhythm in patients with AF is difficult. METHODS: plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models. RESULTS: mean patient age was 68 ± 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR-proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06). CONCLUSION: circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF.

Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.

BACKGROUND AND AIM: We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and ß-blockers). METHODS AND RESULTS: From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04

Anxiolytic-like effects of substance P administration into the dorsal, but not ventral, hippocampus and its influence on serotonin.

Substance P (SP) is known to be involved in processes related to learning and memory, fear, anxiety and stress. SP and NK1 receptors are localized in the hippocampus, a brain structure involved in learning and memory as well as emotional processes. As there is evidence for differential functions of the ventral (VH) and dorsal (DH) hippocampus in a variety of behaviors, we here evaluated the effects of injections of SP into the VH and DH in rats submitted to the elevated plus-maze (EPM) and open field (OF) tests. The results obtained showed that infusions of 100 and 1000 ng of SP into the DH, but not VH, increased open arm activity in the EPM and in the central zone of the OF, indicative of anxiolytic-like action. These effects were observed in the absence of significant changes in general motor activity. In an additional experiment to examine whether these effects of SP are mediated by local serotoninergic mechanisms, extracellular concentrations of this monoamine were assessed by use of in vivo microdialysis. Infusions of SP into the DH did not influence the extracellular concentration of serotonin. These data indicate that neurokinins in the DH, but not VH, are involved in mechanisms associated with anxiety and that the mediation of SP in anxiety-related behaviors is independent of local serotonergic mechanisms.

Role of mast cells in ion transport abnormalities associated with intestinal anaphylaxis. Correction of the diminished secretory response in genetically mast cell-deficient W/Wv mice by bone marrow transplantation.

To investigate the role of mast cells in transport abnormalities during intestinal anaphylaxis, we examined responses to antigen in isolated intestinal preparations from ovalbumin-sensitized genetically mast cell-deficient WBB6F1-W/Wv (W/Wv) mice and congenic normal WBBGF1(-)+/+ (+/+) mice. Changes in ion transport (primarily secretion of chloride ions) were indicated by increases in short-circuit current (Isc). In tissues from +/+ mice, antigen caused increases in Isc which were significantly inhibited by antagonists to histamine (diphenhydramine) and serotonin (ketanserin), by a cyclooxygenase inhibitor (piroxicam) and by a neurotoxin (tetrodotoxin). In preparations from W/Wv mice, antigen-stimulated responses were approximately 30% of that in +/+ mice and were inhibited only by piroxicam. Responses to electrical transmural stimulation of nerves were approximately 50% in W/Wv versus +/+ mice, and were inhibited by antagonists of mast cell mediators in +/+ but not W/Wv mice. Reconstitution of mast cells in W/Wv mice by intravenous injection of +/+ bone marrow cells restored the normal responses to both antigen and nerve stimulation. Our results indicate that mast cell-dependent mechanisms are primarily responsible for the ion secretion associated with intestinal anaphylaxis, but that other cells are also involved. In addition, our data provide evidence for the functional importance of bidirectional communication between nerves and mast cells in the regulation of ion transport in the gastrointestinal tract.

Can a theoretical framework help to embed alcohol screening and brief interventions in an endoscopy day-unit?

INTRODUCTION AND AIMS: The National Institute for Health Care and Excellence recommend that alcohol screening and brief intervention (ASBI) should be routinely implemented in secondary care. This study used theoretical frameworks to understand how health professionals can be supported to adapt their behaviour and clinical practice. DESIGN AND METHODS: Staff training and support was conducted using theoretical frameworks. A 12-week study, delivering ASBI was carried out as part of routine practice in an endoscopy day-unit. Anonymised patient data were collected using the Alcohol Use Disorders Identification Tool (AUDIT) and whether patients received a brief intervention. Staff completed the Shortened Alcohol and Alcohol Problems Perceptions Questionnaire at three time points and took part in a focus group both pre and post study. RESULTS: For staff, levels or role adequacy, role legitimacy, motivation to discuss alcohol, security in their role, job satisfaction and commitment to working with patients who drink increased during the time of the study. 1598 individual patients were seen in the department in the timeframe. Of these, 1180 patients were approached (74%); 18% (n=207) of patients were AUDIT positive. DISCUSSION: This study has shown that it is possible to reach a high number of patients in a busy hospital out-patient department and deliver ASBI by working with staff using theoretical frameworks for training. Embedding evidence-based public health interventions into routine clinical environments is complex. The social system in which professionals operate requires consideration alongside individual professionals' real and perceived barriers and facilitators to change.

Implementation of a 'care bundle' improves the management of patients admitted to hospital with decompensated cirrhosis.

