Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats.

Polyphenols have beneficial neurological effects delaying cognitive and motor decline in aging due to their antioxidant, antiinflammatory and neuroprotective properties. These effects could be related to SIRT1 activation (implicated in synaptic plasticity, memory and inflammation) and monoaminergic synthesis modulation. In this work, we studied in old male rats, the in vivo effects of long-term administration of different polyphenols (silymarin, quercetin and naringenin; 20 mg/kg/day i.p, 4 weeks) (Sprague-Dawley, 18 months) on cognition and motor coordination. We also analyzed in different brain regions: tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities, which mediate central monoaminergic neurotransmitters synthesis; and immunoreactivities of SIRT1 and NF-κB (total and acetylated forms). Results indicated that chronic polyphenolic treatments showed restorative effects on cognition and motor coordination consistently with the biochemical and molecular results. Polyphenols reversed the age-induced deficits in monoaminergic neurotransmitters (serotonin, noradrenaline, and dopamine), increasing TPH and TH activity. In addition, polyphenolic treatments increased SIRT1 levels and decreased NF-κB levels in hippocampus. These results confirm polyphenolic treatments as a valuable potential therapeutic strategy for attenuating inflamm-aging and brain function decline.

Effects of Resveratrol and other Polyphenols on Sirt1: Relevance to Brain Function During Aging.

BACKGROUND: Classically the oxidative stress and more recently inflammatory processes have been identified as the major causes of brain aging. Oxidative stress and inflammation affect each other, but there is more information about the effects of oxidative stress on aging than regarding the contribution of inflammation on it. METHODS: In the intense research for methods to delay or mitigate the effects of aging, are interesting polyphenols, natural molecules synthesized by plants (e.g. resveratrol). Their antioxidant and anti-inflammatory properties make them useful molecules in the prevention of aging. RESULTS: The antiaging effects of polyphenols could be due to several related mechanisms, among which are the prevention of oxidative stress, SIRT1 activation and inflammaging modulation, via regulation of some signaling pathways, such as NF-κB. CONCLUSION: In this review, we describe the positive effects of polyphenols on the prevention of the changes that occur during aging in the brain and their consequences on cognition, emphasizing the possible modulation of inflammaging by polyphenols through a SIRT1-mediated mechanism.

Protective Effects of Melatonin and Mitochondria-targeted Antioxidants Against Oxidative Stress: A Review.

Oxidative damage is related to aging and a wide range of human disorders. Mitochondria are in large part responsible for free radical production and they are also main targets of the attack of these toxic molecules. The resulting deleterious effects of the damage to mitochondria can be prevented by antioxidants. Melatonin is an endogenously-produced indoleamine that modulates numerous functions, including mitochondria-related functions; this result from its capacity to penetrate all morphophysiological barriers and to enter all subcellular compartments due to its amphiphilic nature. Furthermore, this indoleamine and its metabolites are powerful antioxidants and scavengers of free radicals, protecting cellular membranes, the electron transport chain and mitochondrial DNA from oxidative damage. These properties may make melatonin a potent protector against a variety of free radical-related diseases. By comparison, other conventional antioxidants have less efficacy due to their limited access to the mitochondria. In recent years, research has focused on the advancement of mitochondria-targeted antioxidants, such as MitoQ (composed by the lipophilic triphenylphosphonium cation conjugated to the endogenous antioxidant coenzyme Q10) and MitoE (composed by the triphenylphosphonium cation attached to the antioxidant α-tocopherol). Mitochondria-targeted antioxidants accumulate in several hundred-fold greater concentrations within mitochondria and protect these critical organelles from oxidative damage. Melatonin also seems to be a mitochondria-targeted antioxidant and has similar protective actions as the synthetic antioxidants. Further work is required to determine the therapeutic properties of these antioxidants in ameliorating diseases related to mitochondrial dysfunction.

Improving effect of chronic resveratrol treatment on central monoamine synthesis and cognition in aged rats.

