Improving the mix of institutional and community care for older people with dementia: an application of the balance of care approach in eight European countries.

OBJECTIVES: To examine whether the mix of community and institutional long-term care (ILTC) for people with dementia (PwD) in Europe could be improved; assess the economic consequences of providing alternative services for particular groups of ILTC entrants and explore the transnational application of the 'Balance of Care' (BoC) approach. METHOD: A BoC study was undertaken in Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the UK as part of the RightTimePlaceCare project. Drawing on information about 2014 PwD on the margins of ILTC admission, this strategic planning framework identified people whose needs could be met in more than one setting, and compared the relative costs of the possible alternatives. RESULTS: The findings suggest a noteworthy minority of ILTC entrants could be more appropriately supported in the community if enhanced services were available. This would not necessarily require innovative services, but more standard care (including personal and day care), assuming quality was ensured. Potential cost savings were identified in all countries, but community care was not always cheaper than ILTC and the ability to release resources varied between nations. CONCLUSIONS: This is believed to be the first transnational application of the BoC approach, and demonstrates its potential to provide a consistent approach to planning across different health and social care systems. Better comparative information is needed on the number of ILTC entrants with dementia, unit costs and outcomes. Nevertheless, the findings offer important evidence on the appropriateness of current provision, and the opportunity to learn from different countries' experience.

Nanolithium, a New Treatment Approach to Alzheimer's Disease: A Review of Existing Evidence and Clinical Perspectives.

Lithium has been approved and used for several decades in the treatment of psychiatric disorders, and its potential effect in neurodegenerative diseases has been subject to increasing research interest in recent years. Nanolithium is a new experimental product using a novel drug-delivery technology (Aonys®), which optimizes its bioavailability while reducing its toxicity profile. Therapeutic doses of lithium used in Nanolithium are more than 50 times lower than the minimal dose of classical lithium salts. In this review we report data from non-clinical pharmacology studies supporting Nanolithium efficacy and the mechanism of action in Alzheimer's disease. GSK-3ß inhibition is thought to be central to Nanolithium's mechanism of action, triggering a reduction of the production of toxic amyloid plaques and decrease in tau hyperphosphorylation, which could potentially benefit both neuropsychiatric symptoms and cognitive decline. We then summarize outcomes from non-clinical proof-of-concept studies. These data supported the initiation of a currently ongoing phase II proof-of-concept study to evaluate the safety and efficacy of Nanolithium in patients with mild-to-severe Alzheimer's disease. We highlight key aspects of the study design. We finish this review with a discussion on the potential place of Nanolithium in the current and future Alzheimer's disease treatment landscape.

In health and illness: does taste remain consistent? Exploring the influence of inflammation on taste perception through a systematic review and meta-analysis.

OBJECTIVE: Dysgeusia is characterized by a loss of taste perception, leading to malnutrition. This situation affects inflammatory conditions such as respiratory and neurological conditions, obesity, cancer, chemotherapy, aging, and many others. To date, there is not much information on the prevalence and risk of dysgeusia in an inflammatory condition; also, it is unclear which flavor is altered. MATERIALS AND METHODS: We systematically searched three databases from January 2018 to January 2023. Participants were children, adults, or elderly persons with an inflammatory condition and evaluated taste loss. A random effects model was used for statistical analysis to calculate the pooled odds ratio with its corresponding 95.0% confidence interval to estimate the probability of taste alteration (dysgeusia) in an inflammatory condition. RESULTS: The data allowed us to conduct a systematic review, including 63 original articles and 15 studies to perform the meta-analysis. The meta-analysis indicated a heterogenicity of 84.7% with an odds ratio of 3.25 (2.66-3.96), indicating a significant risk of Alzheimer's disease, SARS-CoV-2, chemotherapy, and rhinosinusitis. CONCLUSIONS: Inflammatory conditions and taste alterations are linked. Dysgeusia is associated with a higher risk of malnutrition and poorer general health status, especially in vulnerable populations.

