Impact of COVID-19 on mental health of health care workers in Spain: a mix-methods study.

BACKGROUND: Spain's lockdown measures couldn't prevent the severe impact of the COVID-19 first wave, leading to high infections, deaths, and strain on healthcare workers (HCWs). This study aimed to explore the mental health impact on HCWs in the Balearic Islands during the initial months of the pandemic, the influencing factors, and the experiences of those in a COVID-19 environment. METHODS: Using a mixed-methods approach, the study encompassed quantitative and qualitative elements. Cross-sectional survey data from April to June 2020 comprised HCWs who were emailed invitations. The survey covered demographics, work, clinical and COVID-19 variables, along with psychological distress and PTSD symptoms, using validated measures. Additionally, semi-structured interviews with HCWs offered qualitative insights. RESULTS: Three hundred thirty-six HCWs averaging 46.8 years, mainly women (79.2%), primarily nurses in primary care with over 10 years of experience. Anxiety symptoms were reported by 28.8%, 65.1% noted worsened sleep quality, and 27.7% increased psychoactive drug usage. Psychological distress affected 55.2%, while 27.9% exhibited PTSD symptoms. Gender, age, experience, COVID-19 patient contact, and workload correlated with distress, PTSD symptoms, sleep quality, and psychoactive drug usage. Interviews uncovered discomfort sources, such as fear of infection and lack of control, leading to coping strategies like information avoidance and seeking support. LIMITATIONS: Static cross-sectional design, non-probabilistic sample, and telephone interviews affecting non-verbal cues, with interviews conducted during early pandemic lockdown. CONCLUSIONS: HCWs faced significant psychological distress during the pandemic's first wave, underscoring the necessity for robust support and resources to counteract its impact on mental health.

Experiencia de 20 años en el control de la hipertensión arterial en un centro de salud en España: control estricto versus no estricto / Twenty-year experience in strict versus non-strict control of arterial hypertension in a health center in Spain

Introducción y objetivos En los ensayos clínicos la reducción eficaz de la presión arterial (PA) produce una disminución de la incidencia de la morbimortalidad cardiovascular (CV). Nuestro objetivo principal es conocer si en las condiciones reales de la práctica clínica el control de la PA reduce a largo plazo los eventos CV. Pacientes y métodos El estudio se realizó en 164 pacientes con hipertensión arterial (HTA) elegidos entre los pacientes que acudían a las consultas de medicina de familia por HTA. Se hizo un análisis entre los pacientes que presentaban una PA clínica inferior a 140/90mmHg y los que la tenían más elevada. Los pacientes se seguían hasta que se producía un evento CV o hasta un máximo de 20 años, en que se finalizaba el seguimiento. Resultados Del total de los 164 pacientes alcanzaron un buen control clínico de la HTA 93 (56,7%) pacientes y no lo alcanzaron 71 (42,2%). En el análisis multivariante quedó únicamente como variable predictora de eventos CV la falta de control estricto de la HTA (HR: 2,93; IC 95%: 1,45-5,89; p=0,003), y el sexo femenino fue protector para eventos CV (HR: 0,37; IC 95%: 0,18-0,74; p=0,005) Conclusiones La variable predictora fundamental de morbimortalidad CV en pacientes con HTA es la falta de control estricto de la HTA; las mujeres también tuvieron menos complicaciones CV (AU)

Introduction and aims During clinical trials effective reduction of blood pressure (BP) leads to a reduction in the incidence of cardiovascular (CV) morbimortality. Our main aim is to ascertain whether, under actual conditions of clinical practice, BP monitoring leads to a long-term reduction in CV events. Patients and methods The study was performed on 164 patients with hypertension (HT) selected among patients who came to family medicine consultations because of HT. An analysis was performed between patients who presented clinical BP lower than 140/90mmHg and those that had higher levels. When patients entered the study, they were followed up until a CV event occurred or up to a maximum of 20 years, at which time follow up ended. Results Of the total of 164 patients, good control of BP was attained by 93 (56.7%), and 71 did not attain good control (42.2%). In the multivariate analysis, the only predictive variable for CV events was the lack of strict control of BP (HR: 2.93; 95% CI: 1.45-5.89; p=0.003), and the female sex was protective for CV events (HR: 0.37; 95% CI: 0.18-0.74; p=0.005). Conclusions The fundamental predictor variable of CV morbimortality in patients with HT is the lack of HT strict control; the women also had fewer CV complications (AU)

[Twenty-year experience in strict versus non-strict control of arterial hypertension in a health center in Spain]. / Experiencia de 20 años en el control de la hipertensión arterial en un centro de salud en España: control estricto versus no estricto.

