A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism.

Induction of neuroprotective heat-shock proteins via pharmacological Hsp90 inhibitors is currently being investigated as a potential treatment for neurodegenerative diseases. Two major hurdles for therapeutic use of Hsp90 inhibitors are systemic toxicity and limited central nervous system permeability. We demonstrate here that chronic treatment with a proprietary Hsp90 inhibitor compound (OS47720) not only elicits a heat-shock-like response but also offers synaptic protection in symptomatic Tg2576 mice, a model of Alzheimer's disease, without noticeable systemic toxicity. Despite a short half-life of OS47720 in mouse brain, a single intraperitoneal injection induces rapid and long-lasting (>3 days) nuclear activation of the heat-shock factor, HSF1. Mechanistic study indicates that the remedial effects of OS47720 depend upon HSF1 activation and the subsequent HSF1-mediated transcriptional events on synaptic genes. Taken together, this work reveals a novel role of HSF1 in synaptic function and memory, which likely occurs through modulation of the synaptic transcriptome.

Practical Guidelines for Perioperative Hypersensitivity Reactions.

Perioperative hypersensitivity reactions constitute a first-line problem for anesthesiologists and allergists. Therefore, hospitals should have a consensus protocol for the diagnosis and management of these reactions. However, this kind of protocol is not present in many hospitals, leading to problems with treatment, reporting of incidents, and subsequent etiological diagnosis. In this document, we present a systematic review of the available scientific evidence and provide general guidelines for the management of acute episodes and for referral of patients with perioperative hypersensitivity reactions to allergy units. Members of the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC) have created this document in collaboration with members of the Spanish Anesthesia Society (SEDAR). A practical algorithm is proposed for the etiologic diagnosis, and recommendations are provided for the management of hypersensitive patients.

Comparison of an in-house real-time RT-PCR assay with a commercial assay for detection of enterovirus RNA in clinical samples.

Molecular detection of enterovirus (EV) RNA based on PCR methods is a quicker and more sensitive approach than culture methods. At present, different PCR-based methods for EV RNA detection are available, but comparisons of results obtained according to the different approaches are limited. We evaluated an in-house real-time RT-PCR assay with a commercialized TaqMan real-time RT-PCR kit for detection of EV. Consecutive clinical specimens from paediatric patients less than 6 years old with clinical suspicion of EV infection were analyzed between July and November 2010. After RNA extraction, samples were amplified both by the real-time RT-PCR commercial assay and the in-house assay. A total of 19 of 132 patients (14.4%) involving 20 samples (14 plasma samples and 6 CSF) were positive in at least one of the two assays. The sensitivity of the in-house assay when the MutaPLATE® assay was used as a reference was 90% (IC 95%; 74.35-100) and the specificity was 100% (IC 95%; 99.63-100). Cts results of two methods were statistically correlated (r = 0.774; P = 0.01). In conclusion, these two real-time RT-PCR assays are rapid and easy methods for detection of EV.

Development, equivalence study, and normative data of version B of the Spanish-language Free and Cued Selective Reminding Test.

INTRODUCTION: The Free and Cued Selective Reminding Test (FCSRT) is widely used for the assessment of verbal episodic memory, mainly in patients with Alzheimer disease. A Spanish-language version of the FCSRT and normative data were developed within the NEURONORMA project. Availability of alternative, equivalent versions is useful for following patients up in clinical settings. This study aimed to develop an alternative version of the original FCSRT (version B) and to study its equivalence to the original Spanish-language test (version A), and its performance in a sample of healthy individuals, in order to develop reference data. METHODS: We evaluated 232 healthy participants of the NEURONORMA-Plus project, aged between 18 and 90. Thirty-three participants were assessed with both test versions using a counterbalanced design. RESULTS: High intra-class correlation coefficients (between 0.8 and 0.9) were observed in the equivalence study. While no significant differences in performance were observed in total recall scores, free recall scores were significantly lower for version B. CONCLUSIONS: These preliminary results suggest that the newly developed FCSRT version B is equivalent to version A in the main variables tested. Further studies are necessary to ensure interchangeability between versions. We provide normative data for the new version.

[Postoperative nausea and vomiting and opioid-induced nausea and vomiting: guidelines for prevention and treatment]. / Recomendaciones de prevención y tratamiento de las náuseas y vómitos postoperatorios y/o asociados a las infusiones de opioides.