5-HT denervation of the adult rat prefrontal cortex induces changes in the expression of α4 and α7 nicotinic acetylcholine receptor subtypes.

INTRODUCTION: Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout several brain regions. Formation of the α4ß2 and α7 subtypes in particular is involved in the organisation of different types of memory. Furthermore, due to their location, these receptors can control the release of various types of neurotransmitters and contribute to synaptic plasticity. METHODS: Rats were divided into three groups, an experimental group (E), a sham-operated group, (S) and an intact group (T). In group E, stereotactic guidance was used to induce a chemical lesion with 1 µ/µL of 5,7-dihydroxytryptamine (5,7-DHT) in the anteroventral part of the dorsal raphe nucleus (DRN). In the sham-operated group (S), animals underwent surgery including delivery of the same excipient solution to the same site. The intact group (T) received no treatment whatsoever. Twenty days after surgery, animals in all groups were euthanised by decapitation to evaluate the expression of α4 and α7 nAChRs by means of molecular biology techniques. RESULTS: 5-HT denervation of the rat PFC differentially modified the expression of α4 and α7 receptors: while α4 receptor expression increased, α7 expression decreased. CONCLUSION: Expression differences observed between the two subtypes may be due to their separate locations. The α4 subtype is found in postsynaptic locations and may be related to adaptive changes in postsynaptic cells, while the location of α7 is presynaptic. This explains why the lesion and the elimination of 5-HT fibres in the CPF would cause a decrease in α7 expression.

[Expression of NMDA receptor subunits in rat prefrontal cortex with CCL4-induced hepatic damage after a treatment with Rosmarinus officinalis L]. / Expresión de las subunidades del receptor NMDA en la corteza prefrontal de la rata con daño hepático inducido con CCL4 después del tratamiento con Rosmarinus officinalis L.

INTRODUCTION: In cirrhosis some toxic substances accumulate in brain and modify the expression of several neuronal receptors. Thus, the use of medicinal plants such as Rosmarinus officinalis L. has been proposed in several pathologies due to its hepatoprotective, antioxidant and neuroprotective activity. In this study we evaluated the expression of the subunits NR1, NR2A and NR2B of the glutamate receptor in rat prefrontal cortex in a model of hepatic damage induced with carbon tetrachloride after a treatment with Rosmarinus officinalis L. METHODS: We used a total of 24 male Wistar rats weighing 80-90 g. body weight. We formed three study groups: control group (C) without a treatment, carbon tetrachloride group (CC14), and CC14 group plus Rosmarinus officinalis L (CCl4+ROM; 1.5 g/kg of extract orally). RESULTS: The expression of the NR1, NR2A and NR2B subunits in cirrhotic animals increased compared to the control group, however treatment with Rosmarinus officinalis L. was able to reduce this expression to normal levels compared with CC14 and CCl4+ROM groups. These results could be due to an improvement in hepatic function. CONCLUSION: Treatment with extract of Rosmarinus officinalis L. in cirrhotic animals modifies the expression of subunits of the NMDA receptor due to an improvement in hepatocellular function in the presence of antioxidant compounds and flavonoids.

[Structure and function of NMDA-type glutamate receptor subunits]. / Estructura y función de las subunidades del receptor a glutamato tipo NMDA.

INTRODUCTION: To review the physiology of the glutamate receptor subunits such as N-methyl-D-aspartate (NMDA). DEVELOPMENT: Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system which interacts with two types classified into two types: metabotropic and ionotropic. Ionotropic receptors are classified according to the affinity of their specific agonists: N-methyl-D-aspartate (NMDA), α-amino acid-3-hydroxy-5-methyl-4-isoxazole (AMPA) and kainic acid (KA). NMDA receptors are macromolecular structures that are formed by different combinations of subunits, NMDAR1 (NR1), NMDAR2 (NR2) and NMDAR3 (NR3) CONCLUSIONS: The study of this receptor has been of great interest due to its role in synaptic plasticity, but mainly due to the permeability it has to Ca(++) ion. This review examines the molecular composition of NMDA receptor and the variants of NR1 subunit edition in association with NR2 subunit dimer, the main form of this receptor. The composition, structure and function and their distinct expression patterns in both time and space, has shown the versatility and diversity of functionally different isoforms of the NR1 subunit and various pharmacological properties of the NR2 subunit.