Resveratrol is a polyphenol exhibiting antioxidant and neuroprotective effects in neurodegenerative diseases. However, neuroprotective properties during normal aging have not been clearly demonstrated. We analyzed the in vivo effects of chronic administration of resveratrol (20 mg/kg/day for 4 weeks) in old male rats (Wistar, 20 months), on tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities which mediate central monoaminergic neurotransmitters synthesis, and besides, on hippocampal-dependent working memory test (radial maze). Our results show an age-related decline in neurochemical parameters that were reversed by resveratrol administration. The resveratrol treatment enhances serotonin (5-HT) levels in pineal gland, in hippocampus, and in striatum, and those of noradrenaline (NA) in hippocampus and also dopamine (DA) in striatum. These changes were largely due to an increased activity of TPH-1 (463 % in pineal gland), TPH-2 (70-51 % in hippocampus and striatum), and TH (150-36 % in hippocampus and striatum). Additionally, the observed hippocampal effects correlate with a resveratrol-induced restorative effect on working memory (radial maze). In conclusion, this study suggests resveratrol treatment as a restoring therapy for the impaired cognitive functions occurring along normal aging process, by preventing 5-HT, DA, and NA neurotransmission decline.

Blockade of nociceptive sensory afferent activity of the rat knee joint by the bradykinin B2 receptor antagonist fasitibant.

OBJECTIVE: The aim of this study was to determine in intact and inflamed knee joints of the rat, the effect of the bradykinin (BK) B2 receptor antagonist fasitibant (MEN16132) on nociceptor mechanosensitivity and hyperalgesia. METHODS: Joint afferent sensory fibers of the medial articular nerve of anesthetized animals were electrophysiologically recorded, measuring nerve impulse activity evoked by passive innocuous and noxious movements of the joint, in intact and kaolin and carrageenan-injected joints. Knee joints of rats were also acutely inflamed by intra-articular injection of carrageenan alone. Long term duration of fasitibant antinociceptive effects were behaviorally evaluated using the incapacitance test. RESULTS: BK (100 µM) injected into the saphenous artery, induced excitation and sensitization of multi- and single unit recordings. Fasitibant (300 µM) injected prior to BK, reduced its excitatory effects as well as the overall increase of movement-evoked activity resulting from repeated injections of BK. Fasitibant did not affect movement-evoked activity of sensory fibers of intact, non-inflamed knee joints. Intra-articular fasitibant (100 µg/knee) significantly reduced the carrageenan-induced inflammatory hyperalgesia measured with the incapacitance test up to four days after treatment. This antinociceptive effect was not obtained with systemic endovenous injection of the drug. CONCLUSIONS: Fasitibant prevents B2 receptor-mediated activation and sensitization of peripheral joint afferents and the ensuing inflammatory hyperalgesia, and may be a useful, novel drug for arthritis pain treatment.

[Abdominal compartment syndrome and acute intestinal distress syndrome]. / Síndrome compartimental abdominal y síndrome de distrés intestinal agudo.

Seriously ill patients frequently present intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) as complications, and the associated mortality is very high. This review offers an update on the most controversial aspects of these entities: factors favoring their appearance, the most common causes, prognosis, and methods of measuring intra-abdominal pressure (IAP), physiopathological consequences in relation to the different organs and systems, and the currently accepted treatment measures (medical and/or surgical). Simultaneously to the strictly physical mechanisms of injury, such as direct compression of intra-abdominal organs and vessels, the transmission of IAP to other compartments, and the drop in cardiac output, a series of immune-inflammatory mediators generated in the intestine itself may also intervene. Hypoperfusion, sustained ischemia and the ischemia-reperfusion phenomenon, would act upon the microbiota, intestinal epithelium and intestinal immune system, triggering a systemic inflammatory response and multiorgan dysfunction that appears in the final stages of ACS.

Renal function improvement after conversion to proliferation signal inhibitors during long-term follow-up in heart transplant recipients.

INTRODUCTION: The use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function. METHODS: This prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion. RESULTS: Ninety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04). CONCLUSION: Despite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

[Clinical pathways for the care of multiple sclerosis patients]. / Diseño de una vía clínica para la atención a los pacientes con esclerosis múltiple.