INTRODUCTION AND AIMS: During clinical trials effective reduction of blood pressure (BP) leads to a reduction in the incidence of cardiovascular (CV) morbimortality. Our main aim is to ascertain whether, under actual conditions of clinical practice, BP monitoring leads to a long-term reduction in CV events. PATIENTS AND METHODS: The study was performed on 164 patients with hypertension (HT) selected among patients who came to family medicine consultations because of HT. An analysis was performed between patients who presented clinical BP lower than 140/90mmHg and those that had higher levels. When patients entered the study, they were followed up until a CV event occurred or up to a maximum of 20 years, at which time follow up ended. RESULTS: Of the total of 164 patients, good control of BP was attained by 93 (56.7%), and 71 did not attain good control (42.2%). In the multivariate analysis, the only predictive variable for CV events was the lack of strict control of BP (HR: 2.93; 95% CI: 1.45-5.89; p=0.003), and the female sex was protective for CV events (HR: 0.37; 95% CI: 0.18-0.74; p=0.005). CONCLUSIONS: The fundamental predictor variable of CV morbimortality in patients with HT is the lack of HT strict control; the women also had fewer CV complications.

Descripción de un caso de angioedema hereditario dependiente de estrógenos / A case description of oestrogen-dependent inherited angioedema

Introducción: El angioedema hereditario es una enfermedad genética rara que carece de tratamiento específico. Principales síntomas: Se caracteriza por la aparición recurrente de episodios de edema que afectan fundamentalmente a piel y mucosa. Diagnósticos principales: Existen tres tipos de angioedema hereditario, habiéndose relacionado el tipo III con situaciones que presentan niveles elevados de estrógenos. Intervenciones terapéuticas: Exponemos el caso de una paciente con angioedema hereditario tipo III, que presenta crisis de angioedema coinciciendo con el periodo periovulatorio y premenstrual. Ante dicha relación hormonal, se pautó terapia con gestágenos para intentar reducir el número de ovulaciones. Resultados: Tras varios meses en tratamiento con desogestrel la paciente refiere disminución del número y gravedad de las crisis. Conclusión: La terapia con gestágenos parece resultar útil en el control de los episodios de angioedema hereditario tipo III.(AU)

Introduction: Hereditary angioedema is a rare genetic disease without any specific treatment. Main symptoms: It is characterized by recurrent episodes of skin and mucous oedema. Main diagnoses: There are three types of angioedema and type III has been related to high-level oestrogen conditions. Therapeutic interventions: We describe the case of a patient with hereditary angioedema type III, who had an episode of angioedema associated with the periovulatory and premenstrual period. Due to this hormonal influence, we used gestagen therapy to attempt to reduce the number of ovulations. Results: After several months of treatment with desogestrel, the patient reports a decrease in the number and severity of episodes. Conclusion: Gestagen therapy seems to be useful for controlling episodes of hereditary angioedema type III.(AU)

Modulation of Amyloid-ß and Tau in Alzheimer's Disease Plasma Neuronal-Derived Extracellular Vesicles by Cerebrolysin® and Donepezil.

BACKGROUND: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. OBJECTIVE: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. METHODS: Plasma NDEV levels of Aß42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. RESULTS: NDEV levels of Aß42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aß42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aß42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). CONCLUSION: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.

Clinical Efficacy of Cerebrolysin and Cerebrolysin plus Nootropics in the Treatment of Patients with Acute Ischemic Stroke in Vietnam.