Using Digital Tools to Advance Alzheimer's Drug Trials During a Pandemic: The EU/US CTAD Task Force.

The 2020 COVID-19 pandemic has disrupted Alzheimer's disease (AD) clinical studies worldwide. Digital technologies may help minimize disruptions by enabling remote assessment of subtle cognitive and functional changes over the course of the disease. The EU/US Clinical Trials in Alzheimer's Disease (CTAD) Task Force met virtually in November 2020 to explore the opportunities and challenges associated with the use of digital technologies in AD clinical research. While recognizing the potential of digital tools to accelerate clinical trials, improve the engagement of diverse populations, capture clinically meaningful data, and lower costs, questions remain regarding the stability, validity, generalizability, and reproducibility of digital data. Substantial concerns also exist regarding regulatory acceptance and privacy. Nonetheless, the Task Force supported further exploration of digital technologies through collaboration and data sharing, noting the need for standardization of digital readouts. They also concluded that while it may be premature to employ remote assessments for trials of novel experimental medications, remote studies of non-invasive, multi-domain approaches may be feasible at this time.

Framework Implementation of the INSPIRE ICOPE-CARE Program in Collaboration with the World Health Organization (WHO) in the Occitania Region.

INTRODUCTION: Limiting the number of dependent older people in coming years will be a major economic and human challenge. In response, the World Health Organization (WHO) has developed the «Integrated Care for Older People (ICOPE)¼ approach. The aim of the ICOPE program is to enable as many people as possible to age in good health. To reach this objective, the WHO proposes to follow the trajectory of an individual's intrinsic capacity, which is the composite of all their physical and mental capacities and comprised of multiple domains including mobility, cognition, vitality / nutrition, psychological state, vision, hearing. OBJECTIVE: The main objective of the INSPIRE ICOPE-CARE program is to implement, in clinical practice at a large scale, the WHO ICOPE program in the Occitania region, in France, to promote healthy aging and maintain the autonomy of seniors using digital medicine. METHOD: The target population is independent seniors aged 60 years and over. To follow this population, the 6 domains of intrinsic capacity are systematically monitored with pre-established tools proposed by WHO especially STEP 1 which has been adapted in digital form to make remote and large-scale monitoring possible. Two tools were developed: the ICOPE MONITOR, an application, and the BOTFRAIL, a conversational robot. Both are connected to the Gerontopole frailty database. STEP 1 is performed every 4-6 months by professionals or seniors themselves. If a deterioration in one or more domains of intrinsic capacity is identified, an alert is generated by an algorithm which allows health professionals to quickly intervene. The operational implementation of the INSPIRE ICOPE-CARE program in Occitania is done by the network of Territorial Teams of Aging and Prevention of Dependency (ETVPD) which have more than 2,200 members composed of professionals in the medical, medico-social and social sectors. Targeted actions have started to deploy the use of STEP 1 by healthcare professionals (physicians, nurses, pharmacists,…) or different institutions like French National old age insurance fund (CNAV), complementary pension funds (CEDIP), Departmental Council of Haute Garonne, etc. Perspective: The INSPIRE ICOPE-CARE program draws significantly on numeric tools, e-health and digital medicine to facilitate communication and coordination between professionals and seniors. It seeks to screen and monitor 200,000 older people in Occitania region within 3 to 5 years and promote preventive actions. The French Presidential Plan Grand Age aims to largely implement the WHO ICOPE program in France following the experience of the INSPIRE ICOPE-CARE program in Occitania.

Chronic Inhibition of FAAH Reduces Depressive-Like Behavior and Improves Dentate Gyrus Proliferation after Chronic Unpredictable Stress Exposure.

Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model.