BACKGROUND: Since 1970, there has been a 400% increase in liver-related deaths due to the increasing prevalence of chronic liver disease in the United Kingdom (UK). The 2013 UK National Confidential Enquiry into Patient Outcome and Death report found that only 47% of patients who died from alcohol-related liver disease received 'good care' during their hospital stay. AIM: To develop a 'care bundle' for patients with decompensated cirrhosis, aiming to ensure that evidence-based treatments are delivered within the first 24 h of hospital admission. METHODS: This work gives practical advice about how to implement the bundle and examines its effects on patient care at three National Health Service Hospital Trusts in the UK by collecting data on patient care before and after introduction of the bundle. RESULTS: Data were collected on 228 patients across three centres (59% male, median age 53 years). Alcohol-related liver disease was the aetiology of chronic liver disease in 85% of patients. The overall mortality rate during hospital admission was 15%. The audits demonstrated improvements in patient care for patients with a completed care bundle who were significantly more likely to have a diagnostic ascitic performed within the first 24 h (P = 0.020), have an accurate alcohol history documented (P < 0.0001) and be given antibiotics as prophylaxis against infection following a variceal haemorrhage (P = 0.0096). In Newcastle, the bundle completion rate increased from 25% to 90% during the review periods. CONCLUSIONS: The introduction of a care bundle was associated with increased rates of diagnostic paracentesis and antibiotic prophylaxis with variceal haemorrhage in patients with decompensated cirrhosis.

Hepatic metabolism during constant infusion of fructose; comparative studies with 31P-magnetic resonance spectroscopy in man and rats.

A protocol of constant infusion of fructose has been carried out both in human volunteers and in the perfused rat liver, aiming at a steady-state blood fructose concentration of 6-8 mM. Localized 31P-NMR spectroscopy and biochemical analyses were used to evaluate the metabolic changes. Comparison of the model experiment and the clinical study allowed an evaluation of this protocol as a clinically relevant assessment of the metabolic function of the liver. The time course of change, as well as the quasi steady-state levels reached during fructose infusion, for phosphomonoesters (PME), ATP and inorganic phosphate (Pi) provided the following results: During fructose infusion, ATP and Pi reached a steady-state level of 74.0 +/- 5.9 and 54.6 +/- 3.3% of control respectively, in the human volunteers. The corresponding data in the rat liver was 71.3 +/- 4.3 and 54.4 +/- 4.3%. Hepatic clearance of fructose was 0.53 and 0.52 ml.g liver-1.min-1 for volunteers and rats, respectively. The time course of intracellular metabolite recovery after fructose could be approximated by a first order kinetic. The rate constants for PME and ATP change were similar during fructose infusion and recovery, while after the discontinuation of fructose infusion, Pi increased with a rate constant significantly greater than during its fructose-induced depletion in human liver (P < 0.005). Thus, this relatively simple clinically applicable protocol seems to be verifiable in the well controlled perfused rat liver model, and it is argued that it may be useful in the clinical evaluation of the metabolic functional capacity of the human liver.

Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test.

It has been demonstrated that exposure to a variety of stressful experiences enhances fearful reactions when behavior is tested in current animal models of anxiety. Until now, no study has examined the neurochemical changes during the test and retest sessions of rats submitted to the elevated plus maze (EPM). The present study uses a new approach (HPLC) by looking at the changes in dopamine and serotonin levels in the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens in animals upon single or double exposure to the EPM (one-trial tolerance). The study involved two experiments: i) saline or midazolam (0.5 mg/kg) before the first trial, and ii) saline or midazolam before the second trial. For the biochemical analysis a control group injected with saline and not tested in the EPM was included. Stressful stimuli in the EPM were able to elicit one-trial tolerance to midazolam on re-exposure (61.01%). Significant decreases in serotonin contents occurred in the prefrontal cortex (38.74%), amygdala (78.96%), dorsal hippocampus (70.33%), and nucleus accumbens (73.58%) of the animals tested in the EPM (P < 0.05 in all cases in relation to controls not exposed to the EPM). A significant decrease in dopamine content was also observed in the amygdala (54.74%, P < 0.05). These changes were maintained across trials. There was no change in the turnover rates of these monoamines. We suggest that exposure to the EPM causes reduced monoaminergic neurotransmission activity in limbic structures, which appears to underlie the "one-trial tolerance" phenomenon.

Autonomic cardiovascular modulation with three different anesthetic strategies during neurosurgical procedures.

BACKGROUND: Autonomic cardiovascular modulation during surgery might be affected by different anesthetic strategies. Aim of the present study was to assess autonomic control during three different anesthetic strategies in the course of neurosurgical procedures by the linear and non-linear analysis of two cardiovascular signals. METHODS: Heart rate (EKG-RR intervals) and systolic arterial pressure (SAP) signals were analyzed in 93 patients during elective neurosurgical procedures at fixed points: anesthetic induction, dura mater opening, first and second hour of surgery, dura mater and skin closure. Patients were randomly assigned to three anesthetic strategies: sevoflurane+fentanyl (S-F), sevoflurane+remifentanil (S-R) and propofol+remifentanil (P-R). RESULTS: All the three anesthetic strategies were characterized by a reduction of RR and SAP variability. A more active autonomic sympathetic modulation, as ratio of low to high frequency spectral components of RR variability (LF/HF), was present in the P-R group vs. S-R group. This is confirmed by non-linear symbolic analysis of RR series and SAP variability analysis. In addition, an increased parasympathetic modulation was suggested by symbolic analysis of RR series during the second hour of surgery in S-F group. CONCLUSION: Despite an important reduction of cardiovascular signal variability, the analysis of RR and SAP signals were capable to detect information about autonomic control during anesthesia. Symbolic analysis (non-linear) seems to be able to highlight the differences of both the sympathetic (slow) and vagal (fast) modulation among anesthetics, while spectral analysis (linear) underlines the same differences but only in terms of balance between the two neural control systems.

Identification of a novel protein tyrosine phosphatase with sequence homology to the cytoskeletal proteins of the band 4.1 family.

Use of the polymerase chain reaction (PCR) in conjunction with Southern hybridization, using probes corresponding to known phosphatase sequences, resulted in the identification of rat cDNA clones encoding a novel protein tyrosine phosphatase which was termed rPTP2E. The cDNAs comprise 5,543 bp and predict a polypeptide of 1175 amino acids possessing a single catalytic domain at its C-terminus. The N-terminal region of the deduced polypeptide displays high sequence homology to the cytoskeleton-associated proteins of the band 4.1 family. A variant form, termed rPTP2E1, was also identified which contains the catalytic domain only. rPTP2E and rPTP2E1 were expressed in various rat tissues, particularly abundantly in adrenal glands. The catalytic domain of PTP2E was expressed in Escherichia coli and was shown to possess specific protein tyrosine phosphatase activity. The identification of rPTP2E suggests the existence of a subfamily of band 4.1 domain-containing PTPs which may play an important role in signalling pathway and control of cytoskeletal integrity.

Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium.

OBJECTIVES: We sought to characterize the evolution, during maturational growth and early ageing, of the messenger abundance of four genes involved in cardiac fibrosis regulation (procollagens alpha2(I) and alpha1(III), transforming growth factors beta1, and beta3) and corroborate it with the alterations in collagen deposition in cardiac interstitium and around coronary arteries. METHODS: Messenger RNA was quantified in LV and RV of 2-, 6-, 12- and 19-month-old male Sprague-Dawley rats (n = 5 per group) with Northern blot analysis. Collagen deposition was quantified with a semi-automated image analyser on Sirius red-stained sections of LV tissue. RESULTS: There was an age-related monotonous decrease of procollagen type I (COL-I) transcript abundance in LV (p < 0.001) but not in RV. Procollagen type III (COL-III) expression decreased rapidly during maturational growth, both in LV and RV. On the other hand, collagen deposition in myocardial interstitium and around coronary arteries was slightly augmented during the maturational period of life (2-12 months), but with a higher rate during early ageing (up to 19 months). This was not accompanied by a significant thickening of the wall of coronary arteries. Transforming growth factor beta1, (TGF-beta1) and transforming growth factor beta3 (TGF-beta3) transcript abundance showed no major variations during ageing. CONCLUSIONS: These results reflect a striking ventricular difference regarding the age-dependent expression of COL-I. The expression of TGF-beta(s), pleiotropic factors known to influence collagen pathway at different levels, does not seem to be profoundly altered during ageing. The discrepancy between protein and COL-I and COL-III mRNA levels indicates differences in age-related mRNA stability and/or regulation of collagen translation.

Cardiac protection by pharmacological modulation of inflammation.

Inflammation is a reaction to primary injury of various kinds, such as infection and trauma, which has both beneficial and detrimental effects. Inflammation has been associated with major diseases of the heart and vessels. Research has focused not only on ischaemia but also on post-ischaemic reperfusion, which is known to activate and amplify the inflammatory response. Although reperfusion should always be attempted in the clinical environment, it has been shown experimentally that it can cause some cardiac damage, in addition to that caused by ischaemia. Therefore, it is reasonable to attempt to increase the benefit obtainable with reperfusion by modulating inflammatory processes triggered by reperfusion itself. In this field, different potential therapeutic targets have been identified and interventions have been tested over the last 30 years. With the exception of adenosine, which probably does not act merely through inhibition of the inflammatory response, no other compounds have yet proven successful in clinical trials. Active research is ongoing. Broadening the approach from the heart to the cardiovascular system, promising data is emerging on cardiovascular protection conferred by statins in patients with coronary heart disease (CHD) and high levels of C-reactive protein (CRP), a systemic marker of inflammation. Similarly, results of trials aimed at preventing cardiovascular events by eradicating chronic infections will be among the first to directly test whether such therapies will decrease risks of cardiovascular disease.

The first asymmetric synthesis of alpha-sulfanylphosphonates.

[reaction: see text] Diastereoselectivity of up to 88% was achieved for the synthesis of an alpha-mercapto gamma-unsaturated phosphonate using the readily available chiral dimenthylphosphonyl ester group and a carbanionic [2,3]-sigmatropic rearrangement. Absolute configuration of the newly formed chiral center of this nonracemic thiol was determined, and the corresponding phosphono thiolane and thiolane S-oxide were also stereoselectively prepared.