INTRODUCTION: clinical pathways are standard health care methods to coordinate clinical work, reduce inter-clinician variability, improve patient care and increase staff and patient satisfaction. The aim of this study is to develop a clinical pathway capable of organising and developing standard procedures for diagnosis, treatment and care in patients with multiple sclerosis and to coordinate all medical specialists involved in this disease. METHODS: a multidisciplinary unit for the care of MS patients was developed. All of them and quality specialists analysed some international evidence-based studies, clinical guides, international guidelines and other clinical neurological pathways in several meetings and designed several documents for the clinical pathways. RESULTS: a clinical pathway was created consisting of a scientific-technical framework, which arranges the care in relation to the diagnosis and reatment. The framework is accompanied by various patient-information documents on the disease, an information sheet on diagnostic procedures and a map of the process. Quality standards were established to achieve continuous improvement in patient care. CONCLUSIONS: a clinical pathway for the care of MS patients in a multidisciplinary unit homogenises and organises the care which the MSpatient should receive from the initial symptoms to the progressive stages. This clinical pathway improves the quality of patient care, reduces the variability in work protocols and rationalises the use of the available health care resources.

Systematics and biogeography of the Neotropical genus Mabuya, with special emphasis on the Amazonian skink Mabuya nigropunctata (Reptilia, Scincidae).

Phylogenetic analyses using up to 1532 base pairs (bp) of mitochondrial DNA from 106 specimens of Neotropical Mabuya, including 18 of the 19 recognized South American and Mesoamerican species, indicate that most species of the genus are monophyletic, including M. nigropunctata that had previously been reported to be paraphyletic. The present results shows that this species includes three highly divergent and largely allopatric lineages restricted to occidental, meridional, and oriental Amazonia. Our dataset demonstrates that previous claims regarding the paraphyletic status of M. nigropunctata and the phylogenetic relationships within this species complex based on the analysis of three mitochondrial and four nuclear genes (approx. 5000bp) were erroneous and resulted from two contaminated cytochrome b sequences. The phylogenetic results indicate that diversification in the Neotropical genus Mabuya started approximately in the Middle Miocene (15.5-13.4Ma). The divergence dates estimated for the Mabuya nigropunctata species complex suggest that the major cladogenetic events that produced the three main groups (occidental (oriental+meridional)) occurred during the Late Miocene. These estimations show that diversification within the M. nigropunctata species complex was not triggered by the climatic changes that occurred during the Pleistocene, as has been suggested by several authors. Rather, our data support the hypothesis that the late tertiary (essentially Miocene epoch) was a period that played a very important role in the generation of biological diversity in the Amazonian forests. Speciation between Mabuyacarvalhoi, endemic to the coastal mountain range of Venezuela, and M. croizati, restricted to the Guiana Shield, occurred during the Middle Miocene and may have been as the result of a vicariant event produced by the formation of the present day Orinoco river drainage basin and the consequent appearance of the Llanos del Orinoco, which acted as a barrier to dispersal between these two species. The split between M. bistriata and M. altamazonica and between the occidental and (meridional+oriental) clades of M. nigropunctata fits very well with the biogeographic split between the eastern and western Amazon basins reported for several other taxa.

[Glatiramer acetate in interferon beta non respondent relapsing-remitting multiple sclerosis]. / Acetato de glatiramero en pacientes con esclerosis múltiple remitente-recurrente no respondedores al interferón beta.

INTRODUCTION AND OBJECTIVE: There are 4 immunomodulator treatments approved as first line therapy for patients with re-lapsing-remitting multiple sclerosis (RRMS). The objective of this study is to assess if glatiramer acetate (GA) is useful or not in patients who have discontinued interferon beta due to a suboptimal response or adverse events. METHODS: This is an observational and retrospective study in RRMS patients who discontinued IFN-beta therapy (2.9+/-2.4 years of treatment) and switched to GA (1.9+/-1.4 years). They were classified in 2 groups depending on the reason for discontinuation: suboptimal response or side effects. In both treatments we analysed number of relapses, treatment duration and causes of discontinuation. RESULTS: We included 58 patients of which 20 discontinued IFN-beta for lack of effectiveness whereas 38 were due to adverse events. Patients who discontinued for suboptimal response changed from 1.38 +/- 0.95 relapses per year with IFN-beta to 0.52+/-0.86 with GA. Patients who discontinued for adverse events changed from 0.33 +/- 0.64 relapses per year with IFN-beta to 0.37+/-0.79 with GA. CONCLUSIONS: GA can be considered a good alternative treatment for MS patients with a suboptimal response or adverse events with IFN-beta which confirms the existence of different mechanisms of action in both drugs.