ß-Caryophyllene exerts protective antioxidant effects through the activation of NQO1 in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. ß-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD.

Oxidative, Reductive, and Nitrosative Stress Effects on Epigenetics and on Posttranslational Modification of Enzymes in Cardiometabolic Diseases.

Oxidative (OS), reductive (RS), and nitrosative (NSS) stresses produce carbonylation, glycation, glutathionylation, sulfhydration, nitration, and nitrosylation reactions. OS, RS, and NSS are interrelated since RS results from an overactivation of antioxidant systems and NSS is the result of the overactivation of the oxidation of nitric oxide (NO). Here, we discuss the general characteristics of the three types of stress and the way by which the reactions they induce (a) damage the DNA structure causing strand breaks or inducing the formation of 8-oxo-d guanosine; (b) modify histones; (c) modify the activities of the enzymes that determine the establishment of epigenetic cues such as DNA methyl transferases, histone methyl transferases, acetyltransferases, and deacetylases; (d) alter DNA reparation enzymes by posttranslational mechanisms; and (e) regulate the activities of intracellular enzymes participating in metabolic reactions and in signaling pathways through posttranslational modifications. Furthermore, the three types of stress may establish new epigenetic marks through these reactions. The development of cardiometabolic disorders in adult life may be programed since early stages of development by epigenetic cues which may be established or modified by OS, RS, and NSS. Therefore, the three types of stress participate importantly in mediating the impact of the early life environment on later health and heritability. Here, we discuss their impact on cardiometabolic diseases. The epigenetic modifications induced by these stresses depend on union and release of chemical residues on a DNA sequence and/or on amino acid residues in proteins, and therefore, they are reversible and potentially treatable.

Cytological damage of nasal epithelium associated with decreased glutathione peroxidase in residents from a heavily polluted city.

OBJECTIVE: To evaluate the cytological damage and glutathione peroxidase (GPX) content in the nasal epithelium of residents of Southwest Metropolitan Mexico City (SWMMC) along 1 year of ozone and PM(10) exposure. METHOD: Four nasal scrapings were obtained in 20 volunteers from a control low polluted city and SWMMC permanent residents (n = 20) during 1 year. The scrapings were obtained in September and December 2004, and February and May 2005. One part of the scraping was stained by hematoxylin-eosin technique for cytological evaluation and a second part was stained by immunocytochemistry method to evaluate GPX concentration by morphometry. RESULTS: Control subjects: in total, 30% had no cytological alterations and 70% showed only mild or moderate inflammation in four nasal scrapings. All SWMMC residents showed moderate to severe inflammatory processes in some scrapings. Additionally, dysplasia was found once (in 2 cases) or more than on scraping in five cases (25%). GPX concentration in the control group remained highest in median values throughout the study. SWMMC residents with the highest median values of GPX content were found in the May and September scrapings, and the lowest median values were found in December and February when Ozone and PM(10) levels are increased (P < or = 0.05). A lower GPX content was found as the cytological damage increased (P < or = 0.001). CONCLUSION: Cytological evaluation of nasal epithelium and GPX immunodetection are satisfactory methods to evaluate the earliest damage produced by atmospheric pollution in heavily contaminated cities.

Sleep disorders and their impacts on healthy, dependent, and frail older adults.

