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.

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.

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.

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.

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.

[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.

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.

Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease.

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin-treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid-ß deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin.

Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer's disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin.

BACKGROUND: cerebrolysin is a neuropeptide preparation mimicking the effects of neurotrophic factors. This subgroup analysis assessed safety and efficacy of Cerebrolysin in patients with moderate to moderately severe Alzheimer's disease (AD) (ITT data set: N = 133; MMSE: 14-20) included in a dose-finding study (ITT data set: N = 51; MMSE: 14-25). Results of the mild AD subgroup (ITT data set: N = 118; MMSE: 21-25) are also presented. METHODS: patients with AD received 100 ml IV infusions of Cerebrolysin (10, 30 or 60 ml diluted in saline; N = 32, 34 and 35, respectively) or placebo (saline; N = 32) over twelve weeks (5 days per week for 4 weeks and 2 days per week for another 8 weeks). Primary efficacy criteria ADAS-cog+ (Alzheimer's Disease Assessment Scale Cognitive Subpart Modified) and CIBIC+ (Clinical Interview-based Impression of Change with Caregiver Input) were assessed 24 weeks after baseline. RESULTS: at week 24, Cerebrolysin improved the global clinical function significantly with all three dosages and induced significant improvements in cognition, initiation of activities of daily living (ADL) and neuropsychiatric symptoms at 10-, 30- and 60-ml doses, respectively. Treatment effects on total ADL and other secondary parameters (MMSE, Trail-making test) were not significant. Cerebrolysin was safe and well tolerated. CONCLUSIONS: these results demonstrate the efficacy of Cerebrolysin in moderate to moderately severe AD, showing dose-specific effects similar to those reported for patients with mild to moderate AD. The benefits of Cerebrolysin in advanced AD need to be confirmed in larger trials.

Reactivation of latent tuberculosis in rhesus macaques by coinfection with simian immunodeficiency virus.

BACKGROUND: Tuberculosis (TB) and AIDS together present a devastating public health challenge. Over 3 million deaths every year are attributed to these twin epidemics. Annually, ∼11 million people are coinfected with HIV and Mycobacterium tuberculosis (Mtb). AIDS is thought to alter the spontaneous rate of latent TB reactivation. METHODOLOGY: Macaques are excellent models of both TB and AIDS. Therefore, it is conceivable that they can also be used to model coinfection. Using clinical, pathological, and microbiological data, we addressed whether latent TB infection in rhesus macaques can be reactivated by infection with simian immunodeficiency virus (SIV). RESULTS: A low-dose aerosol infection of rhesus macaques with Mtb caused latent, asymptomatic TB infection. Infection of macaques exhibiting latent TB with a rhesus-specific strain of SIV significantly reactivated TB. CONCLUSIONS: Rhesus macaques are excellent model of TB/AIDS coinfection and can be used to study the phenomena of TB latency and reactivation.

Quality of care of patients with type-2 diabetes in Galicia (NW Spain) [OBTEDIGA project].

AIMS: The aim of this study was to describe the degree of compliance of agreed practices with reference to primary care patients with Type 2 diabetes of 40 years old and older in Galicia (NW Spain). METHODS: A total of 108 primary care physicians were selected at random from the totality of doctors. Each physician selected 30 patients at random from their patients suffering from diabetes of 40 years old or older. External observers gathered information from each patient's medical record regarding their characteristics, condition and degree of compliance of selected indicators of good practice. RESULTS: Group of physicians participated in this study had a mean age of 50 years (standard deviation = 3.9); 48% of them were females; and 17.5% involved in medical residents training. A total of 3078 diabetic patients were included in the study: mean age = 69 years (SD = 10.9), 47.6% women, presence of high blood pressure (72%), hypercholesterolaemia (56%), and regular smokers (10.3%). Compliance with selected indicators such as foot examination (14%), ophthalmological examination (30.6%), abdominal circumference measurement (6.1%), measurement of total or LDL-cholesterol (78.1), blood pressure measurement (84.8), glycosylated haemoglobin measurement < 7% (54.3%) was observed. Adequate monitoring in cases of high blood pressure and hypercholesterolaemia were 34.2% and 27.4%, respectively. Variability between physicians differs according to the different indicators, with interquartile range for compliance of between 16.4 and 66%. CONCLUSIONS: There is a wide margin for improvement in the adaptation of clinical practice to recommendations for diabetic patients. The large variation existing in certain indicators would suggest that certain control objectives are less demanding than advisable in those that comply least, while low compliance and low variability in other indicators point to structural problems or unsatisfactory training of doctors.

Inhibition of intracellular transport of B cell antigen receptor complexes by Kaposi's sarcoma-associated herpesvirus K1.

The B cell antigen receptor (BCR) is a large complex that consists of a disulfide-linked tetramer of two transmembrane heavy (mu) chains and two light (lambda or kappa) chains in association with a heterodimer of Igalpha and Igbeta. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a transforming protein called K1, which has structural and functional similarity to Igalpha and Igbeta. We demonstrate that K1 downregulates the expression of BCR complexes on the surface. The NH(2)-terminal region of K1 specifically interacts with the mu chains of BCR complexes, and this interaction retains BCR complexes in the endoplasmic reticulum, preventing their intracellular transport to the cell surface. Thus, KSHV K1 resembles Igalpha and Igbeta in its ability to induce signaling and to interact with mu chains of the BCR. However, unlike Igalpha and Igbeta, which interact with mu chains to direct BCR complexes to the cell surface, K1 interacts with mu chains to block the intracellular transport of BCR complexes to the cell surface. These results demonstrate a unique feature of the K1 transforming protein, which may confer virus-infected cells with a long-term survival advantage.

Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS.

The macrophage is well established as a target of HIV and simian immunodeficiency virus (SIV) infection and a major contributor to the neuropathogenesis of AIDS. However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined. We demonstrate that the perivascular macrophage and not the parenchymal microglia is the primary cell productively infected by SIV. We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS. The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

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.

Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.

According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimer's disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.

A pilot study to evaluate the effects of Cerebrolysin on cognition and qEEG in vascular dementia: cognitive improvement correlates with qEEG acceleration.

The effects of the neurotrophic compound Cerebrolysin (Cere) on cognitive performance, evaluated with the ADAS-cog, and on qEEG activity were investigated in forty one patients with mild to moderate severe probable vascular dementia (VaD) according to NINDS-AIREN criteria, included in a placebo-controlled pilot study. Patients received i.v. infusions of Cere (10 or 30 ml) or placebo (normal saline) 5 days/week for 4 weeks. Mean score of change from baseline in the ADAS-cog and percent change from baseline in slow to fast EEG power ratio (PR) scores were the two primary endpoints. Correlations between cognition and qEEG were also evaluated for both baseline scores and for scores of change from baseline in ADAS-cog and in qEEG parameters, including EEG power ratio (PR) as an index of EEG slowing. Baseline ADAS-cog scores showed significant positive correlations with delta power, theta power and PR scores, and correlated negatively with alpha activity. These correlations indicating that an increased EEG slowing is associated with a worst cognitive performance in VaD patients. Cere treatment improved cognitive performance significantly at the 10 ml dose and reduced EEG slowing with both 10 and 30 ml dosages. A significant positive correlation between PR and ADAS-cog scores of change from baseline was observed in Cere-treated patients. According to results of this pilot study, it is concluded that Cere improves cognitive performance and reduces EEG slowing in patients with VaD, and that there is a positive relationship between changes in cognition and qEEG activity induced by Cere. The conduction of further regular clinical trials is required to confirm the potential utility of Cere in the treatment of VaD suggested by the present results.

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.

Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor.

Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcomas, body cavity-based lymphomas, and some forms of Castleman's disease. The K9 open reading frame of KSHV encodes a viral interferon regulatory factor (vIRF) which functions as a repressor for cellular interferon-mediated signal transduction and as an oncogene to induce cell growth transformation. We demonstrate that KSHV vIRF directly interacts with cellular transcriptional coactivator p300 and displaces p300/CBP-associated factor from p300 complexes. This interaction inhibits the histone acetyltransferase activity of p300, resulting in drastic reduction of nucleosomal histone acetylation and alteration of chromatin structure. As a consequence, vIRF expression markedly alters cellular cytokine expression, which is regulated by acetylation of nucleosomal histones. These results demonstrate that KSHV vIRF interacts with and inhibits the p300 transcriptional coactivator to circumvent the host antiviral immune response and to induce a global alteration of cellular gene expression. These studies also illustrate how a cellular gene captured by a herpesvirus has evolved several functions that suit the needs of the virus.