Postoperative nausea and vomiting (PONV) causes patient discomfort, lowers patient satisfaction, and increases care requirements. Opioid-induced nausea and vomiting (OINV) may also occur if opioids are used to treat postoperative pain. These guidelines aim to provide recommendations for the prevention and treatment of both problems. A working group was established in accordance with the charter of the Sociedad Española de Anestesiología y Reanimación. The group undertook the critical appraisal of articles relevant to the management of PONV and OINV in adults and children early and late in the perioperative period. Discussions led to recommendations, summarized as follows: 1) Risk for PONV should be assessed in all patients undergoing surgery; 2 easy-to-use scales are useful for risk assessment: the Apfel scale for adults and the Eberhart scale for children. 2) Measures to reduce baseline risk should be used for adults at moderate or high risk and all children. 3) Pharmacologic prophylaxis with 1 drug is useful for patients at low risk (Apfel or Eberhart 1) who are to receive general anesthesia; patients with higher levels of risk should receive prophylaxis with 2 or more drugs and baseline risk should be reduced (multimodal approach). 4) Dexamethasone, droperidol, and ondansetron (or other setrons) have similar levels of efficacy; drug choice should be made based on individual patient factors. 5) The drug prescribed for treating PONV should preferably be different from the one used for prophylaxis; ondansetron is the most effective drug for treating PONV. 6) Risk for PONV should be assessed before discharge after outpatient surgery or on the ward for hospitalized patients; there is no evidence that late preventive strategies are effective. 7) The drug of choice for preventing OINV is droperidol.

Harms and benefits of lymphocyte subpopulations in patients with acute stroke.

UNLABELLED: Lymphocytes are major players in the development of innate and adaptive immune responses but their behavior in patients with acute stroke has received little attention. EXPERIMENTAL PROCEDURES: Using flow cytometry we identified total lymphocytes, T cells, helper T (Th) cells, cytotoxic T lymphocytes (CTL), natural killer (NK) cells, B cells, and regulatory T (Treg) cells in 46 consecutive patients with acute stroke within a median of 180 min of clinical onset, and at days 2, 7, and 90. Daily neurological score (National Institutes of Health Stroke Scale), diffusion-weighted imaging on brain magnetic resonance imaging, functional impairment, and stroke-associated infection (SAI) at day 7 were assessed. Apoptosis in lymphocyte subsets, tumor necrosis factor (TNF) -alpha/interleukin (IL) -4 production in stimulated Th and CTL, cluster of differentiation 86 (CD86) (B7-2) expression in B cells, cortisol and metanephrine in serum were measured. Multivariate analyses were used to evaluate SAI, and stroke outcome. RESULTS: Increased apoptosis and a fall of T, Th, CTL, B, and Treg cells were observed after stroke. Severer stroke on admission and SAI disclosed a greater decline of T, Th, and CTL cells. Increased cortisol and metanephrine was associated with severe stroke and SAI, and inversely correlated with T, and CTL. T cells, and CTL were correlated with infarct growth. Stroke but not SAI resulted in lower TNF-alpha production in Th cells. SAI showed the greatest fall of lymphocytes, T, Th, and CTL, but not B cells, or Treg. Poor outcome was associated with reduced levels of B cells, and increased expression of CD86 in B cells, but not with SAI. CONCLUSION: Lymphopenia and increased apoptosis of T, Th, CTL, Treg and B cells are early signatures after human stroke. A decreased cellular response after stroke is a marker of ongoing brain damage, the stress response, and a higher risk of infection. A lower humoral response is predictor of poorer long-term outcome.

Performance of laser fluorescence for detection of occlusal dentinal caries lesions in permanent molars: an in vivo study with total validation of the sample.

The objective of this in vivo study was to evaluate the performance of a laser fluorescence device in detecting dentinal caries in noncavitated occlusal surfaces. The sample included 102 first and second permanent molars, selected according to the criteria of Ekstrand et al. [Caries Res 1997;31:224-231]: 46 not suspected of having dentinal caries (score: 0-2) and 56 under suspicion (score: 3-4). Once measured by laser fluorescence, all were validated by fissurotomy (gold standard). To avoid ethical questions, the 46 teeth (score: 0-2) used were to serve as abutments for a fixed-fixed bridge. Visual inspection performed well, showing a sensitivity and specificity of 0.93 and 0.88, respectively. Laser fluorescence had an area under the receiver operating characteristic curve of A(z) = 0.85. The cutoff point with the highest sensitivity and specificity was 20, with a sensitivity and specificity of 0.89 and 0.75, respectively.

The association of peripheral arterial occlusive disease with major coronary events in a mediterranean population with low coronary heart disease incidence.

OBJECTIVES: The association of peripheral arterial occlusive disease (PAD) association with major coronary events (MCE) has been well documented, nevertheless data are lacking for populations with a low incidence of coronary heart disease (CHD). We aimed to assess the association of PAD with MCE in a Mediterranean population. DESIGN: Prospective survey of 699 55-74 year-old men representative of an urban district near Barcelona (Spain). METHODS: Baseline cardiovascular risk factors, CHD and PAD (ankle/brachial index<0.9) were recorded. MCE were evaluated during the 5-year follow-up. RESULTS: At recruitment 94 subjects (13.4%) had PAD. During follow-up (mean 69.3 months), 35 (5%) subjects suffered a MCE, of whom 12 had PAD, 9 previous symptomatic CHD and 1 subject both conditions. Higher CHD related mortality (8.6% vs 1.4%; p<0.001) and lower MCE-free survival (78.67% vs 93.26%; p<0.001) was observed for PAD subjects. On Cox regression analysis PAD (RR=3; p=0.003) and previous symptomatic CHD (RR=4.1; p<0.001) were associated independently with MCE during follow-up. CONCLUSIONS: Even in a population with a low incidence of CHD there is a strong relationship between PAD and future MCE. Screening for PAD may improve the selection of patients targeted for cardiovascular risk prevention.

[Violence and adolescence. A perspective from and Emergency Department]. / Violencia y adolescencia. Perspectiva desde un servicio de urgencias.

INTRODUCTION AND AIM: The acts of violence between adolescents are becoming increasingly more common, generating problems of a diverse nature. The knowledge of the circumstances that surround this violence is important to implement measures to decrease their incidence. The aim of this study was to describe the epidemiology of violent assault in teenagers from the perspective of an Emergency Department. MATERIAL AND METHOD: Retrospective analysis of information recorded on adolescent victims of assault, who attended our Emergency Department over a 1 year period (2006), was performed. RESULTS: Of the 105 patients included, the mean age of the assault victims was 15.9 (SD: 1.4) years. Of those, 73.3 % were male. They were seen at holidays (58.1 %) and predominantly between the hours of 8 pm and 4 am (55.2 %). Forty-nine (46.7 %) of the events were classified as fights, 44 (41.9 %) as assaults, 7 (6.7 %) as physical abuse and 5 (4.8 %) as sexual abuse. Overall, 20 (19 %) patients reported that there was a weapon at the scene: in 13.3 % a blunt object and in 5.7 % a knife/piercing object. Bruises or haematomas were present in 93.3 % of patients; lacerations in 19 % and fractures in 11.4 %. Sixty-two (59 %) patients needed an X-ray, 10 (9.5 %) a urineanalysis and 7 (6.7 %) a blood test. Seven (6.7 %) patients were hospitalised and 6 (5.7 %) were evaluated by Social Work. CONCLUSIONS: The knowledge of the epidemiology of this problem and awareness by the professionals involved in handling this, must promote the coordinated creation of protocols and actions that can decrease its impact among adolescents, and in turn, society.

Review of difficult airway management in thoracic surgery. / Revisión del manejo de la vía aérea díficil en cirugía torácica.

The management of difficult airway (DA) in thoracic surgery is more difficult due to the need for lung separation or isolation and frequent presence of associated upper and lower airway problems. We performed an article review analysing 818 papers published with clinical evidence indexed in Pubmed that allowed us to develop an algorithm. The best airway management in predicted DA is tracheal intubation and independent bronchial blockers guided by fibroscopy maintaining spontaneous ventilation. For unpredicted DA, the use of videolaryngoscopes is recommended initially, and adequate neuromuscular relaxation (rocuronium/sugammadex), among other maneuvers. In both cases, double lumen tubes should be reserved for when lung separation is absolutely indicated. Finally, extubation should be a time of maximum care and be performed according to the safety measures of the Difficult Arway Society.

Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke.

BACKGROUND AND PURPOSE: The pathophysiology of stroke-associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI. METHODS: The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)alpha and IL10 were measured in plasma. RESULTS: 17 (15%) patients developed infection and showed time-dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNFalpha and the TNFalpha/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection. CONCLUSIONS: SAI is associated with stroke severity, excessive IL10-mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood-borne anti-inflammatory response that decreases the antimicrobial drive of the immune system.

The heat shock stress response after brain lesions: induction of 72 kDa heat shock protein (cell types involved, axonal transport, transcriptional regulation) and protein synthesis inhibition.

The cerebral stress response is examined following a variety of pathological conditions such as focal and global ischemia, administration of excitotoxins, and hyperthermia. Expression of 72 kDa heat shock protein (Hsp70) and hsp70 mRNA, the mechanism underlying induction of hsp70 mRNA involving activation of heat shock factor 1, and inhibition of cerebral protein synthesis are different aspects of the stress response considered here. The results are compared with those in the literature on induction, transcriptional regulation, expression, and cellular location of Hsp70, with a view to getting more insight into the function of the stress response in the injured brain. The present results illustrate that Hsp70 can be expressed in cells affected at various degrees following an insult that will either survive or dic as the brain lesion develops, depending on the severity of cell injury. This indicates that, under certain circumstances, synthesized Hsp70 might be necessary but not sufficient to ensure cell survival. Other situations involve uncoupling between synthesis of hsp70 mRNA and protein, probably due to very strict protein synthesis blockade, and often result in cell loss. Cells eventually will die if protein synthesis rates do not go back to normal after a period of protein synthesis inhibition. The stress response is a dynamic event that is switched on in neural cells sensitive to a brain insult. The stress response is, however, tricky, as affected cells seem to need it, have to deal transiently with it, but eventually be able to get rid of it, in order to survive. Putative therapeutic treatments can act either selectively, potentiating the synthesis of Hsp70 protein and recovery of protein synthesis, or preventing the stress response by deadening the insult severity.

Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain.

Transforming growth factor alpha (TGF-alpha) and epidermal growth factor-receptor (EGF-R) immunoreactivity is observed in the majority of neurons, and in maturing astrocytes, in the developing and adult brain of humans and different species of animals. TGF-alpha and EGF-R co-localize in most neurons and maturing astrocytes, suggesting that most TGF-alpha-producing cells are EGF-R-expressing cells. TGF-alpha and EGF-R immunoreactivity decrease in damaged areas following different insults. However, EGF-R appears in reactive glia, mostly reactive astrocytes, within and surrounding the damaged areas. TGF-alpha and EGF-R immunoreactivity is found in neurons of patients affected by Alzheimer's disease and other forms of dementia, and in neurons of patients suffering from epilepsy owing to different causes, thus pointing to the conclusion that TGF-alpha does not play a significant role in these pathologies. However, EGF-R immunoreactivity occurs in reactive astrocytes and microglia in subacute but not chronic lesions in human cases. Since TGF-alpha is a membrane-anchored growth factor, which may be cleaved leading to the formation of soluble forms, and both the membrane-anchored and soluble forms have the capacity to activate the EGF-R, it is feasible that TGF-alpha in the nervous system may act upon EGF-R-containing neurons through different mechanisms. In addition to distant effects resulting from the release of soluble TGF-alpha, local effects may be produced by establishing direct cell-to-cell contacts (juxtacrine stimulation), or in cells expressing both TGF-alpha and EGF-R (autocrine stimulation).

Small cell lung cancer cell line derived from a primary tumor with a characteristic deletion of 3p.

Chemotherapy plus surgery is feasible and potentially effective in selected patients with small cell lung cancer (SCLC) and provides a unique opportunity to study SCLC early in its biological history. The in vitro characteristics of a SCLC cell line derived from a resected lung primary tumor after treatment with 3 courses of chemotherapy is described. The original SCLC cell line UMC-SCLC-1 exhibited features of classic SCLC with typical morphology and growth characteristics, high levels of dopa decarboxylase, bombesin-like peptides, neuron-specific enolase and calcitonin, and the presence of neurosecretory granules and demonstrated the deletion of the short arm of chromosome 3. After multiple passages, UMC-SCLC-1 gradually changed its culture characteristics to a cell line, UMC-SCLC-1A, with morphological features of large cell anaplastic carcinoma, an altered growth pattern, decrease in calcitonin, and increase in radioresistance but retained the other biochemical markers of classic SCLC (bombesin and dopa decarboxylase production). Serial DNA content analyses showed that increased aneuploidy during continuous culture in vitro was associated with the morphological changes. Both UMC-SCLC-1 and UMC-SCLC-1A demonstrated the deletion of chromosome 3p, amplification and abundant expression of N-myc, and increased expression of c-raf. Chemotherapy sensitivities were stable throughout multiple passages and correlated with in vivo response. UMC-SCLC-1A represents a unique SCLC cell line with heterogeneous properties of both classic and morphological variant SCLC cell lines. In addition, the characteristic deletion of 3p, previously described in cultures derived from metastatic lesions and heavily pretreated patients, is seen in a primary lesion early in the natural history of SCLC.

Evolution of regional oxygen saturation in the peri-operative of thoracic surgery and its relationship with central venous saturation. / Evolución de la saturación regional cerebral de oxígeno en el perioperatorio de cirugía torácica y su relación con la saturación venosa central.

OBJECTIVE: To study the relationship between the values of SvcO2 and SrcO2 in lung resection with one lung ventilation (OLV) and changes in these variables and mean arterial pressure (MAP) and arterial oxygen saturation (SpO2) during the perioperative period. MATERIAL AND METHODS: Prospective, observational study of 25 patients in whom pulmonary resection was performed with OLV. The values of MAP, SpO2, SvO2, and SrcO2 were recorded at 6 different times: 1)baseline; 2)double-lung ventilation before the OLV (VBP1); 3)during OLV; 4)after double-lung ventilation (VBP2); 5)30minutes after surgery, and 6)6hours after surgery. RESULTS: The SrcO2 showed a significant increase from baseline to starting ventilation (65.72±9.05% vs 70.44±7.24%; P<.01). There were no significant changes in their values at the different intraoperative times. Post-operatively, as in the case of the SvcO2, a significant decrease (P<.001) of its value compared with the previous value was observed. CONCLUSIONS: SrcO2 showed a significant increase after induction of anaesthesia and initiation of mechanical ventilation compared to baseline, and a significant decrease at the end of surgery after extubation in the immediate postoperative period. Being a tissue monitoring, non-invasive technique and with continuous values it can alert the clinician of changes in the ratio of oxygen consumption (VO2) to oxygen delivery (DO2) at times of greatest risk, such as OLV, extubation, and the early postoperative period.

Bacterial 1,3-1,4-beta-glucanases: structure, function and protein engineering.

1,3-1,4-beta-Glucanases (or lichenases, EC 3.2.1.73) hydrolyse linear beta-glucans containing beta-1,3 and beta-1,4 linkages such as cereal beta-glucans and lichenan, with a strict cleavage specificity for beta-1,4 glycosidic bonds on 3-O-substituted glucosyl residues. The bacterial enzymes are retaining glycosyl hydrolases of family 16 with a jellyroll beta-sandwich fold and a substrate binding cleft composed of six subsites. The present paper reviews the structure-function aspects of the enzymatic action including mechanistic enzymology, protein engineering and X-ray crystallographic studies.

The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial.

BACKGROUND AND PURPOSE: Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. OBJECTIVE AND METHODS: The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. RESULTS: Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). CONCLUSIONS: Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke.

Chlorpropamide-induced pure RBC aplasia.

A 70-year-old man experienced pure RBC aplasia after high-dose chlorpropamide therapy. This is the second reported case of pure RBC aplasia associated with chlorpropamide. Cessation of the drug therapy was followed by rapid and sustained complete return to a normal hemoglobin level. A brief review of pure RBC aplasia is presented.

[The role of complementary examinations and home monitoring in patient at risk from apparent life threatening event, apneas and sudden infant death syndrome]. / Papel de las exploraciones complementarias y de la monitorización domiciliaria en los pacientes de riesgo de episodio aparentemente letal, apneas y síndrome de muerte súbita del lactante.

INTRODUCTION: Home apnea monitors detect abnormalities in cardiac and respiratory frequency, but their use in the diagnosis of respiratory -related sleep disturbances in children has not been demonstrated, as was originally thought. OBJECTIVE: To describe the type of patients being monitored, for how long and their outcome. MATERIAL AND METHODS: A retrospective descriptive study was conducted on patients with controlled home cardiorespiratory monitoring from October 2008 to September 2012 in the Outpatient department of a Maternity tertiary hospital. RESULTS: During the study period 88 patients were included, 58% of them were male, with a median age of 15.5 days, and followed up for a period of 4.7 months. The reason for monitoring was in a 20.5% due to a history of sudden death without finding underlying pathology in 20.5%, 25% due to apnea of prematurity, 20.5% due to apparent life-threatening event, and 14.8% due to choking. Other causes accounted for 19.3% (apnea/hypopnea, desaturation and periodic breathing). Of these last three groups, pathological events were observed in 50% of them: reflux disease (9), apnea of prematurity (2), neurological causes (3), and apnea of unknown cause (10). CONCLUSIONS: Suspected infant apnea is a cause for consultation that creates a great deal of concern to the family and the pediatrician. Home monitoring is useful in detecting changes in cardiac and respiratory frequency, but is necessary to limit its indications and ensure proper monitoring of these patients, avoiding the abuse of other tests or treatments.