BACKGROUND: Sleep disorders differ widely in the heterogeneous older adult population. Older adults can be classified into three groups based upon their overall level of disability: healthy, dependent, and frail. Frailty is an emerging concept that denotes older persons at increased risk for poor outcomes. OBJECTIVE: The aim of this consensus review is to describe the sleep disorders observed in healthy and dependent older adults and to discuss the potential sleep disorders associated with frailty as well as their potential consequences on this weakened population. METHODS: A review task force was created including neurologists, geriatricians, sleep specialists and geriatric psychiatrists to discuss age related sleep disorders depending on the three categories of older adults. All published studies on sleep in older adults on Ovid Medline were reviewed and 106 articles were selected for the purpose of this consensus. RESULTS: Many healthy older adults have complains about their sleep such as waking not rested and too early, trouble falling asleep, daytime napping, and multiple nocturnal awakenings. Sleep architecture is modified by age with an increased percentage of time spent in stage one and a decreased percentage spent in stages three and four. Insomnia is frequent and its mechanisms include painful medical conditions, psychological distress, loss of physical activity and iatrogenic influences. Treatments are also involved in older adults' somnolence. The prevalence of primary sleep disorders such as restless legs syndrome, periodic limb movements and sleep disordered breathing increases with age. Potential outcomes relevant to these sleep disorders in old age include mortality, cardiovascular and neurobehavioral co-morbidities. Sleep in dependent older adults such as patients with Alzheimer Disease (AD) is disturbed. The sleep patterns observed in these patients are often similar to those observed in non-demented elderly but alterations are more severe. Nocturnal sleep disruption and daytime sleepiness are the main problems. They are the results of Sleep/wake circadian rhythm disorders, environmental, psychological and iatrogenic factors. They are worsened by other sleep disorders such as sleep disordered breathing. Sleep in frail older adults per se has not yet been formally studied but four axes of investigation should be considered: i) sleep architecture abnormalities, ii) insomnia iii) restless legs syndrome (RLS), iv) sleep disordered breathing. CONCLUSION: Our knowledge in the field of sleep disorders in older adults has increased in recent years, yet some groups within this heterogeneous population, such as frail older adults, remain to be more thoroughly studied and characterized.

Chitosan/copper nanocomposites: Correlation between electrical and antibacterial properties.

Correlation between electrical and antibacterial properties of chitosan/copper nanocomposites (CS/CuNPs) is investigated. We aim at achieving the minimum CuNPs concentration in a CS-matrix while keeping high antibacterial activity. UV-vis, TEM and XRD measurements confirms the formation of polygonal metallic CuNPs (ca. 30-50 nm). Interactions between NH2/OH groups of CS and CuNPs were determined by FTIR and XPS suggesting Cu chelation-induced mechanism during the CuNPs formation. DC electrical conductivity measurements reveals a percolation threshold at CuNPs volumetric concentration of ca. 0.143%. Antibacterial assays against Gram-positive bacteria and DC measurements helps correlate the antibacterial potency to the electron transfer between the negatively charged bacteria and CuNPs. Our study suggests that nanocomposite's maximum antibacterial activity is obtained below the electrical percolation threshold at extremely low CuNPs concentrations; this fact may prove useful in the design of nontoxic nanocomposites for biomedical applications.

Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage. / Efecto del inhibidor de amida hidrolasa de ácidos grasos en el daño neuronal dopaminérgico inducido por MPTP.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHODS: Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. RESULTS: Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. CONCLUSION: Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations.

Role of p38 MAPK and pro-inflammatory cytokines expression in glutamate-induced neuronal death of neonatal rats.

Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 rises significantly during neuronal damage and activate the signaling p38 MAPK pathway, which is involved in the apoptotic (AP) neuronal death. Systemic administration of glutamate as monosodium salt (MSG) to newborn animals induces neuronal death, however whether neurons die by AP or necrosis through MAPK p38 pathway activation it is unknown. In this study, TNF-alpha, IL-1beta and IL-6 expression levels, AP neuronal death and cellular type that produces TNF-alpha was also identified in the cerebral cortex (CC) and striatum (St) of rats at 8, 10, and 14 days of age after neonatal exposure to MSG. TNF-alpha production and AP neuronal death was significantly increased in the CC at PD8-10, and in the St in all ages studied by excitotoxicity effect induced with MSG. This effect was completely inhibited by SB203580 (p38 inhibitor) in both regions studied. TNF-alpha, IL-1beta and IL-6 RNAm increased after MSG administration, whereas SB203580 did not modify their expression. These data indicates that neuronal death induced by excitotoxicity appears to be mediated through p38 signaling pathway activated by TNF-alpha and their inhibition may have an important neuroprotective role as part of anti-inflammatory therapeutic strategy.