[LDL-cholesterol goals and changes in C reactive protein in high coronary risk patients]. / Objetivos terapéuticos del colesterol LDL y cambios de la proteína C reactiva en pacientes de alto riesgo coronario.

INTRODUCTION: We performed this study to compare the achievement of lipid targets as well as the change on C reactive protein (CRP) values of two different strategies, the combination of ezetimibe plus statins compared to the doubling of the previous statin dose. METHODS: Retrospective longitudinal study of 111 dyslipidemic patients, treated with statins, whose cholesterol values were still elevated. In 59 patients the previous statin dose was doubled, in 52 patients ezetimibe was added to the statin. Differences on lipid parameters and CRP were measured. RESULTS: Patients treated with the association of ezetimibe plus statins obtained a higher reduction of LDL-cholesterol levels (38% vs. 18.1%, p<0.001), compared with those doubling the statin dose. A reduction on CRP values was observed only in patients on combined therapy (22.5%; p<0.005), CRP change was not related to lipids variation. More patients with high coronary risk treated with ezetimibe plus statin, reached lipid goals (LDL<100 mg/dl) compared to those whose statin dose was doubled (47% vs 19%; p<0.001) and the same happened on very high coronary risk patients (LDL<70 mg/dl) (43% vs 2%; p<0,001). More patients in the group ezetimibe plus statin achieved the combined target lipid control and CRP<3 mg/l (19% vs. 3%, p=0.002). DISCUSSION: Combination treatment of ezetimibe with statins on high coronary risk patients showed a better achievement of LDL-cholesterol goals with a reduction of CRP values.

Recovery of ventricular function with a left ventricular axial pump in a patient with end-stage toxic cardiomyopathy not a candidate for heart transplantation: first experience in Spain.

BACKGROUND: Toxic cardiomyopathies are rare and the most frequent cause are anthracycline compounds. Early acute toxicity can be reversible, but at present the only effective therapy for late end-stage anthracycline cardiomyopathy seems to be a heart transplantation. Currently, this transplantation is contraindicated in cases of cancer, at least during the first 4 or 5 years. Recently, implantable axial pumps have shown good results and are used with increasing frequency as destination therapy. METHODS: We present a case of end-stage heart failure due to a toxic cardiomyopathy after a bilateral breast cancer treated with resection and chemotherapy (doxorubicin and trastuzumab). Ejection fraction was 23% with dobutamine. A left ventricular axial pump (Incor) was implanted. RESULTS: The immediate postoperative course was uneventful. The left ventricular function improved and on the fourth month the ejection fraction was 55%. On postoperative day 135, the pump was explanted. After 1.5 years, the patient is doing well, with an ejection fraction of 57%. CONCLUSION: This is the first application of an implantable axial pump in Spain. Although toxic cardiomyopathies are rare, in cases of late end-stage left ventricular failure and when the heart transplantation is contraindicated, the implantation of an axial pump can be the solution. The results in previous cases are unknown, although it is possible, as in our case.

Intra-articular injections of hyaluronan solutions of different elastoviscosity reduce nociceptive nerve activity in a model of osteoarthritic knee joint of the guinea pig.

OBJECTIVE: To study in guinea pigs knee joints the effects of intra-articular injection of HYADD 4-G (Fidia-Farmaceutici), a novel hyaluronan (HA)-derived elastoviscous material and of Hyalgan (Fidia-Farmaceutici), a HA product with very low viscoelasticity, on movement-evoked nociceptor impulse activity from normal and inflamed knee joints. DESIGN: Nociceptor impulse activity was recorded from single Adelta and C fibers of the medial articular nerve either under control conditions or after induction of an experimental knee joint osteoarthritis (OA) by partial medial menisectomy and transection of the anterior cruciate ligament (PMM-TACL). The stimuli consisted of standardized innocuous and noxious inward and outward rotations of the tibia against the femur of 50s duration, repeated every 5min for 1.5h. RESULTS: The number of movement-evoked impulses was significantly augmented 1 day and 1 week after PMM-TACL compared with intact knee joint. The enhanced impulse response to joint movements 1 week following surgery was attenuated by repeated intra-articular injection of HYADD 4-G and even more prominently by Hyalgan. CONCLUSIONS: HA products have a reducing action on joint nociceptor discharges that appears to depend predominantly on their role as an elastoviscous filter associated with their rheological properties, but also on a chemical effect on sensitized nociceptive terminals of inflamed joint tissues, possibly linked to the HA concentration.

Clinical evolution of heart transplantation in patients with previous valvular cardiomyopathy.

OBJECTIVE: Heart transplantation (HT) due to valvular cardiomyopathy is rare, namely, about 3% of cases in the Registry of the International Society for Heart and Lung Transplantation (ISHLT). Usually, these patients present some risk factors such as previous valvular operations and pulmonary hypertension. Since there are few studies in the literature, we retrospectively analyzed our early and long-term results. MATERIALS AND METHODS: We studied our experience in 22 HT cases for valvular cardiomyopathy (9.3% of our total experience), namely, 12 men and 10 women, of overall mean age of 52.6 +/- 10 years. Five patients had mitral; 8, aortic; and 1, tricuspid valve disease; 7 had double valve disease and 1, triple valve disease. Nineteen patients (87%) had been operated previously between 1 and 4 times. The mean ejection fraction was 23% +/- 7.3% and the mean New York Heart Association (NYHA) functional class was 3.7. Fifty-three percent of the patients had pulmonary hypertension. Two patients were operated as an emergency "O." We used the standard HT technique. RESULTS: Four patients (18%) were reoperated due to hemorrhage. The hospital mortality was 2 cases (9%). Another patients (9%) died on follow-up due to cardiac allograft vasculopathy. All surviving patients have been followed to the end of 2006. The mean follow-up has been 72 +/- 53 months. They are functional class I or II. CONCLUSIONS: HT for this indication was more frequent in our experience than in the Registry of the ISHLT. The immediate and long-term results were good, with an 82% mean survival at 6 years. HT can be a good treatment for patients with valvular cardiomyopathy and bad ventricular function and/or multiple valvular reoperations.

[The introduction of a programme to improve the treatment compliance of institutionalised elderly patients]. / Implantación de un programa de mejora de la adherencia al tratamiento en personas mayores institucionalizadas.

OBJECTIVE: To assess drug treatment compliance in institutionalised elderly patients, identifying reasons for poor compliance and introducing measures to reduce its prevalence. METHOD: A programme was designed to improve drug treatment compliance in geriatric patients in residential homes. Drug intervention consisted of using an educational technique of a mixed nature (verbal information with written back up). A data collection sheet was designed following a review of the literature. This was carried out by means of a clinical interview and by checking for tablets which were not taken. RESULTS: A total of 62 patients were chosen for drug management at a health and welfare centre in Alicante and 140 interventions were performed (2.8 interventions per patient). Compliance improved and there were significant differences in the variable for distrust due to lack of information (p = 0.009) and almost significant differences in the variable for better understanding of the dispensing system (p = 0.058). Duplicate treatment of the patients was eliminated in all cases after the pharmaceutical intervention. CONCLUSIONS: Our study suggests that pharmacist intervention in the drug management of geriatric patients can lead to improved treatment compliance, with the added benefits of improved knowledge of the medication and a reduction in possible drug-related problems.

[Assessment of a follow-up programme for institutionalised elderly patients on oral anticoagulant treatment]. / Evaluación de un programa de seguimiento de pacientes ancianos institucionalizados en tratamiento con anticoagulantes orales.

OBJECTIVE: To assess an interdisciplinary follow-up programme for institutionalised elderly people on oral anticoagulant treatment. METHOD: The proposed follow-up treatment is of an interdisciplinary nature and includes INR, an interview with the patient and/or carer and an assessment of the treatment plan every week. The quality of drug treatment is assessed by the percentage of time and the percentage of measurements falling within the therapeutic range. The suitability of the programme in comparison to the traditional follow-up was studied in terms of the different proportions for the first variable and by analysing contingency tables for the second. RESULTS: Nine patients were recruited. Six patients (67%) showed a significant increase in the percentage of time they remained within the therapeutic range. 68.5% of INR measurements during the follow-up programme were within therapeutic range. The percentage of INR measurements below the therapeutic range was significantly reduced when compared to the traditional follow up. Thirteen pharmaceutical interventions were documented per patient. CONCLUSIONS: The complexity of oral anticoagulant treatment, the large number of interventions carried out together with elderly patients poor treatment compliance are evidence of the need to introduce follow-up programmes which include the professionals responsible for the patients care.