AIMS: To investigate the efficacy and safety of Cerebrolysin and Cerebrolysin plus nootropics in the routine treatment of patients with acute ischemic stroke (AIS). BACKGROUND: Acute ischemic stroke (AIS) is a leading cause of disability with unmet treatment needs lacking effective drug therapy. Multimodal drugs modulating stroke pathophysiology as Cerebrolysin constitute a good therapeutic option. OBJECTIVE: In this study, we assessed the effects of Cerebrolysin and Cerebrolysin plus nootropics, in comparison with other nootropic drugs alone, on functional, neurological and cognitive recovery of patients with AIS in Vietnam. METHODS: This non-interventional, controlled, open-label, prospective and multicenter study included 398 AIS patients (234 males) treated with Cerebrolysin (n=190; 20 i.v. infusions of 10 ml), other nootropics (comparator group; n=86), or a combination of both (n=122). The study primary endpoint was the modified Ranking Scale (mRS) score on day 90. Secondary endpoints included study-period change in NIHSS score; percentage of well-recovered (mRS 0-2) patients, the proportion of good NIHSS response (≥6 points) cases, and MoCA scores at day 90; and safety indicators. RESULTS: Compared with other nootropics, both Cerebrolysin and combined therapy induced significant improvements (p<0.001) in: Functional recovery (mRS scores); percentage of well-recovered patients (Cerebrolysin: 81.6%; combination: 93.4%; comparator: 43.0%); neurological recovery (study- period NIHSS change); proportion of good NIHSS responders (Cerebrolysin: 77.5%; combination: 92.5%; comparator: 47.6%); and MoCA scores (Cerebrolysin: 23.3±4.8; combination: 23.7±4.1; comparator: 15.9±7.7). Compared to Cerebrolysin, combined therapy improved (p<0.01) mRS outcomes and NIHSS change, but not MoCA scores, in moderate-severe stroke (NIHSS>11) cases only. No drug-related adverse events were reported. CONCLUSION: Cerebrolysin alone or combined with other nootropics was effective and safe in routine AIS treatment, during both acute and recovery phases, which supports its use in daily clinical practice. Others: According to the results of this multicenter study, the importance of reducing differences in the treatment regimens of AIS in Vietnam should be further emphasized.

Serum VEGF Predicts Clinical Improvement Induced by Cerebrolysin Plus Donepezil in Patients With Advanced Alzheimer's Disease.

Serum vascular endothelial growth factor (VEGF) increases with Alzheimer's disease (AD) severity and may prevent cognitive decline. However, information on the influence of AD drug therapy on circulating VEGF is limited. This study assessed changes in serum VEGF levels and its association with clinical and functional responses in mild to moderate AD patients who were treated with Cerebrolysin, donepezil, or the combined therapy in a randomized, controlled trial. Treatment with Cerebrolysin plus donepezil reduced elevated serum VEGF levels and improved functioning and cognition significantly compared with donepezil alone in patients with advanced AD, and treatment differences were more pronounced in patients with higher VEGF levels. Our results indicate that the combined therapy reversed the increase of serum VEGF in advanced AD, which was associated with cognitive and functional responses, particularly in patients with high baseline VEGF.

Cierre de orejuela en pacientes con hemorragia intracraneal y fibrilación auricular / Left atrial appendage closure in patients with intracranial haemorrhage and atrial fibrillation

INTRODUCCIÓN: El uso de anticoagulantes orales es controvertido en pacientes con antecedentes de fibrilación auricular (FA) y hemorragia intracraneal (HIC), por riesgo de recurrencia de ictus hemorrágico. Presentamos la experiencia de nuestro centro en relación con la seguridad y la eficacia del cierre percutáneo de orejuela (CPO), una alternativa a la anticoagulación en dicho contexto. MÉTODOS: Estudio observacional, retrospectivo y unicéntrico. El CPO se realizó en pacientes con antecedentes de HIC y FA no valvular. El riesgo de eventos isquémicos y hemorrágicos se estimó usando las escalas CHA2DS2Vasc y HAS-BLED. Se registraron: complicaciones periprocedimiento, recurrencia de HIC, embolismo cerebral/sistémico, mortalidad tras el cierre y al seguimiento y uso de antitrombóticos tras el procedimiento. RESULTADOS: El CPO se realizó en 9 pacientes (7 hombres, 2 mujeres). Se utilizó en 7 casos el dispositivo Amplatzer Amulet y en 2 el Amplatzer Cardiac Plug. La media de edad fue 72,7 ± 8,2 años. El tiempo entre la HIC y el CPO fue menor de un mes en 5 pacientes y mayor en 4. La mediana y el rango intercuartil para la escala CHA2DS2Vasc fueron de 4 y 2,5, respectivamente, siendo de 3 y 0 para la escala HAS-BLED. No hubo complicaciones periprocedimiento. Todos recibieron antiagregación simple tras el procedimiento (5 clopidogrel y 4 aspirina); en 5 se mantuvo 6 meses, en 4 indefinidamente. Durante el seguimiento (15 meses de promedio) no se registraron eventos isquémicos ni hemorrágicos. CONCLUSIONES: En nuestra serie, el CPO supone una alternativa segura y eficaz en pacientes que han presentado HIC y que precisan ser anticoagulados por FA

INTRODUCTION: The use of oral anticoagulants in patients with a history of atrial fibrillation (AF) and intracranial haemorrhage (ICH) is controversial on account of the risk of haemorrhagic stroke recurrence. This study presents our experience regarding the safety and efficacy of percutaneous left atrial appendage closure (LAAC), an alternative to anticoagulation in these patients. METHODS: We conducted a retrospective, single-centre, observational study. LAAC was performed in patients with a history of ICH and non-valvular AF. Risk of ischaemic and haemorrhagic events was estimated using the CHA2DS2-VASc and HAS-BLED scales. We recorded periprocedural complications, IHC recurrence, cerebral/systemic embolism, mortality and use of antithrombotic drugs following the procedure. RESULTS: LAAC was performed in 9 patients (7 men, 2 women) using the AMPLATZER Amulet device in 7 cases and the AMPLATZER Cardiac Plug device in 2. Mean age was 72.7 ± 8.2 years. Time between ICH and LAAC was less than one month in 5 patients and more than one month in 4 patients. Median CHA2DS2-VASc score was 4 (interquartile range of 2.5). Median HAS-BLED score was 3 (interquartile range of 0). No periprocedural complications were recorded. All patients received single anti-platelet therapy (clopidogrel in 5 patients, aspirin in 4) after the procedure; 5 patients received this treatment for 6 months and 4 received it indefinitely. No ischaemic or haemorrhagic events were recorded during follow-up (mean duration of 15 months). CONCLUSIONS: In our series, LAAC was found to be safe and effective in patients with a history of ICH who required anticoagulation due to AF

Left atrial appendage closure in patients with intracranial haemorrhage and atrial fibrillation. / Cierre de orejuela en pacientes con hemorragia intracraneal y fibrilación auricular.

INTRODUCTION: The use of oral anticoagulants in patients with a history of atrial fibrillation (AF) and intracranial haemorrhage (ICH) is controversial on account of the risk of haemorrhagic stroke recurrence. This study presents our experience regarding the safety and efficacy of percutaneous left atrial appendage closure (LAAC), an alternative to anticoagulation in these patients. METHODS: We conducted a retrospective, single-centre, observational study. LAAC was performed in patients with a history of ICH and non-valvular AF. Risk of ischaemic and haemorrhagic events was estimated using the CHA2DS2-VASc and HAS-BLED scales. We recorded periprocedural complications, IHC recurrence, cerebral/systemic embolism, mortality and use of antithrombotic drugs following the procedure. RESULTS: LAAC was performed in 9 patients (7 men, 2 women) using the AMPLATZER Amulet device in 7 cases and the AMPLATZER Cardiac Plug device in 2. Mean age was 72.7±8.2 years. Time between ICH and LAAC was less than one month in 5 patients and more than one month in 4 patients. Median CHA2DS2-VASc score was 4 (interquartile range of 2.5). Median HAS-BLED score was 3 (interquartile range of 0). No periprocedural complications were recorded. All patients received single anti-platelet therapy (clopidogrel in 5 patients, aspirin in 4) after the procedure; 5 patients received this treatment for 6 months and 4 received it indefinitely. No ischaemic or haemorrhagic events were recorded during follow-up (mean duration of 15 months). CONCLUSIONS: In our series, LAAC was found to be safe and effective in patients with a history of ICH who required anticoagulation due to AF.

A western route of prehistoric human migration from Africa into the Iberian Peninsula.

Being at the western fringe of Europe, Iberia had a peculiar prehistory and a complex pattern of Neolithization. A few studies, all based on modern populations, reported the presence of DNA of likely African origin in this region, generally concluding it was the result of recent gene flow, probably during the Islamic period. Here, we provide evidence of much older gene flow from Africa to Iberia by sequencing whole genomes from four human remains from northern Portugal and southern Spain dated around 4000 years BP (from the Middle Neolithic to the Bronze Age). We found one of them to carry an unequivocal sub-Saharan mitogenome of most probably West or West-Central African origin, to our knowledge never reported before in prehistoric remains outside Africa. Our analyses of ancient nuclear genomes show small but significant levels of sub-Saharan African affinity in several ancient Iberian samples, which indicates that what we detected was not an occasional individual phenomenon, but an admixture event recognizable at the population level. We interpret this result as evidence of an early migration process from Africa into the Iberian Peninsula through a western route, possibly across the Strait of Gibraltar.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers.

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

The loss of CCR6+ and CD161+ CD4+ T-cell homeostasis contributes to disease progression in SIV-infected rhesus macaques.

Although previous studies have shown that CD4+ T cells expressing CCR6 and CD161 are depleted from blood during HIV infection, the mechanisms underlying their loss remain unclear. In this study, we investigated how the homeostasis of CCR6+ and CD161+ CD4+ T cells contributes to SIV disease progression and the mechanisms responsible for their loss from circulation. By comparing SIV infection in rhesus macaques (RMs) and natural host sooty mangabeys (SMs), we found that the loss of CCR6+ and CD161+ CD4+ T cells from circulation is a distinguishing feature of progressive SIV infection in RMs. Furthermore, while viral infection critically contributes to the loss of CD161+CCR6-CD4+ T cells, a redistribution of CCR6+CD161- and CCR6+CD161+CD4+ T cells from the blood to the rectal mucosa is a chief mechanism for their loss during SIV infection. Finally, we provide evidence that the accumulation of CCR6+CD4+ T cells in the mucosa is damaging to the host by demonstrating their reduction from this site following initiation of antiretroviral therapy in SIV-infected RMs and their lack of accumulation in SIV-infected SMs. These data emphasize the importance of maintaining CCR6+ and CD161+ CD4+ T-cell homeostasis, particularly in the mucosa, to prevent disease progression during pathogenic HIV/SIV infection.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases.

BACKGROUND: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer's disease. METHODS: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer's disease patients. RESULTS: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. CONCLUSION: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer's disease cases with apolipoprotein E epsilon-4 allele.

The DEP-6D, a new preference-based measure to assess health states of dependency.

In medical literature there are numerous multidimensional scales to measure health states for dependence in activities of daily living. However, these scales are not preference-based and are not able to yield QALYs. On the contrary, the generic preference-based measures are not sensitive enough to measure changes in dependence states. The objective of this paper is to propose a new dependency health state classification system, called DEP-6D, and to estimate its value set in such a way that it can be used in QALY calculations. DEP-6D states are described as a combination of 6 attributes (eat, incontinence, personal care, mobility, housework and cognition problems), with 3-4 levels each. A sample of 312 Spanish citizens was surveyed in 2011 to estimate the DEP-6D preference-scoring algorithm. Each respondent valued six out of the 24 states using time trade-off questions. After excluding those respondents who made two or more inconsistencies (6% out of the sample), each state was valued between 66 and 77 times. The responses present a high internal and external consistency. A random effect model accounting for main effects was the preferred model to estimate the scoring algorithm. The DEP-6D describes, in general, more severe problems than those usually described by means of generic preference-based measures. The minimum score predicted by the DEP-6D algorithm is -0.84, which is considerably lower than the minimum value predicted by the EQ-5D and SF-6D algorithms. The DEP-6D value set is based on community preferences. Therefore it is consistent with the so-called 'societal perspective'. Moreover, DEP-6D preference weights can be used in QALY calculations and cost-utility analysis.

Spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques.

Innate immune responses have a critical role in the control of early virus replication and dissemination. It remains unknown, however, how severe acute respiratory syndrome coronavirus (SARS-CoV) evades respiratory innate immunity to establish a systemic infection. Here we show in Chinese macaques that SARS-CoV traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by T cells, MAC387(+), and CD163(+) monocytes/macrophages followed by limited viral replication in the lung but persistent viral shedding into the upper airway. Mucosal monocytes/macrophages sequestered virions in intracellular vesicles together with infected Langerhans cells and migrated into the tonsils and/or draining lymph nodes within 2 days. In lymphoid tissues, viral RNA and proteins were detected in infected monocytes upon differentiation into dendritic cells (DCs) within 3 days. Systemic viral dissemination was observed within 7 days. This study provides a comprehensive overview of the spatiotemporal interactions of SARS-CoV, monocytes/macrophages, and the DC network in mucosal tissues and highlights the fact that, while these innate cells contribute to viral clearance, they probably also serve as shelters and vehicles to provide a mechanism for the virus to escape host mucosal innate immunity and disseminate systemically.

Glycosomal targets for anti-trypanosomatid drug discovery.

Glycosomes are peroxisome-related organelles found in all kinetoplastid protists, including the human pathogenic species of the family Trypanosomatidae: Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Glycosomes are unique in containing the majority of the glycolytic/gluconeogenic enzymes, but they also possess enzymes of several other important catabolic and anabolic pathways. The different metabolic processes are connected by shared cofactors and some metabolic intermediates, and their relative importance differs between the parasites or their distinct lifecycle stages, dependent on the environmental conditions encountered. By genetic or chemical means, a variety of glycosomal enzymes participating in different processes have been validated as drug targets. For several of these enzymes, as well as others that are likely crucial for proliferation, viability or virulence of the parasites, inhibitors have been obtained by different approaches such as compound libraries screening or design and synthesis. The efficacy and selectivity of some initially obtained inhibitors of parasite enzymes were further optimized by structure-activity relationship analysis, using available protein crystal structures. Several of the inhibitors cause growth inhibition of the clinically relevant stages of one or more parasitic trypanosomatid species and in some cases exert therapeutic effects in infected animals. The integrity of glycosomes and proper compartmentalization of at least several matrix enzymes is also crucial for the viability of the parasites. Therefore, proteins involved in the assembly of the organelles and transmembrane passage of substrates and products of glycosomal metabolism offer also promise as drug targets. Natural products with trypanocidal activity by affecting glycosomal integrity have been reported.

Effect of an educational intervention in primary care physicians on the compliance of indicators of good clinical practice in the treatment of type 2 diabetes mellitus [OBTEDIGA project].

AIM: To evaluate the effect of an educational intervention among primary care physicians on several indicators of good clinical practice in diabetes care. METHODS: Two groups of physicians were randomly assigned to the intervention or control group (IG and CG). Every physician randomly selected two samples of patients from all type 2 diabetic patients aged 40 years and above and diagnosed more than a year ago. Baseline and final information were collected cross-sectionally 12 months apart, in two independent samples of 30 patients per physician. The educational intervention comprised: distribution of educational materials and physicians' specific bench-marking information, an on-line course and three on-site educational workshops on diabetes. External observers collected information directly from the physicians and from the medical records of the patients on personal and family history of disease and on the evolution and treatment of their disease. Baseline information was collected retrospectively in the control group. RESULTS: Intervention group comprised 53 physicians who included a total of 3018 patients in the baseline and final evaluations. CG comprised 50 physicians who included 2868 patients in the same evaluations. Measurement of micro-albuminuria in the last 12 months (OR = 1.6, 95% CI: 1.1-2.4) and foot examination in the last year (OR = 2.0, 95% CI: 1.1-3.6) were the indicators for which greater improvement was found in the IG. No other indicator considered showed statistically significant improvement between groups. CONCLUSIONS: The identification of indicators with very low level of compliance and the implementation of a simple intervention in physicians to correct them is effective in improving the quality of care of diabetic patients.

Cerebrolysin in Alzheimer's disease.

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on ß-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 ß intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.