Takayasu arteritis: clinical features in 110 Mexican Mestizo patients and cardiovascular impact on survival and prognosis.

OBJECTIVE: Takayasu Arteritis (TA) is a rare disease that mainly affects large elastic arteries. It is more frequently seen in Asia, the Mediterranean basin, South Africa and Latin America. We have characterized its clinical manifestations and identified the cardiovascular mortality predictors in a cohort of 110 Mexican Mestizo patients. MATERIAL AND METHOD: Retrospective review of 110 charts of TA patients complying with the American College of Rheumatology (ACR) criteria, seen in a single hospital between 1976 and 2003. Demographic, clinical, and radiological characteristics were described. With the use of actuarial table analysis at 2, 5, and 10 years, and Kaplan Meier methods applying t function for probability, plus Cox regression analysis, the following factors were identified as mortality predictors: systemic arterial hypertension, coronary heart disease and aortic valve regurgitation. Informed consent and approval from the institutional Internal Review Board (IRB) were obtained. RESULTS: We observed a slowly progressive widespread obstructive arterial disease with cardiovascular (48%), neuro-ophthalmic (36%), and skin morbidity (13%). Systemic hypertension and heart disease were significant mortality predictors. Twenty-six percent of cases died due to myocardial infarction, chronic renal failure, stroke, or surgical complications. CONCLUSION: TA in Mexican Mestizos shows a clinical pattern similar to the one recognized in the Far East. Management strategies must be directed at reducing the identified mortality risk factors.

Combined antibacterial/tissue regeneration response in thermal burns promoted by functional chitosan/silver nanocomposites.

We report the combined antibacterial/tissue regeneration responses to thermal burns promoted by functional chitosan/silver nanocomposites (CS/nAg) with ultralow silver content (0.018wt.%, 7-30nm). Our approach allows one to produce CS/nAg nanocomposites without silver nanoparticles (nAg) agglomeration, with bactericide potency higher than 1wt.% of nAg (ca. 10nm) content and, promoting the healing process in controlled thermal burns. CS/nAg films exhibit high antibacterial activity against S. aureus and P. aeruginosa after 1.5h of incubation, demonstrating the bacterial penetration into hydrated films and their interaction with nAg. Additionally, exceptional healing of induced thermal burns was obtained by increasing myofibroblasts, collagen remodeling, and blood vessel neoformation. These factors are associated with epiderma regeneration after 7days of treatment with no nAg release. Our results corroborate the controlled synthesis of nAg embedded in CS matrix with combined antibacterial/biocompatibility properties aiming to produce functional nanocomposites with potential use in wound dressing and health care applications.

Neuronal damage and changes in the expression of muscarinic acetylcholine receptor subtypes in the neonatal rat cerebral cortical upon exposure to sparteine, a quinolizidine alkaloid.

Sparteine is a quinolizidine alkaloid (QA) produced by Lupine species that has generated much interest due to its anti-hypertensive, anti-pyretic, and anti-inflammatory properties. In the nervous system, sparteine has been shown to display anti-cholinergic and depressive activity, although how sparteine exerts its toxic effects in the brain remains unclear. We have addressed this issue by administering subcutaneous injections of sparteine (25 mg/kg of body weight) to rats on postnatal days 1 and 3, and then examining the expression of the muscarinic acetylcholine receptor (mAChR) subunits m1-m4 in the brains of the neonatal rats 14-60 days later. Administration of sparteine to neonatal rats caused neuronal damage in the cerebral motor cortex accompanied by transient changes in the expression of m1-m4 mAChR subunits as revealed by both RT-PCR and Western blotting. This effect could be prevented by pre-treatment with atropine (10 mg/kg) 1 h prior to the injection of sparteine, suggesting that the cytotoxic activity of sparteine is mediated through mAChRs.

Neuronal cell death due to glutamate excitotocity is mediated by p38 activation in the rat cerebral cortex.

Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4 mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42 microg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions.